73 results on '"Sung Sik Choe"'
Search Results
2. Spatiotemporal contact between peroxisomes and lipid droplets regulates fasting-induced lipolysis via PEX5
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Jinuk Kong, Yul Ji, Yong Geun Jeon, Ji Seul Han, Kyung Hee Han, Jung Hyun Lee, Gung Lee, Hagoon Jang, Sung Sik Choe, Myriam Baes, and Jae Bum Kim
- Subjects
Science - Abstract
Lipid droplets are organelles that regulate lipid metabolism but if organellar contacts play a role during lipolysis is unclear. Here, the authors show that peroxisomes and peroxisomal protein PEX5 play pivotal roles in the spatial and temporal regulation of fasting-induced lipolysis by translocating ATGL onto lipid droplets
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- 2020
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3. Adipocytes Are the Control Tower That Manages Adipose Tissue Immunity by Regulating Lipid Metabolism
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Jeu Park, Jee Hyung Sohn, Sang Mun Han, Yoon Jeong Park, Jin Young Huh, Sung Sik Choe, and Jae Bum Kim
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adipocytes ,lipid metabolite ,invariant natural killer cell ,adipose tissue remodeling ,adipose tissue inflammation ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Accumulating evidence reveals that adipose tissue is an immunologically active organ that exerts multiple impacts on the regulation of systemic energy metabolism. Adipose tissue immunity is modulated by the interactions between adipocytes and various immune cells. Nevertheless, the underlying mechanisms that control inter-cellular interactions between adipocytes and immune cells in adipose tissue have not been thoroughly elucidated. Recently, it has been demonstrated that adipocytes utilize lipid metabolites as a key mediator to initiate and mediate diverse adipose tissue immune responses. Adipocytes present lipid antigens and secrete lipid metabolites to determine adipose immune tones. In addition, the interactions between adipocytes and adipose immune cells are engaged in the control of adipocyte fate and functions upon metabolic stimuli. In this review, we discuss an integrated view of how adipocytes communicate with adipose immune cells using lipid metabolites. Also, we briefly discuss the newly discovered roles of adipose stem cells in the regulation of adipose tissue immunity.
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- 2021
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4. Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation
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Kyung Cheul Shin, Injae Hwang, Sung Sik Choe, Jeu Park, Yul Ji, Jong In Kim, Gha Young Lee, Sung Hee Choi, Jianhong Ching, Jean-Paul Kovalik, and Jae Bum Kim
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Science - Abstract
VLDLR regulates cellular lipoprotein uptake and storage. Here, the authors show that VLDLR, expressed on adipose tissue macrophages, is upregulated in obesity and promotes adipose tissue inflammation by upregulating ceramide production and facilitating M1-like macrophage polarization.
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- 2017
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5. Regulatory Roles of Invariant Natural Killer T Cells in Adipose Tissue Inflammation: Defenders Against Obesity-Induced Metabolic Complications
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Yoon Jeong Park, Jeu Park, Jin Young Huh, Injae Hwang, Sung Sik Choe, and Jae Bum Kim
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adipocytes ,invariant natural killer T cells ,obesity ,inflammation ,CD1d ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Adipose tissue is a metabolic organ that plays a central role in controlling systemic energy homeostasis. Compelling evidence indicates that immune system is closely linked to healthy physiologic functions and pathologic dysfunction of adipose tissue. In obesity, the accumulation of pro-inflammatory responses in adipose tissue subsequently leads to dysfunction of adipose tissue as well as whole body energy homeostasis. Simultaneously, adipose tissue also activates anti-inflammatory responses in an effort to reduce the unfavorable effects of pro-inflammation. Notably, the interplay between adipocytes and resident invariant natural killer T (iNKT) cells is a major component of defensive mechanisms of adipose tissue. iNKT cells are leukocytes that recognize lipids loaded on CD1d as antigens, whereas most other immune cells are activated by peptide antigens. In adipose tissue, adipocytes directly interact with iNKT cells by presenting lipid antigens and stimulate iNKT cell activation to alleviate pro-inflammation. In this review, we provide an overview of the molecular and cellular determinants of obesity-induced adipose tissue inflammation. Specifically, we focus on the roles of iNKT cell-adipocyte interaction in maintaining adipose tissue homeostasis as well as the consequent modulation in systemic energy metabolism. We also briefly discuss future research directions regarding the interplay between adipocytes and adipose iNKT cells in adipose tissue inflammation.
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- 2018
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6. AMPK activation with glabridin ameliorates adiposity and lipid dysregulation in obesity
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Joo-Won Lee, Sung Sik Choe, Hagoon Jang, Jiyeong Kim, Hyun Woo Jeong, Hyunsun Jo, Kyeong-Hoon Jeong, Surendar Tadi, Myoung Gyu Park, Tae Hwan Kwak, Jin Man Kim, Dong-Hoon Hyun, and Jae Bum Kim
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AMP-activated protein kinase ,fatty acid oxidation ,fatty liver ,Biochemistry ,QD415-436 - Abstract
In this study, we demonstrate that activation of AMP-activated protein kinase (AMPK) with glabridin alleviates adiposity and hyperlipidemia in obesity. In several obese rodent models, glabridin decreased body weight and adiposity with a concomitant reduction in fat cell size. Further, glabridin ameliorated fatty liver and plasma levels of triglyceride and cholesterol. In accordance with these findings, glabridin suppressed the expression of lipogenic genes such as sterol regulatory element binding transcription factor (SREBP)-1c, fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase (SCD)-1 in white adipose tissues and liver, whereas it elevated the expression of fatty acid oxidation genes such as carnitine palmitoyl transferase (CPT)1, acyl-CoA oxidase (ACO), and peroxisome proliferator-activated receptor (PPAR)α in muscle. Moreover, glabridin enhanced phosphorylation of AMPK in muscle and liver and promoted fatty acid oxidation by modulating mitochondrial activity. Together, these data suggest that glabridin is a novel AMPK activator that would exert therapeutic effects in obesity-related metabolic disorders.
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- 2012
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7. Depletion of Adipocyte Becn1 Leads to Lipodystrophy and Metabolic Dysregulation
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Sung Sik Choe, Hye Jeong Kim, Tae Wook Nam, Yul Ji, Jae Woo Kim, Chan Bae Park, In Hye Lee, Young Jin, Heeju Na, Jae Bum Kim, Ki Taek Nam, Yong Geun Jeon, Yaechan Song, Han Woong Lee, Je Kyung Seong, Daehee Hwang, Hahn Nahmgoong, and Sung Min Kim
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0301 basic medicine ,Programmed cell death ,Lipodystrophy ,Endocrinology, Diabetes and Metabolism ,Adipose Tissue, White ,Adipose tissue ,030209 endocrinology & metabolism ,White adipose tissue ,Biology ,Pathophysiology ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Metabolic Diseases ,Adipocyte ,Internal Medicine ,medicine ,Adipocytes ,Animals ,Homeostasis ,Inflammation ,Mice, Knockout ,BECN1 ,medicine.disease ,Cell biology ,Fatty Liver ,030104 developmental biology ,chemistry ,Unfolded protein response ,Beclin-1 ,Steatosis ,Insulin Resistance - Abstract
Becn1/Beclin-1 is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although Becn1 has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of Becn1 in white adipose tissue and related metabolic diseases remains elusive. In this study, we show that adipocyte-specific Becn1 knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, and insulin resistance. Ablation of Becn1 in adipocytes stimulates programmed cell death in a cell-autonomous manner, accompanied by elevated endoplasmic reticulum (ER) stress gene expression. Furthermore, we observed that Becn1 depletion sensitized mature adipocytes to ER stress, leading to accelerated cell death. Taken together, these data suggest that adipocyte Becn1 would serve as a crucial player for adipocyte survival and adipose tissue homeostasis.
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- 2020
8. VLDL-VLDLR axis facilitates brown fat thermogenesis through replenishment of lipid fuels and PPARβ/δ activation
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Kyung Cheul Shin, Jin Young Huh, Yul Ji, Ji Seul Han, Sang Mun Han, Jeu Park, Hahn Nahmgoong, Won Taek Lee, Yong Geun Jeon, Bohyeon Kim, Chanyoon Park, Heonjoong Kang, Sung Sik Choe, and Jae Bum Kim
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Mice, Knockout ,Mammals ,Mice ,Adipocytes, Brown ,Adipose Tissue, Brown ,Animals ,Thermogenesis ,Lipoproteins, VLDL ,PPAR-beta ,General Biochemistry, Genetics and Molecular Biology - Abstract
In mammals, brown adipose tissue (BAT) is specialized to conduct non-shivering thermogenesis for survival under cold acclimation. Although emerging evidence suggests that lipid metabolites are essential for heat generation in cold-activated BAT, the underlying mechanisms of lipid uptake in BAT have not been thoroughly understood. Here, we show that very-low-density lipoprotein (VLDL) uptaken by VLDL receptor (VLDLR) plays important roles in thermogenic execution in BAT. Compared with wild-type mice, VLDLR knockout mice exhibit impaired thermogenic features. Mechanistically, VLDLR-mediated VLDL uptake provides energy sources for mitochondrial oxidation via lysosomal processing, subsequently enhancing thermogenic activity in brown adipocytes. Moreover, the VLDL-VLDLR axis potentiates peroxisome proliferator activated receptor (PPAR)β/δ activity with thermogenic gene expression in BAT. Accordingly, VLDL-induced thermogenic capacity is attenuated in brown-adipocyte-specific PPARβ/δ knockout mice. Collectively, these data suggest that the VLDL-VLDLR axis in brown adipocytes is a key factor for thermogenic execution during cold exposure.
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- 2022
9. Adipocyte HIF2α functions as a thermostat via PKA Cα regulation in beige adipocytes
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Ji Seul Han, Yong Geun Jeon, Minsik Oh, Gung Lee, Hahn Nahmgoong, Sang Mun Han, Jeehye Choi, Ye Young Kim, Kyung Cheul Shin, Jiwon Kim, Kyuri Jo, Sung Sik Choe, Eun Jung Park, Sun Kim, and Jae Bum Kim
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Cyclic AMP-Dependent Protein Kinase Catalytic Subunits ,Multidisciplinary ,Adipose Tissue, White ,General Physics and Astronomy ,Thermogenesis ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology ,Cold Temperature ,Mice ,MicroRNAs ,Adipocytes ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Adipocytes, Beige - Abstract
Thermogenic adipocytes generate heat to maintain body temperature against hypothermia in response to cold. Although tight regulation of thermogenesis is required to prevent energy sources depletion, the molecular details that tune thermogenesis are not thoroughly understood. Here, we demonstrate that adipocyte hypoxia-inducible factor α (HIFα) plays a key role in calibrating thermogenic function upon cold and re-warming. In beige adipocytes, HIFα attenuates protein kinase A (PKA) activity, leading to suppression of thermogenic activity. Mechanistically, HIF2α suppresses PKA activity by inducing miR-3085-3p expression to downregulate PKA catalytic subunit α (PKA Cα). Ablation of adipocyte HIF2α stimulates retention of beige adipocytes, accompanied by increased PKA Cα during re-warming after cold stimuli. Moreover, administration of miR-3085-3p promotes beige-to-white transition via downregulation of PKA Cα and mitochondrial abundance in adipocyte HIF2α deficient mice. Collectively, these findings suggest that HIF2α-dependent PKA regulation plays an important role as a thermostat through dynamic remodeling of beige adipocytes.
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- 2021
10. GABA-stimulated adipose-derived stem cells suppress subcutaneous adipose inflammation in obesity
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Assim A. Alfadda, Injae Hwang, Kyuri Jo, Yoon Jeong Park, Jeu Park, Yul Ji, Sujin Suk, Jason K. Kim, Hye Lim Noh, Jae Bum Kim, Sojeong Ka, Sun Kim, Kyung Cheul Shin, Jong In Kim, Yong Geun Jeon, and Sung Sik Choe
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medicine.medical_specialty ,Multidisciplinary ,business.industry ,Glucose uptake ,Monocyte ,Adipose tissue ,Inflammation ,GABAB receptor ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,Insulin resistance ,Internal medicine ,medicine ,medicine.symptom ,Stem cell ,business ,Infiltration (medical) - Abstract
Accumulating evidence suggests that subcutaneous and visceral adipose tissues are differentially associated with metabolic disorders. In obesity, subcutaneous adipose tissue is beneficial for metabolic homeostasis because of repressed inflammation. However, the underlying mechanism remains unclear. Here, we demonstrate that γ-aminobutyric acid (GABA) sensitivity is crucial in determining fat depot-selective adipose tissue macrophage (ATM) infiltration in obesity. In diet-induced obesity, GABA reduced monocyte migration in subcutaneous inguinal adipose tissue (IAT), but not in visceral epididymal adipose tissue (EAT). Pharmacological modulation of the GABA B receptor affected the levels of ATM infiltration and adipose tissue inflammation in IAT, but not in EAT, and GABA administration ameliorated systemic insulin resistance and enhanced insulin-dependent glucose uptake in IAT, accompanied by lower inflammatory responses. Intriguingly, compared with adipose-derived stem cells (ADSCs) from EAT, IAT-ADSCs played key roles in mediating GABA responses that repressed ATM infiltration in high-fat diet-fed mice. These data suggest that selective GABA responses in IAT contribute to fat depot-selective suppression of inflammatory responses and protection from insulin resistance in obesity.
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- 2019
11. Depletion of adipocyte Becn1 leads to lipodystrophy and metabolic dysregulation
- Author
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Han-Woong Lee, Jae Bum Kim, In Hye Lee, Chan Bae Park, Daehee Hwang, Je Kyung Seong, Ki Taek Nam, Jae-woo Kim, Sung Min Kim, Hahn Nahmgoong, Hye Jeong Kim, Tae Wook Nam, Heeju Na, Yong Geun Jeon, Sung Sik Choe, Yaechan Song, Yul Ji, Young Jin, and Ada Admin
- Abstract
Becn1/Beclin-1 is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although Becn1 has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of Becn1 in white adipose tissue and related metabolic diseases remains elusive. Here we show that adipocyte-specific Becn1 knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, insulin resistance. Ablation of Becn1 in adipocytes stimulates programmed cell death in a cell-autonomous manner, accompanied by elevated ER stress gene expression. Furthermore, we observed that Becn1 depletion sensitized mature adipocytes to ER stress, leading to accelerated cell death. Taken together, these data suggest that adipocyte Becn1 would serve as a crucial player for adipocyte survival and adipose tissue homeostasis.
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- 2020
12. Distinct properties of adipose stem cell subpopulations determine fat depot-specific characteristics
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Hahn Nahmgoong, Yong Geun Jeon, Eun Seo Park, Yoon Ha Choi, Sang Mun Han, Jeu Park, Yul Ji, Jee Hyung Sohn, Ji Seul Han, Ye Young Kim, Injae Hwang, Yun Kyung Lee, Jin Young Huh, Sung Sik Choe, Tae Jung Oh, Sung Hee Choi, Jong Kyoung Kim, and Jae Bum Kim
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Mammals ,Adipogenesis ,Adipose Tissue ,Physiology ,Stem Cells ,Genetics ,Adipocytes ,Subcutaneous Fat ,Animals ,Cell Biology ,Biochemistry ,Molecular Biology ,Biotechnology - Abstract
In mammals, white adipose tissues are largely divided into visceral epididymal adipose tissue (EAT) and subcutaneous inguinal adipose tissue (IAT) with distinct metabolic properties. Although emerging evidence suggests that subpopulations of adipose stem cells (ASCs) would be important to explain fat depot differences, ASCs of two fat depots have not been comparatively investigated. Here, we characterized heterogeneous ASCs and examined the effects of intrinsic and tissue micro-environmental factors on distinct ASC features. We demonstrated that ASC subpopulations in EAT and IAT exhibited different molecular features with three adipogenic stages. ASC transplantation experiments revealed that intrinsic ASC features primarily determined their adipogenic potential. Upon obesogenic stimuli, EAT-specific SDC1
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- 2022
13. Spatiotemporal contact between peroxisomes and lipid droplets regulates fasting-induced lipolysis via PEX5
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Yul Ji, Hagoon Jang, Ji Seul Han, Sung Sik Choe, Myriam Baes, Yong Geun Jeon, Jae Bum Kim, Kyung Hee Han, Jung-Hyun Lee, Jinuk Kong, and Gung Lee
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Male ,0301 basic medicine ,Peroxisome-Targeting Signal 1 Receptor ,Lipolysis ,Science ,Kinesins ,Receptors, Cytoplasmic and Nuclear ,General Physics and Astronomy ,Article ,General Biochemistry, Genetics and Molecular Biology ,Energy homeostasis ,Mice ,03 medical and health sciences ,Spatio-Temporal Analysis ,3T3-L1 Cells ,Lipid droplet ,Organelle ,Adipocytes ,Peroxisomes ,Animals ,Super-resolution microscopy ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,lcsh:Science ,Cytoskeleton ,Organelles ,Mice, Knockout ,Multidisciplinary ,030102 biochemistry & molecular biology ,Chemistry ,Lipid metabolism ,Fasting ,Lipid Droplets ,Nutrients ,General Chemistry ,Nutrient signalling ,Peroxisome ,Lipid Metabolism ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Adipose triglyceride lipase ,lcsh:Q ,lipids (amino acids, peptides, and proteins) ,Cues ,Signal transduction ,Signal Transduction - Abstract
Lipid droplets (LDs) are key subcellular organelles for regulating lipid metabolism. Although several subcellular organelles participate in lipid metabolism, it remains elusive whether physical contacts between subcellular organelles and LDs might be involved in lipolysis upon nutritional deprivation. Here, we demonstrate that peroxisomes and peroxisomal protein PEX5 mediate fasting-induced lipolysis by stimulating adipose triglyceride lipase (ATGL) translocation onto LDs. During fasting, physical contacts between peroxisomes and LDs are increased by KIFC3-dependent movement of peroxisomes toward LDs, which facilitates spatial translocations of ATGL onto LDs. In addition, PEX5 could escort ATGL to contact points between peroxisomes and LDs in the presence of fasting cues. Moreover, in adipocyte-specific PEX5-knockout mice, the recruitment of ATGL onto LDs was defective and fasting-induced lipolysis is attenuated. Collectively, these data suggest that physical contacts between peroxisomes and LDs are required for spatiotemporal translocation of ATGL, which is escorted by PEX5 upon fasting, to maintain energy homeostasis., Lipid droplets are organelles that regulate lipid metabolism but if organellar contacts play a role during lipolysis is unclear. Here, the authors show that peroxisomes and peroxisomal protein PEX5 play pivotal roles in the spatial and temporal regulation of fasting-induced lipolysis by translocating ATGL onto lipid droplets
- Published
- 2020
14. Hypoxia-inducible factors: new strategies for treatment of obesity-induced metabolic diseases
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Sung Sik Choe and Jae Bum Kim
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medicine.medical_specialty ,Adipose tissue ,Inflammation ,030204 cardiovascular system & hematology ,Systemic inflammation ,Proinflammatory cytokine ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Metabolic Diseases ,Adipocyte ,Internal medicine ,Drug Discovery ,Medicine ,Humans ,030212 general & internal medicine ,Molecular Targeted Therapy ,Obesity ,Hypoxia ,business.industry ,General Medicine ,Hypoxia (medical) ,Endocrinology ,Hypoxia-inducible factors ,chemistry ,Adipose Tissue ,Hypoxia-Inducible Factor 1 ,medicine.symptom ,business - Abstract
Adipose tissue inflammation has been proposed as a critical link between obesity and metabolic diseases, such as type 2 diabetes and cardiovascular diseases. In obese adipose tissue, macrophages and other immune cells are accumulated, triggering chronic inflammation. Elevated proinflammatory immune cells not only dysregulate adipose tissue function but also subsequently elicit systemic inflammation through the production of inflammatory mediators. Particularly, inflammatory cytokines from adipose tissue have been implicated in the pathogenesis of metabolic disorder, including insulin resistance in peripheral tissues.1 As the correlation between adipose tissue inflammation and metabolic diseases has been well established, the resolution of adipose tissue inflammation using anti-inflammatory agents, including nonsteroidal anti-inflammatory drugs, has gained the attention as one of the therapeutic potentials for prevention and treatment of obesity-induced metabolic diseases.2 In addition, evidence of the relationship between inflammation and hypoxia in obese adipose tissue has highlighted hypoxia-inducible factors (HIFs) as a novel target against adipose tissue inflammation. In obesity, pathological expansion of adipose tissue leads to local hypoxia through several factors, such as adipocyte enlargement, insufficient neovascularisation, decreased blood flow and increased uncoupling respiration.3 Adipose tissue hypoxia could stabilise and activate HIFs that are the key transcription factors to mediate hypoxic responses, such as angiogenesis, vasodilation, erythropoiesis and glycolysis. HIFs are heterodimers composed of oxygen-sensitive α subunit (HIF-α) and constitutively expressed β subunit (HIF-1β). Duplication of ancestral HIF-α coincided with the evolution of vertebrates, and three α subunits …
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- 2020
15. Activation of invariant natural killer T cells stimulates adipose tissue remodeling via adipocyte death and birth in obesity
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Yong Geun Jeon, Jiyoung Oh, Sang Mun Han, Jiyoung Park, Jin Young Huh, Kyung Cheul Shin, Jeu Park, Jong In Kim, Jae Bum Kim, and Sung Sik Choe
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Fas Ligand Protein ,Glucose uptake ,Adipose tissue ,Biology ,Lymphocyte Activation ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Immune system ,Adipocyte ,Genetics ,medicine ,Adipocytes ,Cytotoxic T cell ,Animals ,Obesity ,fas Receptor ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Cell Death ,3T3 Cells ,Hypoxia (medical) ,Cell biology ,Mice, Inbred C57BL ,chemistry ,Adipose Tissue ,Adipogenesis ,030220 oncology & carcinogenesis ,Natural Killer T-Cells ,Adipocyte hypertrophy ,medicine.symptom ,Developmental Biology ,Research Paper - Abstract
In obesity, adipose tissue undergoes dynamic remodeling processes such as adipocyte hypertrophy, hypoxia, immune responses, and adipocyte death. However, whether and how invariant natural killer T (iNKT) cells contribute to adipose tissue remodeling are elusive. In this study, we demonstrate that iNKT cells remove unhealthy adipocytes and stimulate the differentiation of healthy adipocytes. In obese adipose tissue, iNKT cells were abundantly found nearby dead adipocytes. FasL-positive adipose iNKT cells exerted cytotoxic effects to eliminate hypertrophic and pro-inflammatory Fas-positive adipocytes. Furthermore, in vivo adipocyte-lineage tracing mice model showed that activation of iNKT cells by alpha-galactosylceramide promoted adipocyte turnover, eventually leading to potentiation of the insulin-dependent glucose uptake ability in adipose tissue. Collectively, our data propose a novel role of adipose iNKT cells in the regulation of adipocyte turnover in obesity.
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- 2019
16. Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation
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Jean-Paul Kovalik, Sung Sik Choe, Sung Hee Choi, Jae Bum Kim, Kyung Cheul Shin, Yul Ji, Gha Young Lee, Jong In Kim, Jianhong Ching, Injae Hwang, and Jeu Park
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Male ,0301 basic medicine ,medicine.medical_specialty ,Very low-density lipoprotein ,Science ,Blotting, Western ,Macrophage polarization ,General Physics and Astronomy ,Adipose tissue ,030209 endocrinology & metabolism ,Inflammation ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,medicine ,Animals ,Macrophage ,Obesity ,lcsh:Science ,Multidisciplinary ,business.industry ,Macrophages ,Lipid metabolism ,General Chemistry ,Flow Cytometry ,medicine.disease ,Immunohistochemistry ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Adipose Tissue ,Receptors, LDL ,lcsh:Q ,lipids (amino acids, peptides, and proteins) ,Insulin Resistance ,medicine.symptom ,business ,Lipoprotein - Abstract
Obesity is closely associated with increased adipose tissue macrophages (ATMs), which contribute to systemic insulin resistance and altered lipid metabolism by creating a pro-inflammatory environment. Very low-density lipoprotein receptor (VLDLR) is involved in lipoprotein uptake and storage. However, whether lipid uptake via VLDLR in macrophages affects obesity-induced inflammatory responses and insulin resistance is not well understood. Here we show that elevated VLDLR expression in ATMs promotes adipose tissue inflammation and glucose intolerance in obese mice. In macrophages, VLDL treatment upregulates intracellular levels of C16:0 ceramides in a VLDLR-dependent manner, which potentiates pro-inflammatory responses and promotes M1-like macrophage polarization. Adoptive transfer of VLDLR knockout bone marrow to wild-type mice relieves adipose tissue inflammation and improves insulin resistance in diet-induced obese mice. These findings suggest that increased VLDL-VLDLR signaling in ATMs aggravates adipose tissue inflammation and insulin resistance in obesity., VLDLR regulates cellular lipoprotein uptake and storage. Here, the authors show that VLDLR, expressed on adipose tissue macrophages, is upregulated in obesity and promotes adipose tissue inflammation by upregulating ceramide production and facilitating M1-like macrophage polarization.
- Published
- 2017
17. Paradoxical induction of growth arrest and apoptosis by EGF via the up-regulation of PTEN by activating Redox factor-1/Egr-1 in human lung cancer cells
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Sang-wook Lee, Jewon Ryu, Sung Sik Choe, Chang Hoon Ha, Byoung Wook Lee, Eun-Young Park, Seung-Hee Ryu, and Tae Keun Kim
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0301 basic medicine ,medicine.medical_specialty ,Programmed cell death ,Lung Neoplasms ,Cell Survival ,Redox Factor-1(Ref-1) ,Apoptosis ,Epidermal Growth Factor (EGF) ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Epidermal growth factor ,Cell Line, Tumor ,Internal medicine ,DNA-(Apurinic or Apyrimidinic Site) Lyase ,medicine ,Animals ,Humans ,Tensin ,PTEN ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Early Growth Response Protein 1 ,A549 cell ,NADPH oxidase ,Epidermal Growth Factor ,biology ,Cell growth ,PTEN Phosphohydrolase ,NADPH Oxidases ,Purinergic Receptor 2(P2Y) ,Xenograft Model Antitumor Assays ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Endocrinology ,Oncology ,A549 Cells ,030220 oncology & carcinogenesis ,Zinc Finger-containing Transcriptional Regulator 1(EGR1) ,Phosphatase and Tensin Homolog (PTEN) ,Cancer research ,biology.protein ,hormones, hormone substitutes, and hormone antagonists ,Research Paper ,Signal Transduction - Abstract
// Je-won Ryu 1, * , Sung Sik Choe 2, * , Seung-Hee Ryu 1 , Eun-Young Park 1 , Byoung Wook Lee 3 , Tae Keun Kim 4 , Chang Hoon Ha 3 , Sang-wook Lee 1 1 Department of Radiation Oncology, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea 2 Department of Biological Sciences, Institute of Molecular Biology and Genetics, National Creative Research Institutive Center for Adipose Tissue Remodeling, Seoul National University, Seoul, Republic of Korea 3 Asan Institute for Life Science, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Republic of Korea 4 Department of Life Science, College of Natural Science, Hallym University, Kyeongki Province, Republic of Korea * These authors contributed equally to this work Correspondence to: Chang Hoon Ha, email: chhoonha@gmail.com Sang-Wook Lee, email: lsw@amc.seoul.kr Keywords: Epidermal Growth Factor (EGF), Purinergic Receptor 2(P2Y), Redox Factor-1(Ref-1), Zinc Finger-containing Transcriptional Regulator 1(EGR1), Phosphatase and Tensin Homolog (PTEN) Received: September 30, 2016 Accepted: November 24, 2016 Published: December 07, 2016 ABSTRACT Epidermal growth factor (EGF) signaling promotes cell proliferation and survival in several types of cancer. Here, however, we showed that EGF inhibits proliferation and promotes programmed cell death in non-small cell lung cancer (NSCLC) cells. In A549 cells, EGF increased redox factor-1 (Ref-1) expression and the association of Ref-1 with zinc finger-containing transcriptional regulator (EGR1) via activation of p22 phox , RAC1, and an NADPH oxidase subunit. EGF increased p22 phox and RAC1 expression through activation of purinergic receptors (P2Y). Elevated Ref-1/EGR1 levels increased phosphatase and tensin homolog (PTEN) levels, leading to inhibition of the Akt pathway. EGF-induced PTEN upregulation increased apoptosis and autophagy-induced damage in A549 cells, whereas Ref-1 knockdown blocked EGF-induced PTEN upregulation in an NADPH oxidase p22 phox subunit-independent manner. In addition, p22 phox knockdown restored EGF-induced effects, implying that changes in P2Y activity caused by EGF, which activates NADPH oxidase via RAC1, influenced Ref-1-mediated redox regulation. Finally, EGF similarly attenuated cell proliferation and promoted autophagy and apoptosis in vivo in a xenograft model using A549 cells. These findings reveal that EGF-induced redox signaling is linked to Ref-1-induced death in NSCLC cells.
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- 2016
18. RNF20 Functions as a Transcriptional Coactivator for PPARγ by Promoting NCoR1 Degradation in Adipocytes
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Dabin Lee, Lee Jaeho, Yong Geun Jeon, Seul Gi Yoon, Dong Wook Kim, Jeu Park, Sung Sik Choe, Je-Yoel Cho, Kyung Cheul Shin, Je Kyung Seong, Jee Hyung Sohn, Yul Ji, and Jae Bum Kim
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0301 basic medicine ,Endocrinology, Diabetes and Metabolism ,Ubiquitin-Protein Ligases ,Adipose tissue ,Mice, Obese ,030209 endocrinology & metabolism ,Mice, Transgenic ,Diet, High-Fat ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Adipocyte ,Internal Medicine ,Adipocytes ,Animals ,Humans ,Nuclear Receptor Co-Repressor 1 ,Obesity ,Receptor ,Nuclear receptor co-repressor 1 ,Chemistry ,Wild type ,Lipid metabolism ,Cell biology ,Mice, Inbred C57BL ,PPAR gamma ,030104 developmental biology ,HEK293 Cells ,Adipogenesis ,Proteolysis ,Trans-Activators ,Corepressor - Abstract
Adipose tissue is the key organ coordinating whole-body energy homeostasis. Although it has been reported that ring finger protein 20 (RNF20) regulates lipid metabolism in the liver and kidney, the roles of RNF20 in adipose tissue have not been explored. Here, we demonstrate that RNF20 promotes adipogenesis by potentiating the transcriptional activity of peroxisome proliferator–activated receptor-γ (PPARγ). Under normal chow diet feeding, Rnf20 defective (Rnf20+/−) mice exhibited reduced fat mass with smaller adipocytes compared with wild-type littermates. In addition, high-fat diet–fed Rnf20+/− mice alleviated systemic insulin resistance accompanied by a reduced expansion of fat tissue. Quantitative proteomic analyses revealed significantly decreased levels of PPARγ target proteins in adipose tissue of Rnf20+/− mice. Mechanistically, RNF20 promoted proteasomal degradation of nuclear corepressor 1 (NCoR1), which led to stimulation of the transcriptional activity of PPARγ. Collectively, these data suggest that RNF20-NCoR1 is a novel axis in adipocyte biology through fine-tuning the transcriptional activity of PPARγ.
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- 2019
19. During Adipocyte Remodeling, Lipid Droplet Configurations Regulate Insulin Sensitivity through F-Actin and G-Actin Reorganization
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Yong Geun Jeon, Jiwon Kim, Kyuri Jo, Hahn Nahmgoong, Jee Hyung Sohn, Kyung Cheul Shin, Jae Bum Kim, Ji Seul Han, Jeu Park, Sang Mun Han, Yul Ji, Kyung Hee Han, Sung Sik Choe, Jong In Kim, and Sun Kim
- Subjects
Male ,medicine.medical_treatment ,Adipocytes, White ,030209 endocrinology & metabolism ,macromolecular substances ,Filamentous actin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin resistance ,Lipid droplet ,Adipocyte ,medicine ,Adipocytes ,Animals ,Obesity ,Cytoskeleton ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Glucose Transporter Type 4 ,biology ,Insulin ,Cold-Shock Response ,Gene Expression Profiling ,Actin cytoskeleton reorganization ,Cell Biology ,Lipid Droplets ,medicine.disease ,Actins ,Cell biology ,Mice, Inbred C57BL ,Actin Cytoskeleton ,Protein Transport ,Glucose ,chemistry ,Adipose Tissue ,Gene Expression Regulation ,biology.protein ,Insulin Resistance ,GLUT4 ,Research Article - Abstract
Adipocytes have unique morphological traits in insulin sensitivity control. However, how the appearance of adipocytes can determine insulin sensitivity has not been understood. Here, we demonstrate that actin cytoskeleton reorganization upon lipid droplet (LD) configurations in adipocytes plays important roles in insulin-dependent glucose uptake by regulating GLUT4 trafficking. Compared to white adipocytes, brown/beige adipocytes with multilocular LDs exhibited well-developed filamentous actin (F-actin) structure and potentiated GLUT4 translocation to the plasma membrane in the presence of insulin. In contrast, LD enlargement and unilocularization in adipocytes downregulated cortical F-actin formation, eventually leading to decreased F-actin-to-globular actin (G-actin) ratio and suppression of insulin-dependent GLUT4 trafficking. Pharmacological inhibition of actin polymerization accompanied with impaired F/G-actin dynamics reduced glucose uptake in adipose tissue and conferred systemic insulin resistance in mice. Thus, our study reveals that adipocyte remodeling with different LD configurations could be an important factor to determine insulin sensitivity by modulating F/G-actin dynamics.
- Published
- 2019
20. Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity
- Author
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Sung Sik Choe, Jae Bum Kim, Chul-Ho Lee, Yong-Hoon Kim, Goun Choi, Kyung Cheul Shin, Ji-Won Kim, Jewon Ryu, Jung-Ran Noh, Mira Ham, and Kun-Ho Yoon
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Adipose tissue macrophages ,Blotting, Western ,Adipose tissue ,Inflammation ,030204 cardiovascular system & hematology ,Diet, High-Fat ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Downregulation and upregulation ,3T3-L1 Cells ,Internal medicine ,Adipocytes ,Internal Medicine ,medicine ,Animals ,Insulin ,Obesity ,NADPH oxidase ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Macrophages ,nutritional and metabolic diseases ,Fasting ,medicine.disease ,Immunohistochemistry ,Mice, Mutant Strains ,Oxidative Stress ,Glucosephosphate Dehydrogenase Deficiency ,030104 developmental biology ,Endocrinology ,Adipose Tissue ,Culture Media, Conditioned ,Lipogenesis ,biology.protein ,Insulin Resistance ,medicine.symptom ,Reactive Oxygen Species - Abstract
Glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, plays important roles in redox regulation and de novo lipogenesis. It was recently demonstrated that aberrant upregulation of G6PD in obese adipose tissue mediates insulin resistance as a result of imbalanced energy metabolism and oxidative stress. It remains elusive, however, whether inhibition of G6PD in vivo may relieve obesity-induced insulin resistance. In this study we showed that a hematopoietic G6PD defect alleviates insulin resistance in obesity, accompanied by reduced adipose tissue inflammation. Compared with wild-type littermates, G6PD-deficient mutant (G6PDmut) mice were glucose tolerant upon high-fat-diet (HFD) feeding. Intriguingly, the expression of NADPH oxidase genes to produce reactive oxygen species was alleviated, whereas that of antioxidant genes was enhanced in the adipose tissue of HFD-fed G6PDmut mice. In diet-induced obesity (DIO), the adipose tissue of G6PDmut mice decreased the expression of inflammatory cytokines, accompanied by downregulated proinflammatory macrophages. Accordingly, macrophages from G6PDmut mice greatly suppressed lipopolysaccharide-induced proinflammatory signaling cascades, leading to enhanced insulin sensitivity in adipocytes and hepatocytes. Furthermore, adoptive transfer of G6PDmut bone marrow to wild-type mice attenuated adipose tissue inflammation and improved glucose tolerance in DIO. Collectively, these data suggest that inhibition of macrophage G6PD would ameliorate insulin resistance in obesity through suppression of proinflammatory responses.
- Published
- 2016
21. Hypoxia Restrains Lipid Utilization via Protein Kinase A and Adipose Triglyceride Lipase Downregulation through Hypoxia-Inducible Factor
- Author
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Jiwon Kim, Jung Hyun Lee, Yul Ji, Ji Seul Han, Sung Sik Choe, Jae Bum Kim, and Jinuk Kong
- Subjects
Nematoda ,Lipolysis ,Down-Regulation ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Adipocytes ,Animals ,Phosphorylation ,Protein kinase A ,Caenorhabditis elegans ,Hypoxia ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,biology ,Cell Biology ,3T3 Cells ,Lipase ,Hypoxia (medical) ,biology.organism_classification ,Cyclic AMP-Dependent Protein Kinases ,Lipids ,Cell biology ,Hypoxia-inducible factors ,Adipose Tissue ,030220 oncology & carcinogenesis ,Adipose triglyceride lipase ,Hypoxia-Inducible Factor 1 ,medicine.symptom ,Signal transduction ,Carrier Proteins ,Signal Transduction ,Research Article - Abstract
Oxygen is a key molecule for efficient energy production in living organisms. Although aerobic organisms have adaptive processes to survive in low-oxygen environments, it is poorly understood how lipolysis, the first step of energy production from stored lipid metabolites, would be modulated during hypoxia. Here, we demonstrate that fasting-induced lipolysis is downregulated by hypoxia through the hypoxia-inducible factor (HIF) signaling pathway. In Caenorhabditis elegans and mammalian adipocytes, hypoxia suppressed protein kinase A (PKA)-stimulated lipolysis, which is evolutionarily well conserved. During hypoxia, the levels of PKA activity and adipose triglyceride lipase (ATGL) protein were downregulated, resulting in attenuated fasting-induced lipolysis. In worms, HIF stabilization was sufficient to moderate the suppressive effect of hypoxia on lipolysis through ATGL and PKA inhibition. These data suggest that HIF activation under hypoxia plays key roles in the suppression of lipolysis, which might preserve energy resources in both C. elegans and mammalian adipocytes.
- Published
- 2018
22. Roles of Adipose Tissue VLDL-VLDLR Axis in Energy Metabolism
- Author
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Injae Hwang, Sung Sik Choe, Jae Bum Kim, and Kyung Cheul Shin
- Subjects
medicine.medical_specialty ,Very low-density lipoprotein ,business.industry ,Endocrinology, Diabetes and Metabolism ,Adipose tissue macrophages ,Macrophage polarization ,Adipose tissue ,VLDL receptor ,Inflammation ,medicine.disease ,Endocrinology ,Insulin resistance ,Internal medicine ,Internal Medicine ,medicine ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,business ,Lipoprotein - Abstract
Elevated plasma triglyceride-rich lipoprotein, such as very low-density lipoprotein (VLDL), is considered a risk factor for prevalence of obesity, type 2 diabetes mellitus, and atherosclerosis. VLDL receptor (VLDLR), one of the lipoprotein receptor family proteins, is involved in clearance of circulating VLDL. In obese animals, adipose tissue macrophages (ATMs) contain high level of lipid metabolites, which seems to be linked to pro-inflammatory responses. However, it has not been thoroughly understood whether lipid uptake via VLDLR in macrophages is involved in obesity-induced inflammatory responses and insulin resistance. In this study, we demonstrate that elevated VLDLR in ATMs could accelerate adipose tissue inflammation and glucose intolerance in obesity. Expression of VLDLR was increased in ATMs from obese mice. In VLDL-treated macrophages, the level of ceramides was elevated through VLDLR, which potentiates pro-inflammatory responses and augments M1-like macrophage polarization. Moreover, adoptive transfer of VLDLR knockout bone marrow to wild type mice relieved adipose tissue inflammation and improved insulin resistance in diet-induced obesity. Taken together, these findings suggest that increased VLDL-VLDLR axis in ATMs would aggravate adipose tissue inflammation and insulin resistance in obesity. Disclosure J. Kim: None. K. Shin: None. I. Hwang: None. S. Choe: None.
- Published
- 2018
23. The role of glucose-6-phosphate dehydrogenase in adipose tissue inflammation in obesity
- Author
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Yoon Jeong Park, Jee Hyung Sohn, Jae Bum Kim, and Sung Sik Choe
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Histology ,Adipose tissue macrophages ,Adipose tissue ,Inflammation ,Pentose phosphate pathway ,Biology ,Glucosephosphate Dehydrogenase ,Pentose Phosphate Pathway ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,medicine ,Adipocytes ,Glucose-6-phosphate dehydrogenase ,Obesity ,chemistry.chemical_classification ,Reactive oxygen species ,Macrophages ,Cell Biology ,medicine.disease ,Cell biology ,030104 developmental biology ,Endocrinology ,Glucose ,chemistry ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,030220 oncology & carcinogenesis ,Commentary ,Signal transduction ,medicine.symptom ,Insulin Resistance ,Reactive Oxygen Species ,Signal Transduction - Abstract
Obesity is closely associated with metabolic diseases including type 2 diabetes. One hallmark characteristics of obesity is chronic inflammation that is coordinately controlled by complex signaling networks in adipose tissues. Compelling evidence indicates that reactive oxygen species (ROS) and its related signaling pathways play crucial roles in the progression of chronic inflammation in obesity. The pentose phosphate pathway (PPP) is an anabolic pathway that utilizes the glucoses to generate molecular building blocks and reducing equivalents in the form of NADPH. In particular, NADPH acts as one of the key modulators in the control of ROS through providing an electron for both ROS generation and scavenging. Recently, we have reported that glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the PPP, is implicated in adipose tissue inflammation and systemic insulin resistance in obesity. Mechanistically, G6PD potentiates generation of ROS that augments pro-inflammatory responses in adipose tissue macrophages, leading to systemic insulin resistance. Here, we provide an overview of cell type- specific roles of G6PD in the regulation of ROS balance as well as additional details on the significance of G6PD that contributes to pro-oxidant NADPH generation in obesity-related chronic inflammation and insulin resistance.
- Published
- 2017
24. RNF20 Functions as a Transcriptional Coactivator for PPARγ by Promoting NCoR1 Degradation in Adipocytes.
- Author
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Yong Geun Jeon, Jae Ho Lee, Yul Ji, Jee Hyung Sohn, Dabin Lee, Dong Wook Kim, Seul Gi Yoon, Kyung Cheul Shin, Jeu Park, Je Kyung Seong, Je-Yoel Cho, Sung Sik Choe, Jae Bum Kim, Jeon, Yong Geun, Lee, Jae Ho, Ji, Yul, Sohn, Jee Hyung, Lee, Dabin, Kim, Dong Wook, and Yoon, Seul Gi
- Subjects
FAT cells ,ADIPOSE tissues ,TISSUE expansion ,INSULIN resistance ,BIOLOGY ,PROTEIN metabolism ,ANIMAL experimentation ,COMPARATIVE studies ,ANIMAL nutrition ,ENZYMES ,EPITHELIAL cells ,RESEARCH methodology ,MEDICAL cooperation ,METABOLISM ,MICE ,OBESITY ,PROTEINS ,RESEARCH ,EVALUATION research - Abstract
Adipose tissue is the key organ coordinating whole-body energy homeostasis. Although it has been reported that ring finger protein 20 (RNF20) regulates lipid metabolism in the liver and kidney, the roles of RNF20 in adipose tissue have not been explored. Here, we demonstrate that RNF20 promotes adipogenesis by potentiating the transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ). Under normal chow diet feeding, Rnf20 defective (Rnf20+/- ) mice exhibited reduced fat mass with smaller adipocytes compared with wild-type littermates. In addition, high-fat diet-fed Rnf20+/- mice alleviated systemic insulin resistance accompanied by a reduced expansion of fat tissue. Quantitative proteomic analyses revealed significantly decreased levels of PPARγ target proteins in adipose tissue of Rnf20+/- mice. Mechanistically, RNF20 promoted proteasomal degradation of nuclear corepressor 1 (NCoR1), which led to stimulation of the transcriptional activity of PPARγ. Collectively, these data suggest that RNF20-NCoR1 is a novel axis in adipocyte biology through fine-tuning the transcriptional activity of PPARγ. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
25. Adipose tissue remodeling: its role in energy metabolism and metabolic disorders
- Author
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Sung Sik Choe, In Jae Hwang, Jong In Kim, Jin Young Huh, and Jae Bum Kim
- Subjects
0301 basic medicine ,medicine.medical_specialty ,FGF21 ,Endocrinology, Diabetes and Metabolism ,Adipose tissue macrophages ,Adipokine ,Adipose tissue ,White adipose tissue ,Review ,Biology ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,03 medical and health sciences ,chemistry.chemical_compound ,Endocrinology ,Adipocyte ,Internal medicine ,Brown adipose tissue ,Inflammatory Response ,medicine ,Obesity ,lcsh:RC648-665 ,Metabolic disorder ,hypertrophic adipocyte ,Adipose tissue macrophage ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Adipose Tissue ,Adipogenesis ,iNKT cell - Abstract
The adipose tissue is a central metabolic organ in the regulation of whole-body energy homeostasis. The white adipose tissue (WAT) functions as a key energy reservoir for other organs, whereas the brown adipose tissue (BAT) accumulates lipids for cold-induced adaptive thermogenesis. Adipose tissues secret various hormones, cytokines, and metabolites (termed as adipokines) that control systemic energy balance by regulating appetitive signals from the central nerve system as well as metabolic activity in peripheral tissues. In response to changes in the nutritional status, the adipose tissue undergoes dynamic remodeling, including quantitative and qualitative alterations in adipose tissue resident cells. A growing body of evidence indicates that adipose tissue remodeling in obesity is closely associated with adipose tissue function. Changes in the number and size of the adipocytes affect the microenvironment of expanded fat tissues, accompanied by alterations in adipokine secretion, adipocyte death, local hypoxia, and fatty acid fluxes. Concurrently, stromal vascular cells in the adipose tissue, including immune cells, are involved in numerous adaptive processes, such as dead adipocyte clearance, adipogenesis, and angiogenesis, all of which are dysregulated in obese adipose tissue remodeling. Chronic over-nutrition triggers uncontrolled inflammatory responses, leading to systemic low-grade inflammation and metabolic disorders, such as insulin resistance. This review will discuss current mechanistic understandings of adipose tissue remodeling processes in adaptive energy homeostasis and pathological remodeling of adipose tissue in connection with immune response.
- Published
- 2016
26. AMPK activation with glabridin ameliorates adiposity and lipid dysregulation in obesity
- Author
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Tae Hwan Kwak, Hyun-Woo Jeong, Sung Sik Choe, Surendar Tadi, Hagoon Jang, Jiyeong Kim, Hyunsun Jo, Kyeong Hoon Jeong, Dong Hoon Hyun, Jae Bum Kim, Jin-Man Kim, Myoung Gyu Park, and Joo-Won Lee
- Subjects
medicine.medical_specialty ,Peroxisome proliferator-activated receptor ,QD415-436 ,AMP-Activated Protein Kinases ,Biochemistry ,Mice ,chemistry.chemical_compound ,Endocrinology ,Phenols ,AMP-activated protein kinase ,Internal medicine ,medicine ,Animals ,Obesity ,Phosphorylation ,Beta oxidation ,Research Articles ,fatty acid oxidation ,Adiposity ,fatty liver ,chemistry.chemical_classification ,biology ,Chemistry ,Body Weight ,Fatty Acids ,Fatty liver ,AMPK ,Cell Biology ,Lipid Metabolism ,medicine.disease ,Isoflavones ,Mitochondria ,Sterol regulatory element-binding protein ,Mice, Inbred C57BL ,Fatty acid synthase ,biology.protein ,Glabridin - Abstract
In this study, we demonstrate that activation of AMP-activated protein kinase (AMPK) with glabridin alleviates adiposity and hyperlipidemia in obesity. In several obese rodent models, glabridin decreased body weight and adiposity with a concomitant reduction in fat cell size. Further, glabridin ameliorated fatty liver and plasma levels of triglyceride and cholesterol. In accordance with these findings, glabridin suppressed the expression of lipogenic genes such as sterol regulatory element binding transcription factor (SREBP)-1c, fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase (SCD)-1 in white adipose tissues and liver, whereas it elevated the expression of fatty acid oxidation genes such as carnitine palmitoyl transferase (CPT)1, acyl-CoA oxidase (ACO), and peroxisome proliferator-activated receptor (PPAR)α in muscle. Moreover, glabridin enhanced phosphorylation of AMPK in muscle and liver and promoted fatty acid oxidation by modulating mitochondrial activity. Together, these data suggest that glabridin is a novel AMPK activator that would exert therapeutic effects in obesity-related metabolic disorders.
- Published
- 2012
27. Anti-Arthritic and Analgesic Effect of NDI10218, a Standardized Extract of Terminalia chebula, on Arthritis and Pain Model
- Author
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Jae Yeon Jeong, Jong Soon Lim, Tae Gyu Lee, Jong Bae Seo, Do Yang Park, Sung Sik Choe, Jae Young Park, Eun Wook Choi, Sang Ik Lee, Dong Seung Seen, and Eun Mi Jun
- Subjects
Pharmacology ,Traditional medicine ,medicine.drug_class ,business.industry ,T cell ,Arthritis ,Analgesic ,Type II collagen ,Pain ,Articles ,medicine.disease ,Biochemistry ,Anti-inflammatory ,Terminalia chebula ,medicine.anatomical_structure ,Drug Discovery ,medicine ,Splenocyte ,Molecular Medicine ,Lymph ,business - Abstract
The fruit of Terminalia chebula Retzius has been used as a panacea in India and Southeast Asia but its biological activities have not been fully elucidated. Here we report anti-arthritic and analgesic effect of NDI10218, a standardized ethanol extract of Terminalia chebula, on collagen-induced arthritis and acetic acid-induced writhing model, respectively. Arthritis was induced in DBA/1J mice by immunizing bovine type II collagen and mice were treated with NDI10218 daily for 5 weeks after the onset of the disease. NDI10218 reduced the arthritis index and blocked the synovial hyperplasia in a dose-dependent manner. The serum levels of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β were significantly reduced in mice treated with NDI10218. Production of the inflammatory IL-17, but not immunosuppressive IL-10, was also inhibited in splenocytes isolated from NDI10218-treated arthritis mice. Administration of NDI10218 markedly decreased the number of T cell subpopulations in the regional lymph nodes of the arthritis mice. Finally, NDI10218 reduced the number of abdominal contractions in acetic acid-induced writhing model, suggesting an analgesic effect of this extract. Taken together, these results suggest that NDI10218 can be a new therapeutic candidate for the treatment of rheuma-toid arthritis.
- Published
- 2012
28. Foenumoside B from Lysimachia foenum-graecum inhibits adipocyte differentiation and obesity induced by high-fat diet
- Author
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Sang-Wook Park, Hyun-Woo Jeong, Jae-Yeon Jeong, Sung Sik Choe, Eun-Wook Choi, Dong-Seung Seen, Jong Bae Seo, Jae Young Park, and Tae Gyu Lee
- Subjects
Male ,medicine.medical_specialty ,Biophysics ,Gene Expression ,Adipose tissue ,Biology ,Diet, High-Fat ,Biochemistry ,Proinflammatory cytokine ,Mice ,chemistry.chemical_compound ,Insulin resistance ,AMP-Activated Protein Kinase Kinases ,3T3-L1 Cells ,Internal medicine ,Adipocyte ,Adipocytes ,medicine ,Animals ,Obesity ,Protein kinase A ,Molecular Biology ,Primulaceae ,Adipogenesis ,AMPK ,Lipid metabolism ,Cell Biology ,Saponins ,Lipid Metabolism ,medicine.disease ,Enzyme Activation ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Anti-Obesity Agents ,Protein Kinases - Abstract
We have previously reported anti-obesity effects of Lysimachia foenum-graecum in high-fat diet (HFD)-induced obesity model. Here we isolated a triterpene saponin foenumoside B as an active component of L. foenum-graecum. Foenumoside B blocked the differentiation of 3T3-L1 preadipocytes in a dose-dependent manner with an IC50 of 0.2 μg/ml in adipogenesis assay and suppressed the induction of PPARγ, the master regulator of adipogenesis. Foenumoside B induced the activation of AMP-activated protein kinase (AMPK), and modulated the expression of genes involved in lipid metabolism towards lipid breakdown in differentiated adipocytes. In mouse model, oral administration of foenumoside B (10mg/kg/day for 6 weeks) reduced HFD-induced body weight gain significantly without affecting food intake. Treatment of foenumoside B suppressed lipid accumulation in white adipose tissues and the liver, and lowered blood levels of glucose, triglycerides, ALT, and AST in HFD-induced obese mice. Consistent with the in vitro results, foenumoside B activated AMPK signaling, suppressed the expression of lipogenic genes, and enhanced the expression of lipolytic genes in vivo. Foenumoside B also blocked HFD-induced proinflammatory cytokine production in adipose tissue, suggesting its protective role against insulin resistance. Taken together, these findings demonstrate that foenumoside B represents the anti-obesity effects of L. foenum-graecum, and suggest therapeutic potential of foenumoside B in obesity and obesity-related metabolic diseases.
- Published
- 2012
29. A Newly Identified CG301269 Improves Lipid and Glucose Metabolism Without Body Weight Gain Through Activation of Peroxisome Proliferator–Activated Receptor α and γ
- Author
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Ho Seon Park, Hyunjung Shin, Woo-Sik Kim, Gha Young Lee, Joo-Won Lee, Junhee Lee, Han-Jae Lee, Kyong Soo Park, Kyung-Hee Kim, Hyo-Soo Kim, Seonggu Ro, Jae Bum Kim, Hyeon Kyu Lee, Sung Sik Choe, Seung Bum Park, Hyun-Woo Jeong, Heekyoung Chung, Eun Bok Choi, and Dongkyu Shin
- Subjects
medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Peroxisome proliferator-activated receptor ,Myocardial Reperfusion Injury ,Biology ,Carbohydrate metabolism ,Transfection ,Proinflammatory cytokine ,Cell Line ,Mice ,Insulin resistance ,In vivo ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Humans ,Computer Simulation ,PPAR alpha ,Beta oxidation ,Oxazoles ,chemistry.chemical_classification ,Glucose tolerance test ,Analysis of Variance ,medicine.diagnostic_test ,Reverse Transcriptase Polymerase Chain Reaction ,Body Weight ,Lipid metabolism ,Glucose Tolerance Test ,medicine.disease ,Lipid Metabolism ,Rats ,PPAR gamma ,Endocrinology ,Glucose ,chemistry ,Diabetes Mellitus, Type 2 ,Liver ,Carbohydrate Metabolism ,Thiazolidines ,Insulin Resistance ,Obesity Studies - Abstract
OBJECTIVE Peroxisome proliferator–activated receptor (PPAR)-α/γ dual agonists have been developed to alleviate metabolic disorders. However, several PPARα/γ dual agonists are accompanied with unwanted side effects, including body weight gain, edema, and tissue failure. This study investigated the effects of a novel PPARα/γ dual agonist, CG301269, on metabolic disorders both in vitro and in vivo. RESEARCH DESIGN AND METHODS Function of CG301269 as a PPARα/γ dual agonist was assessed in vitro by luciferase reporter assay, mammalian one-hybrid assay, and analyses of PPAR target genes. In vitro profiles on fatty acid oxidation and inflammatory responses were acquired by fatty acid oxidation assay and quantitative (q)RT-PCR of proinflammatory genes. In vivo effect of CG301269 was examined in db/db mice. Total body weight and various tissue weights were measured, and hepatic lipid profiles were analyzed. Systemic glucose and insulin tolerance were measured, and the in vivo effect of CG301269 on metabolic genes and proinflammatory genes was examined by qRT-PCR. RESULTS CG301269 selectively stimulated the transcriptional activities of PPARα and PPARγ. CG301269 enhanced fatty acid oxidation in vitro and ameliorated insulin resistance and hyperlipidemia in vivo. In db/db mice, CG301269 reduced inflammatory responses and fatty liver, without body weight gain. CONCLUSIONS We demonstrate that CG301269 exhibits beneficial effects on glucose and lipid metabolism by simultaneous activation of both PPARα and PPARγ. Our data suggest that CG301269 would be a potential lead compound against obesity and related metabolic disorders.
- Published
- 2011
30. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity
- Author
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Mi Ran Lee, W. S. Kim, Sung Sik Choe, M. Daniel Lane, Hyun-Woo Jeong, Goo Taeg Oh, Yun Sok Lee, Ki Up Lee, Seung Hun Cha, Hye Sun Park, and Jae Bum Kim
- Subjects
Male ,medicine.medical_specialty ,Berberine ,Physiology ,Endocrinology, Diabetes and Metabolism ,Drug Evaluation, Preclinical ,Mice, Transgenic ,Energy homeostasis ,Diabetes Mellitus, Experimental ,Mice ,chemistry.chemical_compound ,AMP-activated protein kinase ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Obesity ,Beta oxidation ,Cells, Cultured ,Dyslipidemias ,Hypolipidemic Agents ,biology ,Cholesterol ,Adenylate Kinase ,Fatty Acids ,Fatty liver ,Skeletal muscle ,AMPK ,Lipid metabolism ,Lipid Metabolism ,medicine.disease ,Enzyme Activation ,Fatty Liver ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,Gene Expression Regulation ,chemistry ,biology.protein ,Receptors, Leptin ,Oxidation-Reduction - Abstract
AMP-activated protein kinase (AMPK) plays an important role in regulating whole body energy homeostasis. Recently, it has been demonstrated that berberine (BBR) exerts antiobesity and antidiabetic effects in obese and diabetic rodent models through the activation of AMPK in peripheral tissues. Here we show that BBR improves lipid dysregulation and fatty liver in obese mice through central and peripheral actions. In obese db/db and ob/ob mice, BBR treatment reduced liver weight, hepatic and plasma triglyceride, and cholesterol contents. In the liver and muscle of db/db mice, BBR promoted AMPK activity and fatty acid oxidation and changed expression of genes involved in lipid metabolism. Additionally, intracerebroventricular administration of BBR decreased the level of malonyl-CoA and stimulated the expression of fatty acid oxidation genes in skeletal muscle. Together, these data suggest that BBR would improve fatty liver in obese subjects, which is probably mediated not only by peripheral AMPK activation but also by neural signaling from the central nervous system.
- Published
- 2009
31. Chronic Activation of Liver X Receptor Induces β-Cell Apoptosis Through Hyperactivation of Lipogenesis
- Author
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Jun-Jae Chung, Inkyu Lee, Kang Ho Kim, Jiyoung Park, Jae Bum Kim, Joo-Won Lee, Kyeong-Min Lee, Keun-Gyu Park, Sung Sik Choe, and A Hyun Choi
- Subjects
medicine.medical_specialty ,Programmed cell death ,Fatty acid metabolism ,Endocrinology, Diabetes and Metabolism ,Pancreatic islets ,Biology ,medicine.disease ,digestive system ,chemistry.chemical_compound ,Endocrinology ,medicine.anatomical_structure ,Lipotoxicity ,chemistry ,Apoptosis ,Internal medicine ,Lipogenesis ,polycyclic compounds ,Internal Medicine ,medicine ,lipids (amino acids, peptides, and proteins) ,Liver X receptor ,Insulinoma - Abstract
Liver X receptor (LXR)α and LXRβ play important roles in fatty acid metabolism and cholesterol homeostasis. Although the functional roles of LXR in the liver, intestine, fat, and macrophages are well established, its role in pancreatic β-cells has not been clearly defined. In this study, we revealed that chronic activation of LXR contributes to lipotoxicity-induced β-cell dysfunction. We observed significantly elevated expression of LXR in the islets of diabetic rodent models, including fa/fa ZDF rats, OLETF rats, and db/db mice. In primary pancreatic islets and INS-1 insulinoma cells, activation of LXR with a synthetic ligand, T0901317, stimulated expression of the lipogenic genes ADD1/SREBP1c, FAS, and ACC and resulted in increased intracellular lipid accumulation. Moreover, chronic LXR activation induced apoptosis in pancreatic islets and INS-1 cells, which was synergistically promoted by high glucose conditions. Taken together, we suggest lipid accumulation caused by chronic activation of LXR in β-cells as a possible cause of β-cell lipotoxicity, a key step in the development of type 2 diabetes.
- Published
- 2007
32. Down-regulation of Histone Deacetylases Stimulates Adipocyte Differentiation
- Author
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Sung Sik Choe, Jun-Jae Chung, Eung Jae Yoo, Jae Bum Kim, and Kang Ho Kim
- Subjects
Down-Regulation ,Histone Deacetylase 1 ,Biochemistry ,Histone Deacetylases ,Histones ,Mice ,chemistry.chemical_compound ,Adipocytes ,Animals ,Enzyme Inhibitors ,Promoter Regions, Genetic ,Molecular Biology ,Histone deacetylase 5 ,Adipogenesis ,HDAC11 ,Histone deacetylase 2 ,HDAC10 ,Cell Differentiation ,Sodium butyrate ,3T3 Cells ,Cell Biology ,Molecular biology ,HDAC4 ,Histone Deacetylase Inhibitors ,PPAR gamma ,chemistry ,Histone deacetylase activity ,Histone deacetylase - Abstract
Specific cell type differentiation is driven by programmed regulation of gene expression, which is the result of coordinated modulation of the transcription machinery and chromatin-remodeling factors. We present evidence here that the down-regulation of histone deacetylases is an important process during adipocyte differentiation. In 3T3-L1 cells, histone hyperacetylation was selectively induced at the promoter regions of adipogenic genes during adipocyte differentiation. Interestingly, this was accompanied by a dramatic decrease in the expression level of several histone deacetylases including HDAC1, -2, and -5 and a reduction in overall histone deacetylase enzyme activity. Inhibition of histone deacetylase activity using sodium butyrate resulted in stimulation of adipogenic gene expression and adipocyte differentiation. Consistently, HDAC1 knock-down promoted adipogenesis whereas HDAC1 overexpression attenuated adipocyte differentiation in 3T3-L1 cells. Together, these results suggest that the regulation of not only adipogenic transcription factors, but also chromatin-modifying enzymes is crucial for the execution of bona fide adipogenesis.
- Published
- 2006
33. During Adipocyte Remodeling, Lipid Droplet Configurations Regulate Insulin Sensitivity through F-Actin and G-Actin Reorganization.
- Author
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Jong In Kim, Jeu Park, Yul Ji, Kyuri Jo, Sang Mun Han, Jee Hyung Sohn, Kyung Cheul Shin, Ji Seul Han, Yong Geun Jeon, Hahn Nahmgoong, Kyung Hee Han, Jiwon Kim, Sun Kim, Sung Sik Choe, and Jae Bum Kim
- Subjects
INSULIN resistance ,F-actin ,ADIPOGENESIS ,LIPIDS ,PERILIPIN ,CYTOSKELETON ,FAT cells ,ADIPOSE tissues - Abstract
Adipocytes have unique morphological traits in insulin sensitivity control. However, how the appearance of adipocytes can determine insulin sensitivity has not been understood. Here, we demonstrate that actin cytoskeleton reorganization upon lipid droplet (LD) configurations in adipocytes plays important roles in insulin-dependent glucose uptake by regulating GLUT4 trafficking. Compared to white adipocytes, brown/beige adipocytes with multilocular LDs exhibited well-developed filamentous actin (F-actin) structure and potentiated GLUT4 translocation to the plasma membrane in the presence of insulin. In contrast, LD enlargement and unilocularization in adipocytes downregulated cortical F-actin formation, eventually leading to decreased F-actin-to-globular actin (G-actin) ratio and suppression of insulin-dependent GLUT4 trafficking. Pharmacological inhibition of actin polymerization accompanied with impaired F/G-actin dynamics reduced glucose uptake in adipose tissue and conferred systemic insulin resistance in mice. Thus, our study reveals that adipocyte remodeling with different LD configurations could be an important factor to determine insulin sensitivity by modulating F/G-actin dynamics. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
34. GABA-stimulated adipose-derived stem cells suppress subcutaneous adipose inflammation in obesity.
- Author
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Injae Hwang, Kyuri Jo, Kyung Cheul Shin, Jong In Kim, Yul Ji, Yoon Jeong Park, Jeu Park, Yong Geun Jeon, Sojeong Ka, Sujin Suk, Hye Lim Noh, Sung Sik Choe, Alfadda, Assim A., Kim, Jason K., Sun Kim, and Jae Bum Kim
- Subjects
STEM cells ,ADIPOSE tissues ,OBESITY ,METABOLIC disorders ,INSULIN resistance ,LIPOXINS - Abstract
Accumulating evidence suggests that subcutaneous and visceral adipose tissues are differentially associated with metabolic disorders. In obesity, subcutaneous adipose tissue is beneficial for metabolic homeostasis because of repressed inflammation. However, the underlying mechanism remains unclear. Here, we demonstrate that γ-aminobutyric acid (GABA) sensitivity is crucial in determining fat depot-selective adipose tissue macrophage (ATM) infiltration in obesity. In diet-induced obesity, GABA reduced monocyte migration in subcutaneous inguinal adipose tissue (IAT), but not in visceral epididymal adipose tissue (EAT). Pharmacological modulation of the GABA
B receptor affected the levels of ATM infiltration and adipose tissue inflammation in IAT, but not in EAT, and GABA administration ameliorated systemic insulin resistance and enhanced insulin-dependent glucose uptake in IAT, accompanied by lower inflammatory responses. Intriguingly, compared with adipose-derived stem cells (ADSCs) from EAT, IAT-ADSCs played key roles in mediating GABA responses that repressed ATM infiltration in high-fat diet-fed mice. These data suggest that selective GABA responses in IAT contribute to fat depot-selective suppression of inflammatory responses and protection from insulin resistance in obesity. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
35. Hypoxia Restrains Lipid Utilization via Protein Kinase A and Adipose Triglyceride Lipase Downregulation through Hypoxia-Inducible Factor.
- Author
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Ji Seul Han, Jung Hyun Lee, Jinuk Kong, Yul Ji, Jiwon Kim, Sung Sik Choe, and Jae Bum Kim
- Subjects
HYPOXEMIA ,PROTEIN kinases ,TRIGLYCERIDES ,DOWNREGULATION ,LIPOLYSIS ,CAENORHABDITIS elegans - Abstract
Oxygen is a key molecule for efficient energy production in living organisms. Although aerobic organisms have adaptive processes to survive in lowoxygen environments, it is poorly understood how lipolysis, the first step of energy production from stored lipid metabolites, would be modulated during hypoxia. Here, we demonstrate that fasting-induced lipolysis is downregulated by hypoxia through the hypoxia-inducible factor (HIF) signaling pathway. In Caenorhabditis elegans and mammalian adipocytes, hypoxia suppressed protein kinase A (PKA)-stimulated lipolysis, which is evolutionarily well conserved. During hypoxia, the levels of PKA activity and adipose triglyceride lipase (ATGL) protein were downregulated, resulting in attenuated fasting-induced lipolysis. In worms, HIF stabilization was sufficient to moderate the suppressive effect of hypoxia on lipolysis through ATGL and PKA inhibition. These data suggest that HIF activation under hypoxia plays key roles in the suppression of lipolysis, which might preserve energy resources in both C. elegans and mammalian adipocytes. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
36. SREBP1c-PAX4 Axis Mediates Pancreatic β-Cell Compensatory Responses Upon Metabolic Stress.
- Author
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Gung Lee, Hagoon Jang, Ye Young Kim, Sung Sik Choe, Jinuk Kong, Injae Hwang, Jeu Park, Seung-Soon Im, Jae Bum Kim, Lee, Gung, Jang, Hagoon, Kim, Ye Young, Choe, Sung Sik, Kong, Jinuk, Hwang, Injae, Park, Jeu, Im, Seung-Soon, and Kim, Jae Bum
- Subjects
STEROL regulatory element-binding proteins ,PANCREATIC beta cells ,GENE expression ,OBESITY ,CELL proliferation ,DIABETES - Abstract
SREBP1c is a key transcription factor for de novo lipogenesis. Although SREBP1c is expressed in pancreatic islets, its physiological roles in pancreatic β-cells are largely unknown. In this study, we demonstrate that SREBP1c regulates β-cell compensation under metabolic stress. SREBP1c expression level was augmented in pancreatic islets from obese and diabetic animals. In pancreatic β-cells, SREBP1c activation promoted the expression of cell cycle genes and stimulated β-cell proliferation through its novel target gene, PAX4 Compared with SREBP1c+/+ mice, SREBP1c-/- mice showed glucose intolerance with low insulin levels. Moreover, β-cells from SREBP1c-/- mice exhibited reduced capacity to proliferate and secrete insulin. Conversely, transplantation of SREBP1c-overexpressing islets restored insulin levels and relieved hyperglycemia in streptozotocin-induced diabetic animals. Collectively, these data suggest that pancreatic SREBP1c is a key player in mediating β-cell compensatory responses in obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
37. Regulatory Role of Glycogen Synthase Kinase 3 for Transcriptional Activity of ADD1/SREBP1c
- Author
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Sung Sik Choe, Eung Jae Yoo, Min Jeong Song, Jae Bum Kim, Kang Ho Kim, and Sang Dai Park
- Subjects
Indoles ,Transcription, Genetic ,macromolecular substances ,In Vitro Techniques ,Biology ,Biochemistry ,Cell Line ,Maleimides ,Glycogen Synthase Kinase 3 ,Mice ,GSK-3 ,3T3-L1 Cells ,Gene expression ,Animals ,Humans ,Insulin ,Phosphorylation ,Glycogen synthase ,Molecular Biology ,GSK3B ,Glycogen Synthase Kinase 3 beta ,Base Sequence ,Lipid metabolism ,DNA ,Cell Biology ,Lipid Metabolism ,Recombinant Proteins ,Rats ,DNA-Binding Proteins ,Fatty acid synthase ,CCAAT-Enhancer-Binding Proteins ,biology.protein ,Signal transduction ,Lithium Chloride ,Sterol Regulatory Element Binding Protein 1 ,Signal Transduction ,Transcription Factors - Abstract
Adipocyte determination- and differentiation-dependent factor 1 (ADD1) plays important roles in lipid metabolism and insulin-dependent gene expression. Because insulin stimulates carbohydrate and lipid synthesis, it would be important to decipher how the transcriptional activity of ADD1/SREBP1c is regulated in the insulin signaling pathway. In this study, we demonstrated that glycogen synthase kinase (GSK)-3 negatively regulates the transcriptional activity of ADD1/SREBP1c. GSK3 inhibitors enhanced a transcriptional activity of ADD1/SREBP1c and expression of ADD1/SREBP1c target genes including fatty acid synthase (FAS), acetyl-CoA carboxylase 1 (ACC1), and steroyl-CoA desaturase 1 (SCD1) in adipocytes and hepatocytes. In contrast, overexpression of GSK3beta down-regulated the transcriptional activity of ADD1/SREBP1c. GSK3 inhibitor-mediated ADD1/SREBP1c target gene activation did not require de novo protein synthesis, implying that GSK3 might affect transcriptional activity of ADD1/SREBP1c at the level of post-translational modification. Additionally, we demonstrated that GSK3 efficiently phosphorylated ADD1/SREBP1c in vitro and in vivo. Therefore, these data suggest that GSK3 inactivation is crucial to confer stimulated transcriptional activity of ADD1/SREBP1c for insulin-dependent gene expression, which would coordinate lipid and glucose metabolism.
- Published
- 2004
38. Roles of G6PD in ROS and inflammatory responses of obese adipose tissue
- Author
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Goun Choi, Sung Sik Choe, Jae Bum Kim, Mira Ham, and Kyung Cheul Shin
- Subjects
medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,General Medicine ,medicine.disease ,Endocrinology ,Diabetes mellitus ,Internal medicine ,Immunology ,Internal Medicine ,medicine ,business - Published
- 2016
39. Macrophage HIF-2α ameliorates adipose tissue inflammation and insulin resistance in obesity
- Author
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Jae Bum Kim, Sung Sik Choe, Yun Kyung Lee, Sojeong Ka, Kyung Cheul Shin, and Jang-Soo Chun
- Subjects
medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Adipose tissue macrophages ,Adipose tissue ,Inflammation ,Biology ,Proinflammatory cytokine ,Nitric oxide ,chemistry.chemical_compound ,Mice ,Insulin resistance ,Internal medicine ,Internal Medicine ,medicine ,Adipocytes ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Obesity ,RNA, Small Interfering ,Gene knockdown ,Macrophages ,medicine.disease ,Arginase ,Endocrinology ,chemistry ,Adipose Tissue ,medicine.symptom ,Insulin Resistance - Abstract
In obesity, adipose tissue macrophages (ATMs) play a key role in mediating proinflammatory responses in the adipose tissue, which are associated with obesity-related metabolic complications. Recently, adipose tissue hypoxia has been implicated in the regulation of ATMs in obesity. However, the role of hypoxia-inducible factor (HIF)-2α, one of the major transcription factors induced by hypoxia, has not been fully elucidated in ATMs. In this study, we demonstrate that elevation of macrophage HIF-2α would attenuate adipose tissue inflammation and improve insulin resistance in obesity. In macrophages, overexpression of HIF-2α decreased nitric oxide production and suppressed expression of proinflammatory cytokines through induction of arginase 1. HIF-2α–overexpressing macrophages alleviated proinflammatory responses and improved insulin resistance in adipocytes. In contrast, knockdown of macrophage HIF-2α augmented palmitate-induced proinflammatory gene expression in adipocytes. Furthermore, compared with wild-type mice, Hif-2α heterozygous-null mice aggravated insulin resistance and adipose tissue inflammation with more M1-like ATMs upon high-fat diet (HFD). Moreover, glucose intolerance in HFD-fed Hif-2α heterozygous-null mice was relieved by macrophage depletion with clodronate treatment, implying that increase of proinflammatory ATMs is responsible for insulin resistance by haplodeficiency of Hif-2α upon HFD. Taken together, these data suggest that macrophage HIF-2α would counteract the proinflammatory responses to relieve obesity-induced insulin resistance in adipose tissue.
- Published
- 2014
40. Ring finger protein20 regulates hepatic lipid metabolism through protein kinase A-dependent sterol regulatory element binding protein1c degradation
- Author
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Jae Bum Kim, Hagoon Jang, Gha Young Lee, Seung Hoi Koo, Lee Jaeho, and Sung Sik Choe
- Subjects
Male ,Ubiquitin-Protein Ligases ,Nutritional Status ,Biology ,Article ,chemistry.chemical_compound ,Steatohepatitis/Metabolic Liver Disease ,Mice ,Chlorocebus aethiops ,Animals ,Humans ,Protein kinase A ,Fatty acid synthesis ,Hepatology ,Fatty acid metabolism ,Catabolism ,Protein Stability ,Lipid Metabolism ,Cyclic AMP-Dependent Protein Kinases ,Mice, Mutant Strains ,Sterol regulatory element-binding protein ,Ubiquitin ligase ,Fatty Liver ,Mice, Inbred C57BL ,Fatty acid synthase ,chemistry ,Biochemistry ,Gene Expression Regulation ,Liver ,Lipogenesis ,COS Cells ,biology.protein ,Sterol Regulatory Element Binding Protein 1 ,HeLa Cells - Abstract
Sterol regulatory element binding proteins (SREBPs) play key roles in lipid homeostasis from yeast to humans.1,2 In mammals, three different SREBP isoforms, including SREBP1a, SREBP1c (also known as ADD1), and SREBP2, are encoded by two genes: SREBF1 and SREBF2. SREBP1 regulates fatty acid metabolism, whereas SREBP2 controls cholesterol metabolism.3 When the cellular sterol level is low, SREBP cleavage-activating protein (SCAP) escorts the SREBP precursors from the endoplasmic reticulum (ER) to the Golgi, where SREBPs are cleaved by Site-1 and Site-2 proteases.4 Subsequently, the mature forms of SREBPs are translocated into the nucleus and stimulate the expression of target genes.5,6 SREBP1a and SREBP1c are generated through transcription from alternative promoters and splicing from a single SREBF1 gene. In metabolic tissues such as adipose tissue and liver, SREBP1c is the predominant isoform of SREBP1.1,7 SREBP1c governs de novo lipogenesis by stimulating its target genes, including fatty acid synthase (FASN), acetyl-CoA carboxylase1 (ACC1), steroyl-CoA desaturase1 (SCD1), and long-chain fatty acid elongase (ELOVL6).8–10 Furthermore, SREBP1c is sensitively regulated by nutritional and hormonal changes to achieve energy balance. For example, SREBP1c is suppressed by fasting, whereas SREBP1c is activated by feeding in adipose tissue and liver.11,12 In parallel, the expression of most lipogenic genes, including FASN, ACC1, and SCD1, is also modulated in a fashion analogous to that of nutritionally regulated SREBP1c.12–14 Accordingly, it has been reported that various hormones, such as insulin, glucagon, and adrenaline, participate in the regulation of SREBP1c and its target lipogenic genes.15,16 Insulin, a key postprandial hormone, stimulates the expression and activity of SREBP1c to accommodate anabolic processes, such as fatty acid synthesis, upon feeding.12,17 In contrast, glucagon, a key catabolic hormone, suppresses the activity of SREBP1c in fasting states, leading to a decrease in lipogenesis.18 In the nucleus, mature SREBPs are very unstable and are rapidly degraded by the proteasome.19,20 Previous reports have shown that SREBP1 is phosphorylated by glycogen synthase kinase-3 beta (GSK-3β), which leads to F-box and WD repeat domain-containing7 (FBXW7)-dependent ubiquitination of SREBP1.21,22 However, a recent in vivo study revealed that inhibition of FBXW7 does not alter the expression of SREBP1c or lipogenic genes in the liver.23 Although SREBP1c-mediated lipogenic program in liver is rapidly repressed by nutritional deprivations, the factors that are involved in the suppression of SREBP1c activity during fasting have not been thoroughly characterized. The finding that ring finger protein20 (RNF20) ubiquitin ligase was identified as one of the novel SREBP1c-interating proteins led us to test whether fasting signaling would promote SREBP1c degradation in an RNF20-dependent manner. In this study, we demonstrate that RNF20 promotes polyubiquitination and degradation of SREBP1c. Overexpression of RNF20 represses SREBP1c activity, leading to a decrease in the expression of lipogenic genes. In obese db/db mice, RNF20 overexpression alleviates hepatic steatosis by reducing the lipogenic program by way of SREBP1c down-regulation. Furthermore, activated PKA, a major signaling cascade that mediates the fasting state, induces degradation of SREBP1c by increasing RNF20 expression. Taken together, these data suggest that RNF20 plays a critical role in the regulation of hepatic lipid metabolism by modulating the protein stability and transcriptional activity of SREBP1c during hormonal changes.
- Published
- 2013
41. Endoplasmic reticulum stress induces hepatic steatosis via increased expression of the hepatic very low-density lipoprotein receptor
- Author
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Sung Sik Choe, Jae Ho Lee, Hyunsun Jo, Kyung Cheul Shin, Jae Bum Kim, Hagoon Jang, Je Kyung Seong, and Sung Hoon Back
- Subjects
medicine.medical_specialty ,Apolipoprotein B ,Lipoproteins ,Very Low-Density Lipoprotein Receptor ,Adipose tissue ,Mice ,Apolipoproteins E ,Internal medicine ,medicine ,Animals ,Triglycerides ,Mice, Knockout ,Hepatology ,biology ,Chemistry ,Endoplasmic reticulum ,medicine.disease ,Endoplasmic Reticulum Stress ,Activating Transcription Factor 4 ,Up-Regulation ,Fatty Liver ,Disease Models, Animal ,Endocrinology ,Liver ,Receptors, LDL ,biology.protein ,Unfolded protein response ,Steatosis ,Signal transduction ,Lipoprotein - Abstract
Recent evidence suggests that obese animals exhibit increased endoplasmic reticulum (ER) stress in the liver and adipose tissue. Although ER stress is closely associated with lipid homeostasis, it is largely unknown how ER stress contributes to hepatic steatosis. In this study, we demonstrate that the induction of ER stress stimulates hepatic steatosis through increased expression of the hepatic very low-density lipoprotein receptor (VLDLR). Among the unfolded protein response sensors, the protein kinase RNA-like ER kinase–activating transcription factor 4 signaling pathway was required for hepatic VLDLR up-regulation. In primary hepatocytes, ER stress–dependent VLDLR expression induced intracellular triglyceride accumulation in the presence of very low-density lipoprotein. Moreover, ER stress–dependent hepatic steatosis was diminished in the livers of VLDLR-deficient and apolipoprotein E–deficient mice compared with wild-type mice. In addition, the VLDLR-deficient mice exhibited decreased hepatic steatosis upon high-fat diet feeding. Conclusion: These data suggest that ER stress–dependent expression of hepatic VLDLR leads to hepatic steatosis by increasing lipoprotein delivery to the liver, which might be a novel mechanism explaining ER stress–induced hepatic steatosis. (HEPATOLOGY 2013;57:1366–1377)
- Published
- 2012
42. Anti-obesity effects of Lysimachia foenum-graecum characterized by decreased adipogenesis and regulated lipid metabolism
- Author
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Jae Young Park, Sang-Wook Park, Eun Wook Choi, Tae Gyu Lee, Jae Bum Kim, Sung Sik Choe, Hyunjung Shin, Dong Seung Seen, Sun Mi Choi, Jong Bae Seo, Jae Yeon Jeong, and Hyun-Woo Jeong
- Subjects
medicine.medical_specialty ,Adipose Tissue, White ,Clinical Biochemistry ,Peroxisome proliferator-activated receptor ,Adipokine ,Adipose tissue ,Gene Expression ,Biology ,Biochemistry ,Eating ,Mice ,In vivo ,Internal medicine ,3T3-L1 Cells ,medicine ,CCAAT-Enhancer-Binding Protein-alpha ,Animals ,Obesity ,Molecular Biology ,Primulaceae ,chemistry.chemical_classification ,Adipogenesis ,Plants, Medicinal ,Adiponectin ,Plant Extracts ,Lipogenesis ,Body Weight ,Fatty Acids ,Lipid metabolism ,Cell Differentiation ,Lipid Metabolism ,Lipids ,Mice, Inbred C57BL ,PPAR gamma ,Endocrinology ,chemistry ,Adipose Tissue ,Molecular Medicine ,Original Article ,Anti-Obesity Agents - Abstract
Lysimachia foenum-graecum has been used as an oriental medicine with anti-inflammatory effect. The anti-obesity effect of L. foenum-graecum extract (LFE) was first discovered in our screening of natural product extract library against adipogenesis. To characterize its anti-obesity effects and to evaluate its potential as an anti-obesity drug, we performed various obesity-related experiments in vitro and in vivo. In adipogenesis assay, LFE blocked the differentiation of 3T3-L1 preadipocyte in a dose-dependent manner with an IC50 of 2.5 µg/ml. In addition, LFE suppressed the expression of lipogenic genes, while increasing the expression of lipolytic genes in vitro at 10 µg/ml and in vivo at 100 mg/kg/day. The anti-adipogenic and anti-lipogenic effect of LFE seems to be mediated by the inhibition of PPARγ and C/EBPα expression as shown in in vitro and in vivo, and the suppression of PPARγ activity in vitro. Moreover, LFE stimulated fatty acid oxidation in an AMPK-dependent manner. In high-fat diet (HFD)-induced obese mice (n = 8/group), oral administration of LFE at 30, 100, and 300 mg/kg/day decreased total body weight gain significantly in all doses tested. No difference in food intake was observed between vehicle- and LFE-treated HFD mice. The weight of white adipose tissues including abdominal subcutaneous, epididymal, and perirenal adipose tissue was reduced markedly in LFE-treated HFD mice in a dose-dependent manner. Treatment of LFE also greatly improved serum levels of obesity-related biomarkers such as glucose, triglycerides, and adipocytokines leptin, adiponectin, and resistin. All together, these results showed anti-obesity effects of LFE on adipogenesis and lipid metabolism in vitro and in vivo and raised a possibility of developing LFE as anti-obesity therapeutics.
- Published
- 2011
43. A nonthiazolidinedione peroxisome proliferator-activated receptor α/γ dual agonist CG301360 alleviates insulin resistance and lipid dysregulation in db/db mice
- Author
-
Dongkyu Shin, Sung Hee Choi, Young Sun Chung, Gyu Hwan Yon, Gha Young Lee, Seonggu Ro, Hyun-Woo Jeong, Hye Ryung Kim, Sung Sik Choe, Heekyoung Chung, Hyunjung Shin, Bongjun Cho, Hyun-Kyu Lee, Jun Hee Lee, Joo-Won Lee, Eun Bok Choi, W. S. Kim, Jae Bum Kim, and Seung Bum Park
- Subjects
Agonist ,medicine.medical_specialty ,Transcription, Genetic ,medicine.drug_class ,Peroxisome proliferator-activated receptor ,Mice, Obese ,Carbohydrate metabolism ,Biology ,Mice ,Insulin resistance ,Internal medicine ,medicine ,Adipocytes ,Animals ,PPAR alpha ,PPAR delta ,Receptor ,Beta oxidation ,Oxazoles ,Cells, Cultured ,Pharmacology ,chemistry.chemical_classification ,Macrophages ,Fatty Acids ,Lipid metabolism ,Stereoisomerism ,medicine.disease ,Lipid Metabolism ,Endocrinology ,Glucose ,chemistry ,Gene Expression Regulation ,Matrix Metalloproteinase 9 ,Cyclooxygenase 2 ,Pipecolic Acids ,Molecular Medicine ,Cytokines ,Peroxisome proliferator-activated receptor delta ,Insulin Resistance ,Oxidation-Reduction - Abstract
Activation of peroxisome proliferator-activated receptors (PPARs) have been implicated in the treatment of metabolic disorders with different mechanisms; PPARα agonists promote fatty acid oxidation and reduce hyperlipidemia, whereas PPARγ agonists regulate lipid redistribution from visceral fat to subcutaneous fat and enhance insulin sensitivity. To achieve combined benefits from activated PPARs on lipid metabolism and insulin sensitivity, a number of PPARα/γ dual agonists have been developed. However, several adverse effects such as weight gain and organ failure of PPARα/γ dual agonists have been reported. By use of virtual ligand screening, we identified and characterized a novel PPARα/γ dual agonist, (R)-1-(4-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl)piperidine-2-carboxylic acid (CG301360), exhibiting the improvement in insulin sensitivity and lipid metabolism. CG301360 selectively stimulated transcriptional activities of PPARα and PPARγ and induced expression of their target genes in a PPARα- and PPARγ-dependent manner. In cultured cells, CG301360 enhanced fatty acid oxidation and glucose uptake and it reduced pro-inflammatory gene expression. In db/db mice, CG301360 also restored insulin sensitivity and lipid homeostasis. Collectively, these data suggest that CG301360 would be a novel PPARα/γ agonist, which might be a potential lead compound to develop against insulin resistance and hyperlipidemia.
- Published
- 2010
44. Chronic activation of liver X receptor induces beta-cell apoptosis through hyperactivation of lipogenesis: liver X receptor-mediated lipotoxicity in pancreatic beta-cells
- Author
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Sung Sik, Choe, A Hyun, Choi, Joo-Won, Lee, Kang Ho, Kim, Jun-Jae, Chung, Jiyoung, Park, Kyeong-Min, Lee, Keun-Gyu, Park, In-Kyu, Lee, and Jae Bum, Kim
- Subjects
DNA, Complementary ,Reverse Transcriptase Polymerase Chain Reaction ,Rats, Inbred OLETF ,Receptors, Cytoplasmic and Nuclear ,Apoptosis ,Fatty Acids, Nonesterified ,Orphan Nuclear Receptors ,Lipids ,Rats ,DNA-Binding Proteins ,Cholesterol ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,Insulin-Secreting Cells ,Animals ,Reactive Oxygen Species ,Triglycerides ,Liver X Receptors - Abstract
Liver X receptor (LXR)alpha and LXRbeta play important roles in fatty acid metabolism and cholesterol homeostasis. Although the functional roles of LXR in the liver, intestine, fat, and macrophages are well established, its role in pancreatic beta-cells has not been clearly defined. In this study, we revealed that chronic activation of LXR contributes to lipotoxicity-induced beta-cell dysfunction. We observed significantly elevated expression of LXR in the islets of diabetic rodent models, including fa/fa ZDF rats, OLETF rats, and db/db mice. In primary pancreatic islets and INS-1 insulinoma cells, activation of LXR with a synthetic ligand, T0901317, stimulated expression of the lipogenic genes ADD1/SREBP1c, FAS, and ACC and resulted in increased intracellular lipid accumulation. Moreover, chronic LXR activation induced apoptosis in pancreatic islets and INS-1 cells, which was synergistically promoted by high glucose conditions. Taken together, we suggest lipid accumulation caused by chronic activation of LXR in beta-cells as a possible cause of beta-cell lipotoxicity, a key step in the development of type 2 diabetes.
- Published
- 2007
45. Increase in glucose-6-phosphate dehydrogenase in adipocytes stimulates oxidative stress and inflammatory signals
- Author
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Yoshihiro Ogawa, Myeong Jin Yoon, Takayoshi Suganami, Sung Sik Choe, Jae Bum Kim, Jiyoung Park, A Hyun Choi, and Kang Ho Kim
- Subjects
Lipopolysaccharides ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,Nitric Oxide Synthase Type II ,Inflammation ,Glucosephosphate Dehydrogenase ,medicine.disease_cause ,Proinflammatory cytokine ,chemistry.chemical_compound ,Mice ,Insulin resistance ,Internal medicine ,Adipocyte ,Internal Medicine ,medicine ,Adipocytes ,Animals ,Obesity ,RNA, Messenger ,NADPH oxidase ,biology ,3T3 Cells ,Dehydroepiandrosterone ,medicine.disease ,Oxidative Stress ,Endocrinology ,chemistry ,Adipose Tissue ,Gene Expression Regulation ,Adipogenesis ,biology.protein ,Macrophages, Peritoneal ,medicine.symptom ,Oxidative stress - Abstract
In adipocytes, oxidative stress and chronic inflammation are closely associated with metabolic disorders, including insulin resistance, obesity, cardiovascular disease, and type 2 diabetes. However, the molecular mechanisms underlying these metabolic disorders have not been thoroughly elucidated. In this report, we demonstrate that overexpression of glucose-6-phosphate dehydrogenase (G6PD) in adipocytes stimulates oxidative stress and inflammatory responses, thus affecting the neighboring macrophages. Adipogenic G6PD overexpression promotes the expression of pro-oxidative enzymes, including inducible nitric oxide synthase and NADPH oxidase, and the activation of nuclear factor-κB (NF-κB) signaling, which eventually leads to the dysregulation of adipocytokines and inflammatory signals. Furthermore, secretory factors from G6PD-overexpressing adipocytes stimulate macrophages to express more proinflammatory cytokines and to be recruited to the adipocytes; this would cause chronic inflammatory conditions in the adipose tissue of obesity. These effects of G6PD overexpression in adipocytes were abolished by pretreatment with NF-κB inhibitors or antioxidant drugs. Thus, we propose that a high level of G6PD in adipocytes may mediate the onset of metabolic disorders in obesity by increasing the oxidative stress and inflammatory signals.
- Published
- 2006
46. Overexpression of glucose-6-phosphate dehydrogenase is associated with lipid dysregulation and insulin resistance in obesity
- Author
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Yun Sok Lee, Sung Sik Choe, Ho Kyung Rho, Jae Bum Kim, Jiyoung Park, and Kang Ho Kim
- Subjects
medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Mice, Obese ,Glucosephosphate Dehydrogenase ,Gene Expression Regulation, Enzymologic ,chemistry.chemical_compound ,Mice ,Insulin resistance ,Adipocyte ,Internal medicine ,hemic and lymphatic diseases ,3T3-L1 Cells ,parasitic diseases ,medicine ,Animals ,Homeostasis ,Resistin ,Obesity ,RNA, Small Interfering ,Molecular Biology ,biology ,Adiponectin ,Tumor Necrosis Factor-alpha ,nutritional and metabolic diseases ,Lipid metabolism ,Cell Differentiation ,Cell Biology ,medicine.disease ,Lipid Metabolism ,Mice, Inbred C57BL ,Insulin receptor ,Endocrinology ,chemistry ,Adipose Tissue ,Adipogenesis ,Lipogenesis ,Hormones, Ectopic ,biology.protein ,Mutagenesis, Site-Directed ,Intercellular Signaling Peptides and Proteins ,Insulin Resistance ,Biomarkers ,Signal Transduction - Abstract
Glucose-6-phosphate dehydrogenase (G6PD) produces cellular NADPH, which is required for the biosynthesis of fatty acids and cholesterol. Although G6PD is required for lipogenesis, it is poorly understood whether G6PD in adipocytes is involved in energy homeostasis, such as lipid and glucose metabolism. We report here that G6PD plays a role in adipogenesis and that its increase is tightly associated with the dysregulation of lipid metabolism and insulin resistance in obesity. We observed that the enzymatic activity and expression levels of G6PD were significantly elevated in white adipose tissues of obese models, including db/db, ob/ob, and diet-induced obesity mice. In 3T3-L1 cells, G6PD overexpression stimulated the expression of most adipocyte marker genes and elevated the levels of cellular free fatty acids, triglyceride, and FFA release. Consistently, G6PD knockdown via small interfering RNA attenuated adipocyte differentiation with less lipid droplet accumulation. Surprisingly, the expression of certain adipocytokines such as tumor necrosis factor alpha and resistin was increased, whereas that of adiponectin was decreased in G6PD overexpressed adipocytes. In accordance with these results, overexpression of G6PD impaired insulin signaling and suppressed insulin-dependent glucose uptake in adipocytes. Taken together, these data strongly suggest that aberrant increase of G6PD in obese and/or diabetic subjects would alter lipid metabolism and adipocytokine expression, thereby resulting in failure of lipid homeostasis and insulin resistance in adipocytes.
- Published
- 2005
47. Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity.
- Author
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Mira Ham, Sung Sik Choe, Kyung Cheul Shin, Goun Choi, Ji-Won Kim, Jung-Ran Noh, Yong-Hoon Kim, Je-won Ryu, Kun-Ho Yoon, Chul-Ho Lee, Jae Bum Kim, Ham, Mira, Choe, Sung Sik, Shin, Kyung Cheul, Choi, Goun, Kim, Ji-Won, Noh, Jung-Ran, Kim, Yong-Hoon, Ryu, Je-Won, and Yoon, Kun-Ho
- Subjects
- *
PENTOSE phosphate pathway , *OXIDATION-reduction reaction , *DEHYDROGENASES , *ENERGY metabolism , *OXIDATIVE stress , *REACTIVE oxygen species , *ADIPOSE tissues , *ANIMAL experimentation , *CELLS , *CULTURE media (Biology) , *DIET , *FASTING , *FAT cells , *IMMUNOHISTOCHEMISTRY , *INFLAMMATION , *INSULIN , *INSULIN resistance , *MACROPHAGES , *INBORN errors of metabolism , *MICE , *OBESITY , *POLYMERASE chain reaction , *WESTERN immunoblotting , *REVERSE transcriptase polymerase chain reaction - Abstract
Glucose-6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme of the pentose phosphate pathway, plays important roles in redox regulation and de novo lipogenesis. It was recently demonstrated that aberrant upregulation of G6PD in obese adipose tissue mediates insulin resistance as a result of imbalanced energy metabolism and oxidative stress. It remains elusive, however, whether inhibition of G6PD in vivo may relieve obesity-induced insulin resistance. In this study we showed that a hematopoietic G6PD defect alleviates insulin resistance in obesity, accompanied by reduced adipose tissue inflammation. Compared with wild-type littermates, G6PD-deficient mutant (G6PD(mut)) mice were glucose tolerant upon high-fat-diet (HFD) feeding. Intriguingly, the expression of NADPH oxidase genes to produce reactive oxygen species was alleviated, whereas that of antioxidant genes was enhanced in the adipose tissue of HFD-fed G6PD(mut) mice. In diet-induced obesity (DIO), the adipose tissue of G6PD(mut) mice decreased the expression of inflammatory cytokines, accompanied by downregulated proinflammatory macrophages. Accordingly, macrophages from G6PD(mut) mice greatly suppressed lipopolysaccharide-induced proinflammatory signaling cascades, leading to enhanced insulin sensitivity in adipocytes and hepatocytes. Furthermore, adoptive transfer of G6PD(mut) bone marrow to wild-type mice attenuated adipose tissue inflammation and improved glucose tolerance in DIO. Collectively, these data suggest that inhibition of macrophage G6PD would ameliorate insulin resistance in obesity through suppression of proinflammatory responses. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
48. Lipid-Overloaded Enlarged Adipocytes Provoke Insulin Resistance Independent of Inflammation.
- Author
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Jong In Kim, Jin Young Huh, Jee Hyung Sohn, Sung Sik Choe, Yun Sok Lee, Chun Yan Lim, Ala Jo, Seung Bum Park, Weiping Han, and Jae Bum Kim
- Subjects
INSULIN resistance ,HYPERTROPHY ,ADIPOSE tissues ,SATURATED fatty acids in human nutrition ,TOLL-like receptors ,CELL membranes - Abstract
In obesity, adipocyte hypertrophy and proinflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but proinflammatory responses were observed only in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplets exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high-fat-diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone may be crucial in causing insulin resistance in obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
49. Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity.
- Author
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Sung Sik Choe, Kyung Cheul Shin, Sojeong Ka, Yun Kyung Lee, Jang-Soo Chun, and Jae Bum Kim
- Subjects
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DIABETES , *OBESITY , *ADIPOSE tissues , *MACROPHAGES , *HYPOXIA-inducible factors , *TRANSCRIPTION factors - Abstract
In obesity, adipose tissue macrophages (ATMs) play a key role in mediating proinflammatory responses in the adipose tissue, which are associated with obesity-related metabolic complications. Recently, adipose tissue hypoxia has been implicated in the regulation of ATMs in obesity. However, the role of hypoxia-inducible factor (HIF)-2α, one of the major transcription factors induced by hypoxia, has not been fully elucidated in ATMs. In this study, we demonstrate that elevation of macrophage HIF-2α would attenuate adipose tissue inflammation and improve insulin resistance in obesity. In macrophages, overexpression of HIF-2α decreased nitric oxide production and suppressed expression of proinflammatory cytokines through induction of arginase 1. HIF-2α-overexpressing macrophages alleviated proinflammatory responses and improved insulin resistance in adipocytes. In contrast, knockdown of macrophage HIF-2α augmented palmitate-induced proinflammatory gene expression in adipocytes. Furthermore, compared with wild-type mice, Hif-2α heterozygous-null mice aggravated insulin resistance and adipose tissue inflammation with more M1-like ATMs upon high-fat diet (HFD). Moreover, glucose intolerance in HFD-fed Hif-2α heterozygous-null mice was relieved by macrophage depletion with clodronate treatment, implying that increase of proinflammatory ATMs is responsible for insulin resistance by haplodeficiency of Hif-2α upon HFD. Taken together, these data suggest that macrophage HIF-2α would counteract the proinflammatory responses to relieve obesity-induced insulin resistance in adipose tissue. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
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50. A Newly Identified CG301269 Improves Lipid and Glucose Metabolism Without Body Weight Gain Through Activation of Peroxisome Proliferator-Activated Receptor α and γ.
- Author
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Hyun Woo Jeong, Joo-Won Lee, Woo Sik Kim, Sung Sik Choe, Kyung-Hee Kim, Ho Seon Park, Hyun Jung Shin, Gha Young Lee, Dongkyu Shin, Hanjae Lee, Jun Hee Lee, Eun Bok Choi, Hyeon Kyu Lee, Heekyoung Chung, Seung Bum Park, Kyong Soo Park, Hyo-Soo Kim, Seonggu Ro, and Jae Bum Kim
- Subjects
PEROXISOMES ,CELL receptors ,METABOLIC disorders ,BIOLOGICAL assay ,FATTY acids ,OXIDATION ,GENES ,LABORATORY mice - Abstract
OBJECTIVE--Peroxisome proliferator-activated receptor (PPAR)-α/γ dual agonists have been developed to alleviate metabolic disorders. However, several PPARα/γ dual agonists are accompanied with unwanted side effects, including body weight gain, edema, and tissue failure. This study investigated the effects of a novel PPARα/γ dual agonist, CG301269, on metabolic disorders both in vitro and in vivo. RESEARCH DESIGN AND METHODS--Function of CG301269 as a PPARα/γ dual agonist was assessed in vitro by luciferase reporter assay, mammalian one-hybrid assay, and analyses of PPAR target genes. In vitro profiles on fatty acid oxidation and inflammatory responses were acquired by fatty acid oxidation assay and quantitative (q)RT-PCR of proinflammatory genes. In vivo effect of CG301269 was examined in db/db mice. Total body weight and various tissue weights were measured, and hepatic lipid profiles were analyzed. Systemic glucose and insulin tolerance were measured, and the in vivo effect of CG301269 on metabolic genes and proinflammatory genes was examined by qRT-PCR. RESULTS--CG301269 selectively stimulated the transcriptional activities of PPARa and PPAR7. CG301269 enhanced fatty acid oxidation in vitro and ameliorated insulin resistance and hyper-lipidemia in vivo, hi db/db mice, CG301269 reduced inflammatory responses and fatty liver, without body weight gain. CONCLUSIONS--We demonstrate that CG301269 exhibits beneficial effects on glucose and lipid metabolism by simultaneous activation of both PPARα and PPARγ. Our data suggest that CG301269 would be a potential lead compound against obesity and related metabolic disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
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