41 results on '"Chitoku Toda"'
Search Results
2. Editorial: Crosstalk Between the Metabolic and Cardiovascular Systems in the Brain
- Author
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Jin Kwon Jeong, Hai-Bin Ruan, and Chitoku Toda
- Subjects
metabolic syndrome ,(pro)renin receptor ,vascular endothelial growth factor ,cardiometabolism ,CNS ,Physiology ,QP1-981 - Published
- 2022
- Full Text
- View/download PDF
3. Refeeding activates neurons in the dorsomedial hypothalamus to inhibit food intake and promote positive valence
- Author
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Daigo Imoto, Izumi Yamamoto, Hirokazu Matsunaga, Toya Yonekura, Ming-Liang Lee, Kan X. Kato, Takeshi Yamasaki, Shucheng Xu, Taiga Ishimoto, Satoshi Yamagata, Ken-ichi Otsuguro, Motohiro Horiuchi, Norifumi Iijima, Kazuhiro Kimura, and Chitoku Toda
- Subjects
Refeeding ,Hypothalamus ,Satiety ,Opioid ,Positive valence ,Internal medicine ,RC31-1245 - Abstract
Objective: The regulation of food intake is a major research area in the study of obesity, which plays a key role in the development of metabolic syndrome. Gene targeting studies have clarified the roles of hypothalamic neurons in feeding behavior, but the deletion of a gene has a long-term effect on neurophysiology. Our understanding of short-term changes such as appetite under physiological conditions is therefore still limited. Methods: Targeted recombination in active populations (TRAP) is a newly developed method for labeling active neurons by using tamoxifen-inducible Cre recombination controlled by the promoter of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), a member of immediate early genes. Transgenic mice for TRAP were fasted overnight, re-fed with normal diet, and injected with 4-hydroxytamoxifen 1 h after the refeeding to label the active neurons. The role of labeled neurons was examined by expressing excitatory or inhibitory designer receptors exclusively activated by designer drugs (DREADDs). The labeled neurons were extracted and RNA sequencing was performed to identify genes that are specifically expressed in these neurons. Results: Fasting-refeeding activated and labeled neurons in the compact part of the dorsomedial hypothalamus (DMH) that project to the paraventricular hypothalamic nucleus. Chemogenetic activation of the labeled DMH neurons decreased food intake and developed place preference, an indicator of positive valence. Chemogenetic activation or inhibition of these neurons had no influence on the whole-body glucose metabolism. The labeled DMH neurons expressed prodynorphin (pdyn), gastrin-releasing peptide (GRP), cholecystokinin (CCK), and thyrotropin-releasing hormone receptor (Trhr) genes. Conclusions: We identified a novel cell type of DMH neurons that can inhibit food intake and promote feeding-induced positive valence. Our study provides insight into the role of DMH and its molecular mechanism in the regulation of appetite and emotion.
- Published
- 2021
- Full Text
- View/download PDF
4. Activation of AMPK-Regulated CRH Neurons in the PVH is Sufficient and Necessary to Induce Dietary Preference for Carbohydrate over Fat
- Author
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Shiki Okamoto, Tatsuya Sato, Michihiro Tateyama, Haruaki Kageyama, Yuko Maejima, Masanori Nakata, Satoshi Hirako, Takashi Matsuo, Sanda Kyaw, Tetsuya Shiuchi, Chitoku Toda, Udval Sedbazar, Kumiko Saito, Nur Farehan Asgar, Boyang Zhang, Shigefumi Yokota, Kenta Kobayashi, Fabienne Foufelle, Pascal Ferré, Masamitsu Nakazato, Hiroaki Masuzaki, Seiji Shioda, Toshihiko Yada, Barbara B. Kahn, and Yasuhiko Minokoshi
- Subjects
food preference ,AMPK ,CRH ,PVH ,CPT1c ,Biology (General) ,QH301-705.5 - Abstract
Food selection is essential for metabolic homeostasis and is influenced by nutritional state, food palatability, and social factors such as stress. However, the mechanism responsible for selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) remains unknown. Here, we show that activation of a subset of corticotropin-releasing hormone (CRH)-positive neurons in the rostral region of the paraventricular hypothalamus (PVH) induces selection of an HCD over an HFD in mice during refeeding after fasting, resulting in a rapid recovery from the change in ketone metabolism. These neurons manifest activation of AMP-activated protein kinase (AMPK) during food deprivation, and this activation is necessary and sufficient for selection of an HCD over an HFD. Furthermore, this effect is mediated by carnitine palmitoyltransferase 1c (CPT1c). Thus, our results identify the specific neurons and intracellular signaling pathway responsible for regulation of the complex behavior of selection between an HCD and an HFD.
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- 2018
- Full Text
- View/download PDF
5. Macrophage ubiquitin-specific protease 2 modifies insulin sensitivity in obese mice
- Author
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Natsuko Saito, Shunsuke Kimura, Tomomi Miyamoto, Sanae Fukushima, Misato Amagasa, Yoshinori Shimamoto, Chieko Nishioka, Shiki Okamoto, Chitoku Toda, Kohei Washio, Atsushi Asano, Ichiro Miyoshi, Eiki Takahashi, and Hiroshi Kitamura
- Subjects
Diabetes ,Obesity ,Macrophage ,Insulin ,USP ,Biology (General) ,QH301-705.5 ,Biochemistry ,QD415-436 - Abstract
We previously reported that ubiquitin-specific protease (USP) 2 in macrophages down-regulates genes associated with metabolic diseases, suggesting a putative anti-diabetic role for USP2 in macrophages. In this study, we evaluate this role at both cellular and individual levels. Isolated macrophages forcibly expressing Usp2a, a longer splicing variant of USP2, failed to modulate the insulin sensitivity of 3T3-L1 adipocytes. Similarly, macrophage-selective overexpression of Usp2a in mice (Usp2a transgenic mice) had a negligible effect on insulin sensitivity relative to wild type littermates following a three-month high-fat diet. However, Usp2a transgenic mice exhibited fewer M1 macrophages in their mesenteric adipose tissue. Following a six-month high-fat diet, Usp2a transgenic mice exhibited a retarded progression of insulin resistance in their skeletal muscle and liver, and an improvement in insulin sensitivity at an individual level. Although conditioned media from Usp2a-overexpressing macrophages did not directly affect the insulin sensitivity of C2C12 myotubes compared to media from control macrophages, they did increase the insulin sensitivity of C2C12 cells after subsequent conditioning with 3T3-L1 cells. These results indicate that macrophage USP2A hampers obesity-elicited insulin resistance via an adipocyte-dependent mechanism.
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- 2017
- Full Text
- View/download PDF
6. Regulatory role of leptin in glucose and lipid metabolism in skeletal muscle
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Yasuhiko Minokoshi, Chitoku Toda, and Shiki Okamoto
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AMP-activated protein kinase ,hypothalamus ,leptin ,skeletal muscle ,sympathetic nervous system ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Leptin is a hormone secreted by adipocytes that plays a pivotal role in regulation of food intake, energy expenditure, and neuroendocrine function. Several lines of evidences indicate that independent of the anorexic effect, leptin regulates glucose and lipid metabolism in peripheral tissues in rodents and humans. It has been shown that leptin improves the diabetes phenotype in lipodystrophic patients and rodents. Moreover, leptin suppresses the development of severe, progressive impairment of glucose metabolism in insulin-deficient diabetes in rodents. We found that leptin increases glucose uptake and fatty acid oxidation in skeletal muscle in rats and mice in vivo. Leptin increases glucose uptake in skeletal muscle via the hypothalamic-sympathetic nervous system axis and β-adrenergic mechanism, while leptin stimulates fatty acid oxidation in muscle via AMP-activated protein kinase (AMPK). Leptin-induced fatty acid oxidation results in the decrease of lipid accumulation in muscle, which can lead to functional impairments called as "lipotoxicity." Activation of AMPK occurs by direct action of leptin on muscle and through the medial hypothalamus-sympathetic nervous system and α-adrenergic mechanism. Thus, leptin plays an important role in the regulation of glucose and fatty acid metabolism in skeletal muscle.
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- 2012
- Full Text
- View/download PDF
7. Ubiquitin-Specific Protease 2 in the Ventromedial Hypothalamus Modifies Blood Glucose Levels by Controlling Sympathetic Nervous Activation
- Author
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Mayuko Hashimoto, Masaki Fujimoto, Kohtarou Konno, Ming-Liang Lee, Yui Yamada, Koya Yamashita, Chitoku Toda, Michio Tomura, Masahiko Watanabe, Osamu Inanami, and Hiroshi Kitamura
- Subjects
Blood Glucose ,Male ,Sympathetic Nervous System ,General Neuroscience ,AMP-Activated Protein Kinases ,Oxidative Phosphorylation ,Mice ,Neuroblastoma ,Norepinephrine ,Glucose ,Ventromedial Hypothalamic Nucleus ,Animals ,Humans ,Reactive Oxygen Species ,Ubiquitin Thiolesterase ,Research Articles - Abstract
Ubiquitin-specific protease 2 (USP2) participates in glucose metabolism in peripheral tissues such as the liver and skeletal muscles. However, the glucoregulatory role of USP2 in the CNS is not well known. In this study, we focus on USP2 in the ventromedial hypothalamus (VMH), which has dominant control over systemic glucose homeostasis. ISH, using a Usp2-specific probe, showed that Usp2 mRNA is present in VMH neurons, as well as other glucoregulatory nuclei, in the hypothalamus of male mice. Administration of a USP2-selective inhibitor ML364 (20 ng/head), into the VMH elicited a rapid increase in the circulating glucose level in male mice, suggesting USP2 has a suppressive role on glucose mobilization. ML364 treatment also increased serum norepinephrine concentration, whereas it negligibly affected serum levels of insulin and corticosterone. ML364 perturbated mitochondrial oxidative phosphorylation in neural SH-SY5Y cells and subsequently promoted the phosphorylation of AMP-activated protein kinase (AMPK). Consistent with these findings, hypothalamic ML364 treatment stimulated AMPKα phosphorylation in the VMH. Inhibition of hypothalamic AMPK prevented ML364 from increasing serum norepinephrine and blood glucose. Removal of ROS restored the ML364-evoked mitochondrial dysfunction in SH-SY5Y cells and impeded the ML364-induced hypothalamic AMPKα phosphorylation as well as prevented the elevation of serum norepinephrine and blood glucose levels in male mice. These results indicate hypothalamic USP2 attenuates perturbations in blood glucose levels by modifying the ROS–AMPK–sympathetic nerve axis. SIGNIFICANCE STATEMENT Under normal conditions (excluding hyperglycemia or hypoglycemia), blood glucose levels are maintained at a constant level. In this study, we used a mouse model to identify a hypothalamic protease controlling blood glucose levels. Pharmacological inhibition of USP2 in the VMH caused a deviation in blood glucose levels under a nonstressed condition, indicating that USP2 determines the set point of the blood glucose level. Modification of sympathetic nervous activity accounts for the USP2-mediated glucoregulation. Mechanistically, USP2 mitigates the accumulation of ROS in the VMH, resulting in attenuation of the phosphorylation of AMPK. Based on these findings, we uncovered a novel glucoregulatory axis consisting of hypothalamic USP2, ROS, AMPK, and the sympathetic nervous system.
- Published
- 2022
8. Expectation for sweet taste changes peripheral glucose metabolism via basolateral amygdala
- Author
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Izumi Yamamoto, Toya Yonekura, Taiga Ishimoto, Shu-Cheng Xu, Norifumi Iijima, Kazuhiro Kimura, Sabrina Diano, and Chitoku Toda
- Subjects
psychological phenomena and processes - Abstract
Anticipatory physiological responses to food were first reported by Ivan Pavlov a century ago but the associated neural mechanism is still ill-defined. Here, we identified two types of neurons in the basolateral amygdala (BLA), which are activated by sweetener (saccharin) or water after sucrose conditioning, representing expected sweet taste and unmet expectation, respectively. Saccharin-induced met-expectation of sweet taste enhances, while H2O-induced unmet-expectation deteriorates, glucose metabolism in peripheral tissues. Deletion of saccharin-responsive neurons in BLA impaired saccharin-induced increase in insulin sensitivity. Deletion of H2O-responsive neurons in BLA improved glucose intolerance by unmet-expectation. Saccharin- and H2O-responsive neurons had different gene expressions. Our data suggest that the gap between the expected incoming sugar and sweet taste is evaluated by distinct BLA neurons to control peripheral glucose metabolism.One-Sentence SummaryNeurons in the basolateral amygdala control blood glucose levels by comparing anticipated sugar intake and sweet taste
- Published
- 2022
9. Editorial: Crosstalk Between the Metabolic and Cardiovascular Systems in the Brain
- Author
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Jin Kwon Jeong, Hai-Bin Ruan, and Chitoku Toda
- Subjects
vascular endothelial growth factor ,Physiology ,Physiology (medical) ,cardiometabolism ,QP1-981 ,(pro)renin receptor ,CNS ,metabolic syndrome - Published
- 2021
10. Activation of prodynorphin neurons in the dorsomedial hypothalamus inhibits food intake and promotes positive valence
- Author
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Ming-Liang Lee, Motohiro Horiuchi, Norifumi Iijima, Takeshi Yamasaki, Ken-ichi Otsuguro, Kazuhiro Kimura, Hirokazu Matsunaga, Chitoku Toda, Toya Yonekura, Daigo Imoto, Kan X. Kato, and Izumi Yamamoto
- Subjects
Arc (protein) ,nervous system ,Hypothalamus ,medicine ,Gene targeting ,Premovement neuronal activity ,Dynorphin ,Biology ,medicine.disease ,Neuroscience ,Gene ,Obesity ,Cholecystokinin - Abstract
The regulation of food intake is one of the major research areas in the study of metabolic syndromes such as obesity. Gene targeting studies have clarified the roles of hypothalamic neurons in feeding behaviour. However, our understanding of neural function under physiological conditions is still limited. Immediate early genes, such as activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), are useful markers of neuronal activity. Here, we investigated the role of Arc/Arg3.1 gene-expressing neurons in the hypothalamus after refeeding using the targeted recombination in active populations method. We identified refeeding-responsive prodynorphin/cholecystokinin neurons in the dorsomedial hypothalamus that project to the paraventricular hypothalamic nucleus. Chemogenetic activation of these neurons decreased food intake and promoted positive valence. Our findings provide insight into the role of newly identified hedonic neurons in the process of feeding-induced satiety.
- Published
- 2020
11. Prostaglandin in the ventromedial hypothalamus regulates peripheral glucose metabolism
- Author
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Izumi Yamamoto, Ming-Liang Lee, Sabrina Diano, Hirokazu Matsunaga, Chitoku Toda, Yuki Sugiura, Kazuhiro Kimura, Daigo Imoto, Takahiro Hayasaka, Norifumi Iijima, and Makoto Suematsu
- Subjects
medicine.medical_specialty ,biology ,Phospholipid ,Prostaglandin ,Metabolism ,Carbohydrate metabolism ,chemistry.chemical_compound ,Cytosol ,Endocrinology ,Phospholipase A2 ,chemistry ,Hypothalamus ,Internal medicine ,medicine ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Arachidonic acid - Abstract
The hypothalamus plays a central role in monitoring and regulating systemic glucose metabolism. The brain is enriched with phospholipids containing poly-unsaturated fatty acids, which are biologically active in physiological regulation. Here, we show that intraperitoneal glucose injection induced changes in hypothalamic distribution and amount of phospholipids, especially arachidonic-acid-containing phospholipids, that were then metabolized to produce prostaglandins. Knockdown of cytosolic phospholipase A2 (cPLA2), a key enzyme for generating arachidonic acid from phospholipids, in the hypothalamic ventromedial nucleus (VMH), lowered insulin sensitivity in muscles during regular chow diet (RCD) feeding. Conversely, the down-regulation of glucose metabolism by high fat diet (HFD) feeding was improved by knockdown of cPLA2 in the VMH through changing hepatic insulin sensitivity and hypothalamic inflammation. Our data suggest that cPLA2-mediated hypothalamic phospholipid metabolism is critical for controlling systemic glucose metabolism during RCD, while continuous activation of the same pathway to produce prostaglandins during HFD deteriorates glucose metabolism.
- Published
- 2020
12. Refeeding activates neurons in the dorsomedial hypothalamus to inhibit food intake and promote positive valence
- Author
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Kan X. Kato, Daigo Imoto, Kazuhiro Kimura, Chitoku Toda, Takeshi Yamasaki, Taiga Ishimoto, Satoshi Yamagata, Ming-Liang Lee, Norifumi Iijima, Ken-ichi Otsuguro, Motohiro Horiuchi, Hirokazu Matsunaga, Toya Yonekura, Shucheng Xu, and Izumi Yamamoto
- Subjects
Male ,Normal diet ,media_common.quotation_subject ,Hypothalamus ,Dorsomedial Hypothalamic Nucleus ,Mice, Transgenic ,Opioid ,Dynorphin ,Biology ,Eating ,Mice ,Animals ,Protein Precursors ,Receptor ,Internal medicine ,Molecular Biology ,media_common ,Cholecystokinin ,Neurons ,Refeeding ,Arc (protein) ,Appetite ,Enkephalins ,Feeding Behavior ,Cell Biology ,RC31-1245 ,Positive valence ,Satiety ,Cell biology ,Hormone receptor ,Original Article - Abstract
Objective The regulation of food intake is a major research area in the study of obesity, which plays a key role in the development of metabolic syndrome. Gene targeting studies have clarified the roles of hypothalamic neurons in feeding behavior, but the deletion of a gene has a long-term effect on neurophysiology. Our understanding of short-term changes such as appetite under physiological conditions is therefore still limited. Methods Targeted recombination in active populations (TRAP) is a newly developed method for labeling active neurons by using tamoxifen-inducible Cre recombination controlled by the promoter of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1), a member of immediate early genes. Transgenic mice for TRAP were fasted overnight, re-fed with normal diet, and injected with 4-hydroxytamoxifen 1 h after the refeeding to label the active neurons. The role of labeled neurons was examined by expressing excitatory or inhibitory designer receptors exclusively activated by designer drugs (DREADDs). The labeled neurons were extracted and RNA sequencing was performed to identify genes that are specifically expressed in these neurons. Results Fasting-refeeding activated and labeled neurons in the compact part of the dorsomedial hypothalamus (DMH) that project to the paraventricular hypothalamic nucleus. Chemogenetic activation of the labeled DMH neurons decreased food intake and developed place preference, an indicator of positive valence. Chemogenetic activation or inhibition of these neurons had no influence on the whole-body glucose metabolism. The labeled DMH neurons expressed prodynorphin (pdyn), gastrin-releasing peptide (GRP), cholecystokinin (CCK), and thyrotropin-releasing hormone receptor (Trhr) genes. Conclusions We identified a novel cell type of DMH neurons that can inhibit food intake and promote feeding-induced positive valence. Our study provides insight into the role of DMH and its molecular mechanism in the regulation of appetite and emotion., Graphical abstract Image 1, Highlights • Fasting-refeeding activates a subset of neurons in the dorsomedial hypothalamus (DMH). • Chemogenetic inhibition of the DMH neurons increases food intake. • Chemogenetic activation of the DMH neurons inhibits food intake and promotes positive valence. • The DMH neurons express pdyn, GRP, CCK and Trhr genes.
- Published
- 2021
13. Macrophage ubiquitin-specific protease 2 modifies insulin sensitivity in obese mice
- Author
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Tomomi Miyamoto, Eiki Takahashi, Ichiro Miyoshi, Natsuko Saito, Atsushi Asano, Yoshinori Shimamoto, Kohei Washio, Sanae Fukushima, Shunsuke Kimura, Chitoku Toda, Misato Amagasa, Hiroshi Kitamura, Chieko Nishioka, and Shiki Okamoto
- Subjects
0301 basic medicine ,DMEM, Dulbecco's modified Eagle medium ,HFD, high-fat diet ,Macrophage ,medicine.medical_treatment ,GAPDH, glyceraldehyde 3-phosphate dehydrogenase ,PI3K, phosphatidylinositol 3-phosphate kinase ,Biochemistry ,pIRβ, phosphorylated insulin receptor β chain ,USP, ubiquitin-specific protease ,0302 clinical medicine ,Insulin ,lcsh:QD415-436 ,pAkt, phosphorylated Akt ,lcsh:QH301-705.5 ,SOCS, suppressor of cytokine signaling ,Myogenesis ,Diabetes ,ELISA, enzyme-linked immunosorbent assay ,HOMA-IR, homeostatic model assessment as an index of insulin resistance ,NEFA, nonesterified fatty acid ,medicine.anatomical_structure ,IR, insulin receptor ,IRS, insulin receptor substrate ,Research Article ,Genetically modified mouse ,medicine.medical_specialty ,KD, knock down ,Adipose tissue macrophages ,Biophysics ,030209 endocrinology & metabolism ,Biology ,lcsh:Biochemistry ,03 medical and health sciences ,Insulin resistance ,Tg, transgenic ,Internal medicine ,medicine ,Obesity ,KO, knockout ,Protease ,NCD, normal chow diet ,Wild type ,Skeletal muscle ,T2DM, type 2 diabetes mellitus ,medicine.disease ,USP ,IL, interleukin ,030104 developmental biology ,Endocrinology ,lcsh:Biology (General) ,PDK, phosphoinositide-dependent kinase - Abstract
We previously reported that ubiquitin-specific protease (USP) 2 in macrophages down-regulates genes associated with metabolic diseases, suggesting a putative anti-diabetic role for USP2 in macrophages. In this study, we evaluate this role at both cellular and individual levels. Isolated macrophages forcibly expressing Usp2a, a longer splicing variant of USP2, failed to modulate the insulin sensitivity of 3T3-L1 adipocytes. Similarly, macrophage-selective overexpression of Usp2a in mice (Usp2a transgenic mice) had a negligible effect on insulin sensitivity relative to wild type littermates following a three-month high-fat diet. However, Usp2a transgenic mice exhibited fewer M1 macrophages in their mesenteric adipose tissue. Following a six-month high-fat diet, Usp2a transgenic mice exhibited a retarded progression of insulin resistance in their skeletal muscle and liver, and an improvement in insulin sensitivity at an individual level. Although conditioned media from Usp2a-overexpressing macrophages did not directly affect the insulin sensitivity of C2C12 myotubes compared to media from control macrophages, they did increase the insulin sensitivity of C2C12 cells after subsequent conditioning with 3T3-L1 cells. These results indicate that macrophage USP2A hampers obesity-elicited insulin resistance via an adipocyte-dependent mechanism., Highlights • USP2A controls macrophage population in mesenteric adipose tissue during obesity. • Overexpression of USP2A in macrophages retards progression of insulin resistance. • Overexpression of USP2A in macrophages represses high-fat diet-induced obesity. • Macrophage USP2A controls insulin sensitivity of muscle dependent on adipocytes.
- Published
- 2017
14. Prostaglandin in the ventromedial hypothalamus regulates peripheral glucose metabolism
- Author
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Izumi Yamamoto, Taiga Ishimoto, Makoto Suematsu, Ming Liang Lee, Chitoku Toda, Sabrina Diano, Yuki Sugiura, Norifumi Iijima, Daigo Imoto, Takahiro Hayasaka, Kazuhiro Kimura, and Hirokazu Matsunaga
- Subjects
Male ,0301 basic medicine ,Phospholipases A2, Cytosolic ,General Physics and Astronomy ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Phospholipids ,Arachidonic Acid ,Multidisciplinary ,biology ,Chemistry ,Type 2 diabetes ,Hypothalamus ,Gene Knockdown Techniques ,lipids (amino acids, peptides, and proteins) ,Arachidonic acid ,medicine.medical_specialty ,Science ,Phospholipid ,Neurophysiology ,Prostaglandin ,Mice, Transgenic ,Carbohydrate metabolism ,Diet, High-Fat ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Insulin resistance ,Phospholipase A2 ,Internal medicine ,medicine ,Animals ,Group IV Phospholipases A2 ,General Chemistry ,Metabolism ,medicine.disease ,Biosynthetic Pathways ,Mice, Inbred C57BL ,Disease Models, Animal ,Glucose ,030104 developmental biology ,Endocrinology ,Ventromedial Hypothalamic Nucleus ,Hyperglycemia ,Lipidomics ,Prostaglandins ,biology.protein ,Insulin Resistance ,030217 neurology & neurosurgery - Abstract
The hypothalamus plays a central role in monitoring and regulating systemic glucose metabolism. The brain is enriched with phospholipids containing poly-unsaturated fatty acids, which are biologically active in physiological regulation. Here, we show that intraperitoneal glucose injection induces changes in hypothalamic distribution and amounts of phospholipids, especially arachidonic-acid-containing phospholipids, that are then metabolized to produce prostaglandins. Knockdown of cytosolic phospholipase A2 (cPLA2), a key enzyme for generating arachidonic acid from phospholipids, in the hypothalamic ventromedial nucleus (VMH), lowers insulin sensitivity in muscles during regular chow diet (RCD) feeding. Conversely, the down-regulation of glucose metabolism by high fat diet (HFD) feeding is improved by knockdown of cPLA2 in the VMH through changing hepatic insulin sensitivity and hypothalamic inflammation. Our data suggest that cPLA2-mediated hypothalamic phospholipid metabolism is critical for controlling systemic glucose metabolism during RCD, while continuous activation of the same pathway to produce prostaglandins during HFD deteriorates glucose metabolism., The ventromedial hypothalamus regulates systemic glucose metabolism. Here the authors show that cytosolic phospholipase A2 mediated phospholipid metabolism contributes to this regulation in healthy animals but exert deteriorating effects on glucose homeostasis under high-fat-diet feeding.
- Published
- 2021
15. UCP2 Regulates Mitochondrial Fission and Ventromedial Nucleus Control of Glucose Responsiveness
- Author
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Chitoku Toda, Daniela Impellizzeri, Salvatore Cuzzocrea, Jung Dae Kim, Zhong-Wu Liu, Sabrina Diano, Toda, Chitoku, Kim, Jung Dae, Impellizzeri, Daniela, Cuzzocrea, Salvatore, Liu, Zhong-Wu, and Diano, Sabrina
- Subjects
0301 basic medicine ,UNCOUPLING PROTEIN 2, SKELETAL MUSCLE, NERVOUS SYSTEM, NEURONS, LEPTIN, HOMEOSTASIS, METABOLISM, RESPONSES, ENERGY, BRAIN ,Bioinformatics ,Mitochondrial Dynamics ,Ion Channels ,ENERGY ,Mice ,0302 clinical medicine ,Ion Channel ,Homeostasis ,Glucose homeostasis ,Uncoupling Protein 2 ,Gene Knock-In Techniques ,BRAIN ,Cell Nucleu ,Neurons ,Mice, Knockout ,chemistry.chemical_classification ,Cell biology ,medicine.anatomical_structure ,Ventromedial nucleus of the hypothalamus ,Mitochondrial fission ,SKELETAL MUSCLE ,Reactive Oxygen Specie ,Dynamins ,NERVOUS SYSTEM ,METABOLISM ,Carbohydrate metabolism ,Biology ,Gene Knock-In Technique ,General Biochemistry, Genetics and Molecular Biology ,Mitochondrial Proteins ,03 medical and health sciences ,LEPTIN ,Homeostasi ,medicine ,Animals ,Mitochondrial Protein ,Gene ,Cell Nucleus ,Reactive oxygen species ,Biochemistry, Genetics and Molecular Biology (all) ,Biochemistry, Genetics and Molecular Biology(all) ,Animal ,Neuron ,Ventromedial Hypothalamic Nucleu ,Mitochondrial Dynamic ,Mice, Inbred C57BL ,Dynamin ,Glucose ,030104 developmental biology ,nervous system ,chemistry ,Ventromedial Hypothalamic Nucleus ,Reactive Oxygen Species ,Nucleus ,030217 neurology & neurosurgery ,RESPONSES - Abstract
The ventromedial nucleus of the hypothalamus (VMH) plays a critical role in regulating systemic glucose homeostasis. How neurons in this brain area adapt to the changing metabolic environment to regulate circulating glucose levels is ill defined. Here, we show that glucose load results in mitochondrial fission and reduced reactive oxygen species in VMH neurons mediated by dynamin-related peptide 1 (DRP1) under the control of uncoupling protein 2 (UCP2). Probed by genetic manipulations and chemical-genetic control of VMH neuronal circuitry, we unmasked that this mitochondrial adaptation determines the size of the pool of glucose-excited neurons in the VMH and that this process regulates systemic glucose homeostasis. Thus, our data unmasked a critical cellular biological process controlled by mitochondrial dynamics in VMH regulation of systemic glucose homeostasis.
- Published
- 2016
16. Induction of glucose uptake in skeletal muscle by central leptin is mediated by muscle β2-adrenergic receptor but not by AMPK
- Author
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Chitoku Toda, Shiki Okamoto, Tetsuya Shiuchi, Yasuhiko Minokoshi, Osamu Ezaki, K. Saito, Shinji Miura, and Eulalia A. Coutinho
- Subjects
Leptin ,0301 basic medicine ,medicine.medical_specialty ,Glucose uptake ,lcsh:Medicine ,AMP-Activated Protein Kinases ,Carbohydrate metabolism ,Article ,Receptors, G-Protein-Coupled ,Mice ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Muscle, Skeletal ,lcsh:Science ,Protein kinase B ,Multidisciplinary ,biology ,Chemistry ,lcsh:R ,Skeletal muscle ,AMPK ,Insulin receptor ,Glucose ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,biology.protein ,Phosphorylation ,lcsh:Q ,Receptors, Adrenergic, beta-2 - Abstract
Leptin increases glucose uptake and fatty acid oxidation (FAO) in red-type skeletal muscle. However, the mechanism remains unknown. We have investigated the role of β2-adrenergic receptor (AR), the major β-AR isoform in skeletal muscle, and AMPK in leptin-induced muscle glucose uptake of mice. Leptin injection into the ventromedial hypothalamus (VMH) increased 2-deoxy-D-glucose (2DG) uptake in red-type skeletal muscle in wild-type (WT) mice accompanied with increased phosphorylation of the insulin receptor (IR) and Akt as well as of norepinephrine (NE) turnover in the muscle. Leptin-induced 2DG uptake was not observed in β-AR-deficient (β-less) mice despite that AMPK phosphorylation was increased in the muscle. Forced expression of β2-AR in the unilateral hind limb of β-less mice restored leptin-induced glucose uptake and enhancement of insulin signalling in red-type skeletal muscle. Leptin increased 2DG uptake and enhanced insulin signalling in red-type skeletal muscle of mice expressing a dominant negative form of AMPK (DN-AMPK) in skeletal muscle. Thus, leptin increases glucose uptake and enhances insulin signalling in red-type skeletal muscle via activation of sympathetic nerves and β2-AR in muscle and in a manner independent of muscle AMPK.
- Published
- 2017
17. Activation of AMPK-Regulated CRH Neurons in the PVH is Sufficient and Necessary to Induce Dietary Preference for Carbohydrate over Fat
- Author
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Satoshi Hirako, Chitoku Toda, Pascal Ferré, Masanori Nakata, Shiki Okamoto, Yuko Maejima, Michihiro Tateyama, Haruaki Kageyama, Boyang Zhang, Toshihiko Yada, K. Saito, Udval Sedbazar, Tatsuya Sato, Fabienne Foufelle, Masamitsu Nakazato, Tetsuya Shiuchi, Nur Farehan Asgar, Barbara B. Kahn, Sanda Kyaw, Seiji Shioda, Hiroaki Masuzaki, Yasuhiko Minokoshi, Kenta Kobayashi, Takashi Matsuo, and Shigefumi Yokota
- Subjects
AMPK ,0301 basic medicine ,Male ,medicine.medical_specialty ,Corticotropin-Releasing Hormone ,Carbohydrates ,Biology ,AMP-Activated Protein Kinases ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Palatability ,Protein kinase A ,lcsh:QH301-705.5 ,Neurons ,Mechanism (biology) ,digestive, oral, and skin physiology ,Carbohydrate ,Diet ,030104 developmental biology ,Endocrinology ,nervous system ,CPT1c ,lcsh:Biology (General) ,CRH ,Hypothalamus ,Ketone bodies ,food preference ,PVH ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Hormone - Abstract
Summary Food selection is essential for metabolic homeostasis and is influenced by nutritional state, food palatability, and social factors such as stress. However, the mechanism responsible for selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) remains unknown. Here, we show that activation of a subset of corticotropin-releasing hormone (CRH)-positive neurons in the rostral region of the paraventricular hypothalamus (PVH) induces selection of an HCD over an HFD in mice during refeeding after fasting, resulting in a rapid recovery from the change in ketone metabolism. These neurons manifest activation of AMP-activated protein kinase (AMPK) during food deprivation, and this activation is necessary and sufficient for selection of an HCD over an HFD. Furthermore, this effect is mediated by carnitine palmitoyltransferase 1c (CPT1c). Thus, our results identify the specific neurons and intracellular signaling pathway responsible for regulation of the complex behavior of selection between an HCD and an HFD. Video Abstract
- Published
- 2017
18. POMC Neurons: From Birth to Death
- Author
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Chitoku Toda, Jung Dae Kim, Anna Santoro, Sabrina Diano, Toda, Chitoku, Santoro, Anna, Kim, Jung Dae, and Diano, Sabrina
- Subjects
0301 basic medicine ,endocrine system ,Pro-Opiomelanocortin ,Physiology ,Hypothalamus ,Biology ,Development ,Article ,03 medical and health sciences ,0302 clinical medicine ,Food intake ,Homeostasi ,medicine ,Hypothalamu ,Animals ,Homeostasis ,Humans ,Obesity ,Organism ,Neurons ,Animal ,digestive, oral, and skin physiology ,POMC ,Neuron ,Spinal cord ,030104 developmental biology ,medicine.anatomical_structure ,Neuronal circuits ,nervous system ,Melanocortin ,Neuroscience ,030217 neurology & neurosurgery ,Intracellular ,hormones, hormone substitutes, and hormone antagonists ,Human - Abstract
The hypothalamus is an evolutionarily conserved brain structure that regulates an organism's basic functions, such as homeostasis and reproduction. Several hypothalamic nuclei and neuronal circuits have been the focus of many studies seeking to understand their role in regulating these basic functions. Within the hypothalamic neuronal populations, the arcuate melanocortin system plays a major role in controlling homeostatic functions. The arcuate pro-opiomelanocortin (POMC) neurons in particular have been shown to be critical regulators of metabolism and reproduction because of their projections to several brain areas both in and outside of the hypothalamus, such as autonomic regions of the brain stem and spinal cord. Here, we review and discuss the current understanding of POMC neurons from their development and intracellular regulators to their physiological functions and pathological dysregulation.
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- 2017
19. Hypothalamic Ventromedial Lin28a Enhances Glucose Metabolism in Diet-Induced Obesity
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Carlos Fernández-Hernando, Sabrina Diano, Cristina M. Ramírez, Chitoku Toda, Jung Dae Kim, Kim, Jung Dae, Toda, Chitoku, Ramírez, Cristina M., Fernández-Hernando, Carlo, and Diano, Sabrina
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0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Down-Regulation ,Gene Expression ,RNA-Binding Protein ,Protein-Serine-Threonine Kinase ,Carbohydrate metabolism ,Biology ,Protein Serine-Threonine Kinases ,Diet, High-Fat ,03 medical and health sciences ,Mice ,Insulin resistance ,Downregulation and upregulation ,Internal medicine ,Glucose Intolerance ,Internal Medicine ,medicine ,Glucose homeostasis ,Animals ,Obesity ,Protein kinase B ,Animal ,Body Weight ,RNA-Binding Proteins ,medicine.disease ,Ventromedial Hypothalamic Nucleu ,Mice, Inbred C57BL ,Insulin receptor ,030104 developmental biology ,Endocrinology ,Glucose ,Metabolism ,Hypothalamus ,Ventromedial Hypothalamic Nucleus ,biology.protein ,Signal transduction ,Insulin Resistance ,Energy Metabolism ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
The Lin28a/Let-7 axis has been studied in peripheral tissues for its role in metabolism regulation. However, its central function remains unclear. Here we found that Lin28a is highly expressed in the hypothalamus compared with peripheral tissues. Its expression is positively correlated with positive energy balance, suggesting a potential central role for Lin28a in metabolism regulation. Thus, we targeted the hypothalamic ventromedial nucleus (VMH) to selectively overexpress (Lin28aKIVMH) or downregulate (Lin28aKDVMH) Lin28a expression in mice. With mice on a standard chow diet, body weight and glucose homeostasis were not affected in Lin28aKIVMH or Lin28aKDVMH mice. On a high-fat diet, although no differences in body weight and composition were observed, Lin28aKIVMH mice showed improved glucose tolerance and insulin sensitivity compared with controls. Conversely, Lin28aKDVMH mice displayed glucose intolerance and insulin resistance. Changes in VMH AKT activation of diet-induced obese Lin28aKIVMH or Lin28aKDVMH mice were not associated with alterations in Let-7 levels or insulin receptor activation. Rather, we observed altered expression of TANK-binding kinase-1 (TBK-1), which was found to be a direct Lin28a target mRNA. VMH-specific inhibition of TBK-1 in mice with diet-induced obesity impaired glucose metabolism and AKT activation. Altogether, our data show a TBK-1–dependent role for central Lin28a in glucose homeostasis.
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- 2016
20. Beneficial effects of Brazilian propolis on type 2 diabetes inob/obmice
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Tomomi Miyamoto, Yoshinori Naoe, Hiroshi Kitamura, Ichiro Miyoshi, Shiki Okamoto, Chitoku Toda, Yoshinori Shimamoto, Toshihiko Iwanaga, and Shunsuke Kimura
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medicine.medical_specialty ,Histology ,business.industry ,Adipose tissue macrophages ,Adipose tissue ,Cell Biology ,Type 2 diabetes ,ob/ob mouse ,Propolis ,medicine.disease ,Immune system ,Endocrinology ,Mesenteric adipose tissue ,Internal medicine ,parasitic diseases ,medicine ,business ,Beneficial effects ,geographic locations - Abstract
The anti-diabetic effects of Brazilian propolis were examined using ob/ob mice. Although repeated injection of an ethanol extract of Brazilian propolis (100 mg/kg, ip, twice a week for 12 weeks) di...
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- 2013
21. Ubiquitin‐specific protease 2‐69 in macrophages potentially modulates metainflammation
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Osamu Ohara, Shunsuke Kimura, Tomomi Miyamoto, Yoshinori Naoe, Koji Hase, Assam El-Osta, Jun Okabe, Chisato Kikuguchi, Mayumi Ishizuka, Hiroshi Kitamura, Ichiro Miyoshi, Bob Meek, Yoshinori Shimamoto, Hiroshi Watarai, Masatoshi Ito, Shiki Okamoto, Katsushi Kanehira, and Chitoku Toda
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Histone H3 Lysine 4 ,Transcription, Genetic ,Biochemistry ,Cell Line ,Epigenesis, Genetic ,Histones ,Histone H4 ,Mice ,Endopeptidases ,Plasminogen Activator Inhibitor 1 ,Adipocytes ,Genetics ,Animals ,Humans ,Myeloid Cells ,Molecular Biology ,Inflammation ,Serum Amyloid A Protein ,Gene knockdown ,biology ,Interleukin-6 ,Macrophages ,Transfection ,Chromatin Assembly and Disassembly ,Molecular biology ,Chromatin ,Mice, Inbred C57BL ,Histone ,Transcription Factor AP-2 ,Cell culture ,Acetylation ,biology.protein ,Ubiquitin-Specific Proteases ,Ubiquitin Thiolesterase ,Biotechnology - Abstract
Macrophages play a critical role in chronic inflammation and metabolic diseases. We identified a longer splice variant of ubiquitin specific protease (USP) 2-69 as a novel molecule that modulates pathways implicated in metabolic disorders. Expression levels of aP2/FABP4 and PAI-1/SERPINE1 genes were increased by 4- and 1.8-fold, respectively, after short hairpin RNA-mediated knockdown (KD) of the USP2 gene, and such expression was alleviated by overexpression of USP2-69 in human myeloid cell lines. Supernatants derived from USP2-KD cells induced IL6 (∼6-fold) and SAA3 (∼15-fold) in 3T3-L1 adipocytes to suggest the anti-inflammatory properties of USP2. In addition, we observed a 30% decrease in the number of macrophages in mesenteric adipose tissue derived from USP2-69 transgenic mice fed a high-fat diet for 14 wk compared with that in their C57BL/6 littermates (P0.01), which was consistent with a ∼40% decrease in transcription of aP2 and PAI-1. The aP2 locus exhibited elevated chromatin accessibility (2.1-fold), methylation of histone H3 lysine 4 (4.5-fold), and acetylation of histone H4 (2.5-fold) in USP2-KD cells. Transfection of isopeptidase-mutated USP2-69 did not alter chromatin conformation on the aP2 locus in USP2-KD cells. Our results suggest that USP2-69 suppresses meta-inflammatory molecules involved in the development of type-2 diabetes.
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- 2013
22. Extracellular Signal–Regulated Kinase in the Ventromedial Hypothalamus Mediates Leptin-Induced Glucose Uptake in Red-Type Skeletal Muscle
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Seiji Shioda, Yasuhiko Minokoshi, Tatsuya Sato, Eulalia A. Coutinho, Haruaki Kageyama, Lijun Tang, Kazuyo Takagi, Shigefumi Yokota, Chitoku Toda, Yuko Okamatsu-Ogura, K. Saito, Shiki Okamoto, and Tetsuya Shiuchi
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Leptin ,Male ,MAPK/ERK pathway ,medicine.medical_specialty ,Morpholines ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,medicine.medical_treatment ,Carbohydrate metabolism ,Biology ,Mice ,Internal medicine ,Nitriles ,Butadienes ,Internal Medicine ,medicine ,Animals ,Insulin ,Melanocyte-Stimulating Hormones ,Enzyme Inhibitors ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Muscle, Skeletal ,Original Research ,Body Weight ,digestive, oral, and skin physiology ,Skeletal muscle ,Glucose ,Metabolism ,medicine.anatomical_structure ,Endocrinology ,Receptors, Corticotropin ,Chromones ,Ventromedial Hypothalamic Nucleus ,Hypothalamus ,Signal transduction ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
Leptin is a key regulator of glucose metabolism in mammals, but the mechanisms of its action have remained elusive. We now show that signaling by extracellular signal–regulated kinase (ERK) and its upstream kinase MEK in the ventromedial hypothalamus (VMH) mediates the leptin-induced increase in glucose utilization as well as its insulin sensitivity in the whole body and in red-type skeletal muscle of mice through activation of the melanocortin receptor (MCR) in the VMH. In contrast, activation of signal transducer and activator of transcription 3 (STAT3), but not the MEK-ERK pathway, in the VMH by leptin enhances the insulin-induced suppression of endogenous glucose production in an MCR-independent manner, with this effect of leptin occurring only in the presence of an increased plasma concentration of insulin. Given that leptin requires 6 h to increase muscle glucose uptake, the transient activation of the MEK-ERK pathway in the VMH by leptin may play a role in the induction of synaptic plasticity in the VMH, resulting in the enhancement of MCR signaling in the nucleus and leading to an increase in insulin sensitivity in red-type muscle.
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- 2013
23. Regulatory role of leptin in glucose and lipid metabolism in skeletal muscle
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Shiki Okamoto, Yasuhiko Minokoshi, and Chitoku Toda
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,Review Article ,Biology ,leptin ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,chemistry.chemical_compound ,Endocrinology ,AMP-activated protein kinase ,Internal medicine ,medicine ,hypothalamus ,skeletal muscle ,lcsh:RC799-869 ,sympathetic nervous system ,Leptin receptor ,lcsh:RC648-665 ,Fatty acid metabolism ,Leptin ,digestive, oral, and skin physiology ,Skeletal muscle ,Lipid metabolism ,medicine.anatomical_structure ,Lipotoxicity ,chemistry ,biology.protein ,lcsh:Diseases of the digestive system. Gastroenterology ,hormones, hormone substitutes, and hormone antagonists - Abstract
Leptin is a hormone secreted by adipocytes that plays a pivotal role in regulation of food intake, energy expenditure, and neuroendocrine function. Several lines of evidences indicate that independent of the anorexic effect, leptin regulates glucose and lipid metabolism in peripheral tissues in rodents and humans. It has been shown that leptin improves the diabetes phenotype in lipodystrophic patients and rodents. Moreover, leptin suppresses the development of severe, progressive impairment of glucose metabolism in insulin-deficient diabetes in rodents. We found that leptin increases glucose uptake and fatty acid oxidation in skeletal muscle in rats and mice in vivo. Leptin increases glucose uptake in skeletal muscle via the hypothalamic-sympathetic nervous system axis and β-adrenergic mechanism, while leptin stimulates fatty acid oxidation in muscle via AMP-activated protein kinase (AMPK). Leptin-induced fatty acid oxidation results in the decrease of lipid accumulation in muscle, which can lead to functional impairments called as "lipotoxicity." Activation of AMPK occurs by direct action of leptin on muscle and through the medial hypothalamus-sympathetic nervous system and α-adrenergic mechanism. Thus, leptin plays an important role in the regulation of glucose and fatty acid metabolism in skeletal muscle.
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- 2012
24. Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in Insr/+P1195L/+ mice fed high-fat-diet
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Yasuhiko Minokoshi, Takashi Miki, Tomoaki Tanaka, Eun Young Lee, Kenichi Sakurai, Takuji Shirasawa, Kaori Tachibana, Antonio Vidal-Puig, Chitoku Toda, Meizi Jiang, Xilin Zhang, and Koutaro Yokote
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Blood Glucose ,Glycerol ,G6PC ,medicine.medical_treatment ,Adipose tissue ,Physiology ,Fats ,Mice ,Adipose Tissue, Brown ,Pyruvic Acid ,Adipocytes ,Insulin ,Phosphorylation ,Multidisciplinary ,biology ,digestive, oral, and skin physiology ,food and beverages ,Liver ,lipids (amino acids, peptides, and proteins) ,hormones, hormone substitutes, and hormone antagonists ,medicine.medical_specialty ,Genotype ,Adipose Tissue, White ,Lipolysis ,Mice, Transgenic ,Diet, High-Fat ,Models, Biological ,Article ,Bile Acids and Salts ,Insulin resistance ,Internal medicine ,medicine ,Animals ,Body Weight ,Gluconeogenesis ,nutritional and metabolic diseases ,medicine.disease ,Receptor, Insulin ,Transplantation ,Insulin receptor ,Disease Models, Animal ,Endocrinology ,Hyperglycemia ,Mutation ,biology.protein ,Insulin Resistance ,Energy Metabolism ,Proto-Oncogene Proteins c-akt - Abstract
High-fat diet (HFD) triggers insulin resistance and diabetes mellitus, but their link remains unclear. Characterization of overt hyperglycemia in insulin receptor mutant (InsrP1195L/+) mice exposed to HFD (InsrP1195L/+/HFD mice) revealed increased glucose-6-phosphatase (G6pc) expression in liver and increased gluconeogenesis from glycerol. Lipolysis in white adipose tissues (WAT) and lipolysis-induced blood glucose rise were increased in InsrP1195L/+/HFD mice, while wild-type WAT transplantation ameliorated the hyperglycemia and the increased G6pc expression. We found that the expressions of genes involved in bile acid (BA) metabolism were altered in InsrP1195L/+/HFD liver. Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in InsrP1195L/+/HFD liver. Reduced Cyp7a1 expression in InsrP1195L/+/HFD liver was rescued by WAT transplantation and the expression of Cyp7a1 was suppressed by glycerol administration in wild-type liver. These findings suggest that unsuppressed lipolysis in adipocytes elicited by HFD feeding is linked with enhanced gluconeogenesis from glycerol and with alterations in BA physiology in InsrP1195L/+/HFD liver.
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- 2015
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25. Distinct Effects of Leptin and a Melanocortin Receptor Agonist Injected Into Medial Hypothalamic Nuclei on Glucose Uptake in Peripheral Tissues
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Maya Yamato-Esaki, Suni Lee, Chitoku Toda, Yasuhiko Minokoshi, Yusuke Fujino, Tetsuya Shiuchi, Shiki Okamoto, and Atsushi Suzuki
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Leptin ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Glucose uptake ,Immunoblotting ,Hypothalamus, Middle ,Adipose tissue ,Adipokine ,Mice, Inbred Strains ,Biology ,Tritium ,Peptides, Cyclic ,Cerebral Ventricles ,Injections ,Mice ,Adipose Tissue, Brown ,Melanocortin receptor ,Internal medicine ,Brown adipose tissue ,Internal Medicine ,medicine ,Animals ,Melanocyte-Stimulating Hormones ,Muscle, Skeletal ,Leptin receptor ,Reverse Transcriptase Polymerase Chain Reaction ,Myocardium ,Receptors, Melanocortin ,digestive, oral, and skin physiology ,Glucose ,Metabolism ,Endocrinology ,medicine.anatomical_structure ,Ventromedial Hypothalamic Nucleus ,alpha-MSH ,Hypothalamus ,Original Article ,hormones, hormone substitutes, and hormone antagonists - Abstract
OBJECTIVE The medial hypothalamus mediates leptin-induced glucose uptake in peripheral tissues, and brain melanocortin receptors (MCRs) mediate certain central effects of leptin. However, the contributions of the leptin receptor and MCRs in individual medial hypothalamic nuclei to regulation of peripheral glucose uptake have remained unclear. We examined the effects of an injection of leptin and the MCR agonist MT-II into medial hypothalamic nuclei on glucose uptake in peripheral tissues. RESEARCH DESIGN AND METHODS Leptin or MT-II was injected into the ventromedial (VMH), dorsomedial (DMH), arcuate nucleus (ARC), or paraventricular (PVH) hypothalamus or the lateral ventricle (intracerebroventricularly) in freely moving mice. The MCR antagonist SHU9119 was injected intracerebroventricularly. Glucose uptake was measured by the 2-[3H]deoxy-d-glucose method. RESULTS Leptin injection into the VMH increased glucose uptake in skeletal muscle, brown adipose tissue (BAT), and heart, whereas that into the ARC increased glucose uptake in BAT, and that into the DMH or PVH had no effect. SHU9119 abolished these effects of leptin injected into the VMH. Injection of MT-II either into the VMH or intracerebroventricularly increased glucose uptake in skeletal muscle, BAT, and heart, whereas that into the PVH increased glucose uptake in BAT, and that into the DMH or ARC had no effect. CONCLUSIONS The VMH mediates leptin- and MT-II–induced glucose uptake in skeletal muscle, BAT, and heart. These effects of leptin are dependent on MCR activation. The leptin receptor in the ARC and MCR in the PVH regulate glucose uptake in BAT. Medial hypothalamic nuclei thus play distinct roles in leptin- and MT-II–induced glucose uptake in peripheral tissues.
- Published
- 2009
26. Uncoupling protein 1 contributes to fat-reducing effect of leptin
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Chitoku Toda, Yuko Okamatsu-Ogura, Hitoshi Yamashita, Akihiro Uozumi, Kazuhiro Kimura, and Masayuki Saito
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medicine.medical_specialty ,Nutrition and Dietetics ,Adrenergic receptor ,Triglyceride ,Endocrinology, Diabetes and Metabolism ,Leptin ,digestive, oral, and skin physiology ,White adipose tissue ,Thermogenin ,chemistry.chemical_compound ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Internal medicine ,Brown adipose tissue ,Knockout mouse ,medicine ,Thermogenesis ,hormones, hormone substitutes, and hormone antagonists - Abstract
Summary Leptin is proposed to reduce body fat by increasing energy expenditure, in addition to decreasing food intake, through the activation of brown adipose tissue (BAT) thermogenesis. To confirm this, we investigated the effects of leptin on whole body energy expenditure, BAT functions and adiposity in wild-type (WT) mice, and compared with those in mice deficient in uncoupling protein 1 (UCP1), a key molecule for BAT thermogenesis. Chronic hyperleptinemia induced by adenovirus gene transfer reduced food intake in both WT and UCP1-KO mice. WT mice with hyperleptinemia, compared to pair-fed controls, showed increased oxygen consumption, elevated UCP1 expression in BAT, ectopic UCP1 induction in white adipose tissue (WAT), and reduced body fat content. These effects of chronic hyperleptinemia were not observed in UCP1-KO mice. It was concluded that the fat-reducing effect of leptin is due to not only decreased food intake, but also increased UCP1-dependent energy expenditure.
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- 2007
27. β3-Adrenoceptor agonist AJ-9677 reduces body fat in obese beagles
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Masayuki Saito, Akihiro Uozumi, Kazuhiro Kimura, Chitoku Toda, Asako Omachi, Katsumi Ishioka, and Akihiro Kamikawa
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Blood Glucose ,Male ,Agonist ,medicine.medical_specialty ,Indoles ,medicine.drug_class ,medicine.medical_treatment ,Adipose tissue ,Adrenergic beta-3 Receptor Agonists ,Acetates ,Fatty Acids, Nonesterified ,Dogs ,Insulin resistance ,Oral administration ,Internal medicine ,Animals ,Insulin ,Medicine ,Obesity ,General Veterinary ,Adiponectin ,business.industry ,Leptin ,medicine.disease ,Endocrinology ,Adipose Tissue ,Female ,Anti-Obesity Agents ,Insulin Resistance ,business - Abstract
A selective beta3-adrenoceptor agonist, AJ-9677, was reported to ameliorate obesity and insulin resistance in KK-Ay mice. We examined the acute and chronic effects of AJ-9677 on obese dogs. Oral administration of AJ-9677 (0.01 or 0.1 mg/kg) to overnight fasted obese beagles produced a dose-dependent rise in the plasma levels of non-esterified fatty acids and insulin in 1h, followed by a gradual drop of the plasma glucose level. It produced no apparent abnormal behaviors, but easily detectable cutaneous flushing. Daily treatment of AJ-9677 at a lower dose (0.01 mg/kg) for three weeks produced no notable change in body weight, but at a higher dose (0.1 mg/kg) it reduced the body weight compared to a placebo treatment after seven weeks. Computed tomographic examinations revealed a remarkable reduction of body fat after the AJ treatment, being consistent with the histological observations that the adipose tissue of AJ-9677-treated dogs consisted of smaller and some multilocular adipocytes. The plasma levels of leptin and adiponectin were decreased and increased, respectively, after the AJ treatment, reflecting the reduction of adiposity. It was concluded that AJ-9677 is useful for the treatment of obesity in the dog.
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- 2007
28. Sympathetic Nerve Activity Maintains an Anti-Inflammatory State in Adipose Tissue in Male Mice by Inhibiting TNF-α Gene Expression in Macrophages
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K. Saito, Shiki Okamoto, Shigefumi Yokota, Chitoku Toda, Tetsuya Shiuchi, Tatsuya Sato, Kazuyo Takagi, Yasuhiko Minokoshi, and Lijun Tang
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Male ,medicine.medical_specialty ,Sympathetic Nervous System ,Adipose tissue macrophages ,Adipose Tissue, White ,Adrenergic beta-Antagonists ,Immunoblotting ,Adipose tissue ,Gene Expression ,White adipose tissue ,Biology ,Proinflammatory cytokine ,Cell Line ,Endocrinology ,Adipose Tissue, Brown ,Internal medicine ,Brown adipose tissue ,Receptors, Adrenergic, beta ,medicine ,Animals ,Agouti-Related Protein ,News & Views ,Sympathectomy ,Injections, Intraventricular ,Denervation ,Epididymis ,Mice, Knockout ,Reverse Transcriptase Polymerase Chain Reaction ,Tumor Necrosis Factor-alpha ,Macrophages ,Stromal vascular fraction ,Propranolol ,Peptide Fragments ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Tumor necrosis factor alpha ,Inflammation Mediators - Abstract
Adipose tissue macrophages (ATMs) play an important role in the inflammatory response in obese animals. How ATMs are regulated in lean animals has remained elusive, however. We now show that the sympathetic nervous system (SNS) is necessary to maintain the abundance of the mRNA for the proinflammatory cytokine TNF-α at a low level in ATMs of lean mice. Intracerebroventricular injection of agouti-related neuropeptide increased the amount of TNF-α mRNA in epididymal (epi) white adipose tissue (WAT), but not in interscapular brown adipose tissue (BAT), through inhibition of sympathetic nerve activity in epiWAT. The surgical denervation and β-adrenergic antagonist propranolol up-regulated TNF-α mRNA in both epiWAT and BAT in vivo. Signaling by the β2-adrenergic receptor (AR) and protein kinase A down-regulated TNF-α mRNA in epiWAT explants and suppressed lipopolysaccharide-induced up-regulation of TNF-α mRNA in the stromal vascular fraction of this tissue. β-AR-deficient (β-less) mice manifested an increased plasma TNF-α concentration and increased TNF-α mRNA abundance in epiWAT and BAT. TNF-α mRNA abundance was greater in ATMs (CD11b+ cells of the stromal vascular fraction) from epiWAT or BAT of wild-type mice than in corresponding CD11b− cells, and β2-AR mRNA abundance was greater in ATMs than in CD11b− cells of epiWAT. Our results show that the SNS and β2-AR-protein kinase A pathway maintain an anti-inflammatory state in ATMs of lean mice in vivo, and that the brain melanocortin pathway plays a role in maintaining this state in WAT of lean mice via the SNS.
- Published
- 2015
29. Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice
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Jin Kwon Jeong, Jung Dae Kim, Mari Savolainen, Ralph J. DiLeone, Giuseppe D'Agostino, John D. Elsworth, Caroline J. Zeiss, Sabrina Diano, Timo T. Myöhänen, Owen Chan, Richard G. Kibbey, Chitoku Toda, Brandon K. Harvey, Christopher T. Richie, Kim, Jung Dae, Toda, Chitoku, D'Agostino, Giuseppe, Zeiss, Caroline J, Dileone, Ralph J, Elsworth, John D, Kibbey, Richard G, Chan, Owen, Harvey, Brandon K, Richie, Christopher T, Savolainen, Mari, Myöhänen, Timo, Jeong, Jin Kwon, and Diano, Sabrina
- Subjects
Blood Glucose ,Male ,Indoles ,medicine.medical_treatment ,Gene Expression ,Ion Channels ,Impaired glucose tolerance ,Mice ,0302 clinical medicine ,Ion Channel ,Insulin Secretion ,Hypothalamu ,Pancrea ,Insulin ,Thiazolidine ,Phosphorylation ,Uncoupling Protein 1 ,0303 health sciences ,Multidisciplinary ,Serine Endopeptidases ,Glucagon secretion ,Glucose clamp technique ,Recombinant Protein ,Biological Sciences ,Recombinant Proteins ,3. Good health ,Serine Endopeptidase ,peripheral hormonal regulation ,medicine.anatomical_structure ,Gene Knockdown Techniques ,Thiazolidines ,Serine Proteinase Inhibitor ,Prolyl Oligopeptidases ,medicine.drug ,medicine.medical_specialty ,Serine Proteinase Inhibitors ,Hypothalamus ,Mice, Transgenic ,Carbohydrate metabolism ,Biology ,Glucagon ,Mitochondrial Proteins ,03 medical and health sciences ,central glucose sensing ,Prolyl endopeptidase ,Internal medicine ,Glucose Intolerance ,medicine ,Mitochondrial Protein ,Animals ,Pancreas ,030304 developmental biology ,sympathetic nervous system ,Animal ,Pancreatic islets ,medicine.disease ,Receptor, Insulin ,Endocrinology ,Indole ,Ventromedial Hypothalamic Nucleus ,Gene Knockdown Technique ,Glucose Clamp Technique ,030217 neurology & neurosurgery - Abstract
Prolyl endopeptidase (PREP) has been implicated in neuronal functions. Here we report that hypothalamic PREP is predominantly expressed in the ventromedial nucleus (VMH), where it regulates glucose-induced neuronal activation. PREP knockdown mice (Prep(gt/gt)) exhibited glucose intolerance, decreased fasting insulin, increased fasting glucagon levels, and reduced glucose-induced insulin secretion compared with wild-type controls. Consistent with this, central infusion of a specific PREP inhibitor, S17092, impaired glucose tolerance and decreased insulin levels in wild-type mice. Arguing further for a central mode of action of PREP, isolated pancreatic islets showed no difference in glucose-induced insulin release between Prep(gt/gt) and wild-type mice. Furthermore, hyperinsulinemic euglycemic clamp studies showed no difference between Prep(gt/gt) and wild-type control mice. Central PREP regulation of insulin and glucagon secretion appears to be mediated by the autonomic nervous system because Prep(gt/gt) mice have elevated sympathetic outflow and norepinephrine levels in the pancreas, and propranolol treatment reversed glucose intolerance in these mice. Finally, re-expression of PREP by bilateral VMH injection of adeno-associated virus-PREP reversed the glucose-intolerant phenotype of the Prep(gt/gt) mice. Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function.
- Published
- 2014
30. PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding
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Sabrina Diano, Tamas L. Horvath, Lihong Long, Jing Kwon Jeong, Chitoku Toda, Long, Lihong, Toda, Chitoku, Jeong, Jing Kwon, Horvath, Tamas L, and Diano, Sabrina
- Subjects
Leptin ,Male ,medicine.medical_specialty ,Pro-Opiomelanocortin ,Peroxisome proliferator-activated receptor ,Carbohydrate metabolism ,Hyperphagia ,Motor Activity ,Diet, High-Fat ,Energy homeostasis ,Rosiglitazone ,Mice ,Insulin resistance ,Proopiomelanocortin ,Internal medicine ,medicine ,Animals ,Anilides ,chemistry.chemical_classification ,Neurons ,biology ,Animal ,digestive, oral, and skin physiology ,Anilide ,Thiazolidinedione ,General Medicine ,Neuron ,medicine.disease ,PPAR gamma ,Endocrinology ,Glucose ,chemistry ,Nuclear receptor ,nervous system ,biology.protein ,Female ,Thiazolidinediones ,Insulin Resistance ,Reactive Oxygen Specie ,Energy Metabolism ,Reactive Oxygen Species ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Research Article - Abstract
Activation of central PPARγ promotes food intake and body weight gain; however, the identity of the neurons that express PPARγ and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPARγ in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPARγ in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPARγ in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPARγ activator or inhibitor failed to affect food intake of mice with POMC-specific PPARγ ablation. Taken together, our data indicate that PPARγ mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance.
- Published
- 2014
31. Mitochondrial UCP2 in the central regulation of metabolism
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Sabrina Diano, Chitoku Toda, Toda, Chitoku, and Diano, Sabrina
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UCP2 ,Endocrinology, Diabetes and Metabolism ,Hypothalamus ,Oxidative phosphorylation ,Biology ,Ion Channels ,Mitochondrial Proteins ,Endocrinology ,Ion Channel ,mitochondrial dynamic ,Animals ,Humans ,Glucose homeostasis ,Mitochondrial Protein ,Uncoupling Protein 2 ,Inner mitochondrial membrane ,Electrochemical gradient ,chemistry.chemical_classification ,Reactive oxygen species ,synaptic plasticity ,Animal ,POMC ,Metabolism ,hypothalamu ,Mitochondria ,chemistry ,Biochemistry ,reward system ,ghrelin ,Synaptic plasticity ,dopamine ,Reactive Oxygen Species ,AgRP ,Energy Metabolism ,Reactive Oxygen Specie ,Homeostasis ,Human - Abstract
Uncoupling protein 2 (UCP2) is a mitochondrial anion carrier protein, which uncouples the oxidative phosphorylation from ATP production by dissipating the proton gradient generated across the mitochondrial inner membrane. UCP2 regulates not only mitochondrial ATP production, but also the generation of reactive oxygen species (ROS), considered important second-messenger signals within the cell. The importance of UCP2 was firstly reported in macrophages and pancreatic beta cells. However, several studies have revealed the important role of UCP2 in the Central Nervous System (CNS) in the regulation of homeostatic mechanisms including food intake, energy expenditure, glucose homeostasis and reward behaviors. The mechanisms by which central UCP2 affect these processes seem to be associated with synaptic and mitochondrial plasticity. In this review, we will describe recent findings on central UCP2 and discuss its role in CNS regulation of homeostasis.
- Published
- 2014
32. 234: Leptin mediated model of pre-eclampsia in mice
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Sabrina Diano, Shouhua Yang, Masaru Negi, Michela Campolo, and Chitoku Toda
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medicine.medical_specialty ,Eclampsia ,Leptin receptor ,Endocrinology ,business.industry ,Internal medicine ,Leptin ,medicine ,Obstetrics and Gynecology ,business ,medicine.disease - Published
- 2016
33. [Mechanism of dysregulated energy homeostasis in metabolic syndrome]
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Chitoku Toda
- Subjects
Leptin ,Metabolic Syndrome ,Animals ,Homeostasis ,Humans ,Energy Metabolism - Published
- 2011
34. Role of central leptin signaling in the starvation-induced alteration of B-cell development
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Makoto Tsuiji, Kozue Ochi, Chitoku Toda, Yasutomi Kamei, Takayoshi Suganami, Yoshihiro Ogawa, Miyako Tanaka, Misa Kim-Saijo, and Yasuhiko Minokoshi
- Subjects
Blood Glucose ,Leptin ,Male ,medicine.medical_specialty ,Hypothalamus ,Adipose tissue ,Biology ,Energy homeostasis ,Mice ,Immune system ,Internal medicine ,medicine ,Animals ,B cell ,B-Lymphocytes ,Reverse Transcriptase Polymerase Chain Reaction ,General Neuroscience ,Adrenalectomy ,Cell Differentiation ,Articles ,Neuropeptide Y receptor ,Flow Cytometry ,Endocrinology ,medicine.anatomical_structure ,Adipose Tissue ,Starvation ,Bone marrow ,Homeostasis ,Signal Transduction - Abstract
Nutritional deprivation or malnutrition suppresses immune function in humans and animals, thereby conferring higher susceptibility to infectious diseases. Indeed, nutritional deprivation induces atrophy of lymphoid tissues such as thymus and spleen and decreases the number of circulating lymphocytes. Leptin, a major adipocytokine, is exclusively produced in the adipose tissue in response to the nutritional status and acts on the hypothalamus, thereby regulating energy homeostasis. Although leptin plays a critical role in the starvation-induced T-cell-mediated immunosuppression, little is known about its role in B-cell homeostasis under starvation conditions. Here we show the alteration of B-cell development in the bone marrow of fasted mice, characterized by decrease in pro-B, pre-B, and immature B cells and increase in mature B cells. Interestingly, intracerebroventricular leptin injection was sufficient to prevent the alteration of B-cell development of fasted mice. The alteration of B lineage cells in the bone marrow of fasted mice was markedly prevented by oral administration of glucocorticoid receptor antagonist RU486 (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one). It was also effectively prevented by intracerebroventricular injection of neuropeptide Y Y(1) receptor antagonist BIBP3226 [(2R)-5-(diaminomethylideneamino)-2-[(2,2-diphenylacetyl)amino]-N-[(4-hydroxyphenyl)methyl]pentanamide], along with suppression of the otherwise increased serum corticosterone concentrations. This study provides the first in vivo evidence for the role of central leptin signaling in the starvation-induced alteration of B-cell development. The data of this study suggest that the CNS, which is inherent to integrate information from throughout the organism, is able to control immune function.
- Published
- 2011
35. Hypothalamic Ventromedial Lin28a Enhances Glucose Metabolism in Diet-Induced Obesity.
- Author
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Jung Dae Kim, Chitoku Toda, Ramírez, Cristina M., Fernández-Hernando, Carlos, Diano, Sabrina, Kim, Jung Dae, and Toda, Chitoku
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METABOLIC regulation , *HYPOTHALAMUS , *LABORATORY mice , *HOMEOSTASIS , *GLUCOSE , *INSULIN resistance , *PROTEIN metabolism , *GLUCOSE metabolism , *ANIMAL experimentation , *BIOCHEMISTRY , *BODY weight , *CELLULAR signal transduction , *DIET , *ENERGY metabolism , *GENE expression , *PHENOMENOLOGY , *MICE , *OBESITY , *PROTEINS , *RESEARCH funding , *TRANSFERASES , *GLUCOSE intolerance - Abstract
The Lin28a/Let-7 axis has been studied in peripheral tissues for its role in metabolism regulation. However, its central function remains unclear. Here we found that Lin28a is highly expressed in the hypothalamus compared with peripheral tissues. Its expression is positively correlated with positive energy balance, suggesting a potential central role for Lin28a in metabolism regulation. Thus, we targeted the hypothalamic ventromedial nucleus (VMH) to selectively overexpress (Lin28aKIVMH ) or downregulate (Lin28aKDVMH ) Lin28a expression in mice. With mice on a standard chow diet, body weight and glucose homeostasis were not affected in Lin28aKIVMH or Lin28aKDVMH mice. On a high-fat diet, although no differences in body weight and composition were observed, Lin28aKIVMH mice showed improved glucose tolerance and insulin sensitivity compared with controls. Conversely, Lin28aKDVMH mice displayed glucose intolerance and insulin resistance. Changes in VMH AKT activation of diet-induced obese Lin28aKIVMH or Lin28aKDVMH mice were not associated with alterations in Let-7 levels or insulin receptor activation. Rather, we observed altered expression of TANK-binding kinase-1 (TBK-1), which was found to be a direct Lin28a target mRNA. VMH-specific inhibition of TBK-1 in mice with diet-induced obesity impaired glucose metabolism and AKT activation. Altogether, our data show a TBK-1-dependent role for central Lin28a in glucose homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
36. Uncoupling protein 1 is necessary for norepinephrine-induced glucose utilization in brown adipose tissue
- Author
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Chitoku Toda, Ken-ichi Inokuma, Hitoshi Yamashita, Yuko Ogura-Okamatsu, Masayuki Saito, and Kazuhiro Kimura
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Blood Glucose ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,Carbohydrate metabolism ,Biology ,Deoxyglucose ,Ion Channels ,Mitochondrial Proteins ,Mice ,Norepinephrine ,Adipose Tissue, Brown ,Internal medicine ,Brown adipose tissue ,Internal Medicine ,medicine ,Uncoupling protein ,Animals ,Insulin ,RNA, Messenger ,Protein kinase A ,Uncoupling Protein 1 ,Mice, Knockout ,Myocardium ,Glucose transporter ,Membrane Proteins ,Biological Transport ,Heart ,Thermogenin ,medicine.anatomical_structure ,Endocrinology ,Glucose ,Carrier Proteins ,Thermogenesis ,Body Temperature Regulation - Abstract
Sympathetic stimulation activates glucose utilization in parallel with fatty acid oxidation and thermogenesis in brown adipose tissue (BAT) through the β-adrenergic receptors. To clarify the roles of the principal thermogenic molecule mitochondrial uncoupling protein 1 (UCP1) in the sympathetically stimulated glucose utilization, we investigated the uptake of 2-deoxyglucose (2-DG) into BAT and some other tissues of UCP1-knockout (KO) mice in vivo. In wild-type (WT) mice, administration of norepinephrine (NE) accelerated the disappearance of plasma 2-DG and increased 2-DG uptake into BAT and heart without any rise of plasma insulin level. In UCP1-KO mice, the stimulatory effect of NE on 2-DG uptake into BAT, but not into heart, disappeared completely. Insulin administration increased 2-DG uptake into BAT and also heart similarly in WT and UCP1-KO mice. NE also increased the activity of AMP-activated protein kinase (AMP kinase) in BAT of WT but not UCP1-KO mice. Our results, together with reports that the activation of AMP kinase increases glucose transport in myocytes, suggest that the sympathetically stimulated glucose utilization in BAT is due to the serial activation of UCP1 and AMP kinase.
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- 2005
37. Role of ventromedial hypothalamus on leptin-induced glucose uptake in peripheral tissues
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Tetsuya Shiuchi, Yasuhiko Minokoshi, and Chitoku Toda
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medicine.medical_specialty ,Endocrinology ,Hypothalamus ,Chemistry ,General Neuroscience ,Internal medicine ,Glucose uptake ,Leptin ,medicine ,General Medicine ,Peripheral - Published
- 2009
38. Orexins increase glucose uptake in skeletal muscle via the hypothalamus-sympathetic nervous system-β2-adrenergic pathway
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Yasuhiko Minokoshi, K. Saito, Suni Lee, Atsushi Suzuki, Shiki Okamoto, Chitoku Toda, and Tetsuya Shiuchi
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medicine.medical_specialty ,Sympathetic nervous system ,Endocrine and Autonomic Systems ,Chemistry ,Glucose uptake ,Adrenergic ,Skeletal muscle ,Cellular and Molecular Neuroscience ,Endocrinology ,medicine.anatomical_structure ,Hypothalamus ,Internal medicine ,medicine ,Neurology (clinical) - Published
- 2007
39. PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding.
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Lihong Long, Chitoku Toda, Jing Kwon Jeong, Horvath, Tamas L., and Diano, Sabrina
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BODY weight , *NEURONS , *HOMEOSTASIS , *ENDOPLASMIC reticulum , *MITOCHONDRIA - Abstract
Activation of central PPARγ promotes food intake and body weight gain; however, the identity of the neurons that express PPARγ and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPARγ in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPARγ in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPARγ in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPARγ activator or inhibitor failed to affect food intake of mice with POMC-specific PPARγ ablation. Taken together, our data indicate that PPARγ mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance. [ABSTRACT FROM AUTHOR]
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- 2014
- Full Text
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40. Ubiquitin-specific protease 2-69 in macrophages potentially modulates metainflammation.
- Author
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Hiroshi Kitamura, Shunsuke Kimura, Yoshinori Shimamoto, Okabe, Jun, Masatoshi Ito, Tomomi Miyamoto, Yoshinori Naoe, Chisato Kikuguchi, Meek, Bob, Chitoku Toda, Shiki Okamoto, Katsushi Kanehira, Koji Hase, Hiroshi Watarai, Mayumi Ishizuka, El-Osta, Assam, Osamu Ohara, and Ichiro Miyoshi
- Subjects
UBIQUITIN ,PROTEINS ,PROTEOLYTIC enzymes ,HYDROLASES ,MACROPHAGES - Abstract
Macrophages play a critical role in chronic inflammation and metabolic diseases. We identified longer splice variant of ubiquilin specific protease (USP) 2-69 as a novel molecule that modulates pathways implicated in metabolic disorders. Expression levels of aP2/FABP4 and PAI-1/SERPINE1 genes were increased by 4-and 1.8-fold, respectively, after short hairpin RNA-mediated knockdown (KD) of the USP2 gene, and such expression was alleviated by overexpression of USP2-69 in human myeloid cell lines. Supernatants derived from USP2-KD cells induced I6 (~6-fold) and SAA3 (~ 15-fold) in 3T3-L1 adipocytes to suggest the anti-inflammatory properties of USP2. In addition, we observed a 30% decrease in the number of macrophages in mesenteric adipose tissue derived from USP2-69 transgenic mice a high-fat diet for 14 wk compared with that in their C57BL/6 littermates (P<0.01), which was consistent with a ~40% decrease in transcription of aP2 and PAI-1. The aP2 locus exhibited elevated chromatin accessibility (>2.1-fold), methylation of histone H3 lysine 4 (>4.5-fold), and acetylation of histone H4 (>2.5-fold) in USP2-KD cells. Transfection of isopeptidase-mutated USP2-69 did not alter chromafin conformation on the aP2 locus in USP2-KD cells. Our results suggest that USP2-69 suppresses meta-inflammatory molecules involved in the development of type-2 diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
41. Distinct effects of leptin and melanocortin agonist in medial hypothalamic nuclei on glucose uptake in peripheral tissues
- Author
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Chitoku, TODA
- Abstract
レプチンは脂肪細胞より分泌される抗肥満ホルモンである。レプチンを投与すると摂食量が減少し、エネルギー消費が増加することによって体重が減少する。レプチンによる抗肥満作用の大部分は、視床下部のレプチン受容体を介することが知られている。また、最近の研究により、レプチンの摂食抑制作用は、脳内のメラノコルチン受容体(MCR)を介することも明らかとなった。MCRは、視床下部弓状核(ARC)に存在するpro-opiomelanocortin (POMC)ニューロンから放出されるα-melanocyte-stimulating hormone (α-MSH) によって活性化され、逆にARCに存在するagouti-related peptide(AgRP)発現ニューロンによって抑制される。レプチンはPOMCニューロンを活性化すると同時に、AgRPニューロンを抑制することでMCRを活性化して、抗肥満作用を引き起こす。 最近の研究により、レプチンは、抗肥満作用とは独立に、糖、脂質代謝を強く調節し、抗糖尿病作用を持つことが明らかとなった。 例えば、レプチン欠乏状態にある脂肪萎縮症の症例にレプチンを投与すると、糖尿病や高脂血症が解消されるなどの劇的な治療効果がある。これまでの研究で、レプチンを内側視床下部に投与すると、骨格筋、褐色脂肪(BAT)および心臓において選択的にグルコースの取り込みが増加することが分かっている(Minokoshi Y, et al. Diabetes 48:287, 1999)。しかし、レプチンによる糖代謝調節作用において視床下部のどの神経核が重要であるか、また脳内MCRが関与するか否かは不明である。本研究の目的は、レプチンによる末梢組織での糖代謝調節作用、特に糖取り込み促進作用において、視床下部のどの神経核が重要であるかを、マウスを用いて明らかにすることである。さらに、脳内MCRがレプチンによる糖取り込み促進作用にどのような調節作用を営むかを調べた。 レプチンを内側視床下部に投与したことによるグルコースの取り込み促進作用は交感神経節遮断薬や神経切除によって抑制される (Haque MS, et al. Diabetes 48:1706, 1999)。そこで、内側視床下部の中でレプチン受容体を高発現し、且つ交感神経の活動調節に関与する4つの神経核、腹内側核(VMH)、背内側核(DMH)、室傍核(PVH)およびARCに、レプチンを選択的に投与して末梢組織でのグルコースの取り込みを測定した。グルコースの取り込みは2-[3H]deoxy-D-glucose(2DG)法を用いて測定した。レプチン投与の成否は、レプチンを投与後、それぞれの神経核を採取し、レプチンの細胞内シグナル分子の一つであるsignal transducer and activator of transcription 3 (STAT3) のリン酸化をウェスタンブロット法で検出することにより確認した。 レプチンをマウスのVMHに投与すると、骨格筋、BATおよび心臓において2DGの取り込みが増加した。レプチンをARCに投与すると、BATにおいてのみ2DGの取り込みが増加した。レプチンをDMHやPVHに投与してもグルコースの取り込みは増加しなかった。レプチンをいずれの神経核に投与しても脾臓および白色脂肪において2DGの取り込みは増加しなかった。これらの結果から、調べた内側視床下部の中でVMHおよびARCのレプチン受容体が、末梢組織のグルコースの取り込みを調節することが明らかとなった。また、VMH及びARCで、その組織が異なることも明らかとなった。 次に、レプチンを末梢に投与した時の2DGの取り込み促進作用に、VMHのレプチン受容体がどのような調節作用を営むかを明らかにするため、レプチン中和抗体を両側VMHに投与した後、レプチンを腹腔内に投与して末梢組織におけるグルコースの取り込みを調べた。レプチンを腹腔内に投与すると、レプチンをVMHに投与した時と同様、骨格筋、BATおよび心臓において2DGの取り込みが増加した。脾臓および白色脂肪では増加しなかった。レプチン中和抗体をVMHに投与すると、レプチンによる上記組織での2DGの取り込み増加作用が抑制された。これらの実験結果から、VMHは、レプチンによる末梢組織でのグルコースの取り込みに必須であることが明らかとなった。 次に脳内MCRが、レプチンによる末梢組織でのグルコースの取り込みにどのような調節作用を及ぼすかを調べた。MCRアンタゴニストであるSHU9119を脳室内に投与すると、レプチンをVMHに投与した時の末梢組織での2DGの取り込み増加作用は完全に抑制された。さらに、MCRアゴニストであるMT-IIを脳室内に投与すると、レプチンと同様、骨格筋、BATおよび心臓において2DGの取り込みが増加した。このことから、レプチンによる末梢組織でのグルコースの取り込みはMCRを介することが明らかとなった。 VMHの一部のニューロンを刺激すると、ARCのα-MSHニューロンが活性化することが示されている(Sternson SM. et al. Nat Neurosci. 8:1356 2005)。また、本研究において、レプチンをVMHに投与すると、VMHだけでなくARCにおいてc-FOSの発現が増加した。これに対して、STAT3は、VMHにおいてのみリン酸化が増加し、ARCでは変化しなかった。この実験結果は、レプチンがVMHニューロンを活性化した後、ARCのα-MSHニューロンを二次的に活性化し、その結果、 末梢組織でのグルコースの取り込みを増加させることを示唆する。 それでは、どの神経核のMCRが末梢組織でのグルコースの取り込みに関与するのであろうか。このことを調べるために、MCRを高発現し、且つ交感神経の活性化に関与するVMH、DMH、PVHおよびARCに、各々MT-IIを選択的に投与して末梢組織でのグルコースの取り込みを測定した。MT-IIをVMHに投与すると、レプチンと同様に、骨格筋、BATおよび心臓において2DGの取り込みが増加した。これに対して、PVHに投与するとBATにおいてのみ2DGの取り込みが増加した。MT-IIをDMHおよびARCに投与しても2DGの取り込みは増加しなかった。 以上の結果から、VMHのレプチン受容体は、レプチンによる骨格筋、BATおよび心臓でのグルコース取り込みに関与することが明らかとなった。また、その作用は脳内のMCRを介することが示された。さらに、VMHはMT-IIによる骨格筋、BATおよび心臓のグルコース取り込みにも関与すること、ARCのレプチン受容体およびPVHのMCRは褐色脂肪でのグルコースの取り込みに関与することが明らかとなった。以上のことから、内側視床下部の各神経核は、レプチンおよびメラノコルチン受容体作動薬による末梢組織のグルコース取り込み促進作用に異なる調節作用を営むことが、本研究において初めて明らかとなった。
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