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Obesity has become an ongoing global crisis, since it increases the risks of cardiovascular disease, type 2 diabetes, fatty liver, cognitive decline, and some cancers. Adipose tissue is closely associated with the disorder of lipid metabolism. Several efforts have been made toward the modulation of lipid accumulation, but have been hindered by poor efficiency of cellular uptake, low safety, and uncertain effective dosage. Herein, we design an Fe3O4 microsphere-doped composite hydrogel (Fe3O4 microspheres @chitosan/ β -glycerophosphate/collagen), termed as Fe3O4@Gel, as the magnetocaloric agent for magnetic hyperthermia therapy (MHT), aiming to promote lipolysis in white adipocytes. The experimental results show that the obtained Fe3O4@Gel displays a series of advantages, such as fast sol–gel transition, high biocompatibility, and excellent magneto-thermal performance. MHT, which is realized by Fe3O4@Gel subjected to an alternating magnetic field, leads to reduced lipid accumulation, lower triglyceride content, and increased mitochondrial activity in white adipocytes. This work shows that Fe3O4@Gel-mediated MHT can effectively promote lipolysis in white adipocytes in vitro, which provides a potential approach to treat obesity and associated metabolic disorders. [ABSTRACT FROM AUTHOR]

Overweight is an urgent concern of majority of health organizations where it is rising incidence of metabolic syndromes and diseases. Molecular genetics studies on obesity investigated several adipocyte biomarkers with clinical significance. Increased non-blocked synthetic pathways in adipose tissues caused by excess calories consequence overweight and obese populations. Visceral fat adipocytes are strictly associated with metabolic dysfunctions, insulin resistance, heart conditions and others than subcutaneous fats. Adipocytes are the key endocrine like cells that release verities of biological protein adipokines derivatives causing different anti-inflammatory events. Disbalance in the adipokines synthesis and excretions will affect different fat tissues causing complications and pathogenesis related obesity. To combat obesity and its progression, the current study is focusing on the benefits of adipokines as a new trend biomarker for detecting obesity updates. [ABSTRACT FROM AUTHOR]

The marker genes associated with white adipocytes and brown adipocytes have been previously identified; however, these markers have not been updated in several years, and the differentiation process of preadipocytes remains relatively fixed. Consequently, there has been a lack of exploration into alternative differentiation schemes. In this particular study, we present a transcriptional signature specific to brown adipocytes and white adipocytes. Notably, our findings reveal that ZNF497, ZIC1, ZFY, UTY, USP9Y, TXLNGY, TTTY14, TNNT3, TNNT2, TNNT1, TNNI1, TNNC1, TDRD15, SOX11, SLN, SFRP2, PRKY, PAX3KLHL40, PAX3, INKA2-AS1, SOX11, and TDRD15 exhibit high expression levels in brown adipocytes. XIST, HOXA10, PCAT19, HOXA7, PLSCR3, and AVPR1A exhibited high expression levels in white adipocytes, suggesting their potential as novel marker genes for the transition from white to brown adipocytes. Furthermore, our analysis revealed the coordinated activation of several pathways, including the PPAR signaling pathway, focal adhesion, retrograde endocannabinoid signaling, oxidative phosphorylation, PI3K-Akt signaling pathway, and thermogenesis pathways, in brown adipocytes. Moreover, in contrast to prevailing culture techniques, we conducted a comparative analysis of the differentiation protocols for white preadipocytes and brown preadipocytes, revealing that the differentiation outcome remained unaffected by the diverse culture schemes employed. However, the expression levels of certain marker genes in both adipocyte types were found to be altered. This investigation not only identified potential novel marker genes for adipocytes but also examined the impact of different differentiation methods on preadipocyte maturation. Consequently, these findings offer significant insights for further research on the differentiation processes of diverse adipocyte subtypes. [ABSTRACT FROM AUTHOR]

Animals have two types of adipose tissue differing in structure and function: white (WAT) and brown (BAT). Beige adipose tissue (BeAT) is a result of WAT browning, when beige adipocytes appear between white adipocytes in response to exposure to cold, diet or physical activity. BeAT shares morphological and biochemical characteristics with BAT, is thermogenic and dissipates energy in the form of heat, unlike WAT, which is responsible for energy storage. Pigs do not have classic BAT, and modern breeds are sensitive to cold. There is literature information that BeAT has been found in cold-resistant pigs. The aim of the work was to study adipose tissue of piglets of the Kemerovo cold-resistant breed under growing conditions in the cold season and to identify the localization of BeAT. Histological studies have shown two types of adipocytes in subcutaneous fat samples (lateral, backfat and axillary): white, with one large fat droplet, and beige, multilocular. Larger cells were detected in backfat fat (69.36±12.98 µm) compared with lateral (53.25±9.27 µm) and axillary fat (45.94±8.29 µm). Only WAT with a diameter of 35.69±6.96 µm was present in the internal perirenal fat. Raman spectroscopy was used to evaluate the overall fatty acid profile of the tested samples. The main peaks were noted in all samples: 970 cm-1 (=C-H out-of-plane bend), 1266/1272 cm-1 (=C-H symmetrical rock) and 1655 cm-1 (C=C stretching) responsible for unsaturated bonds, and signals at 1297/1301 cm-1 (CH2 twisting), 1430/1460 cm-1 (CH2 symmetrical deformation (scissoring)) and 1735/1746 cm-1 (C=O stretching) corresponding to saturated bonds or ester groups. Internal perirenal fat contained the largest number of saturated fatty acid bonds, subcutaneous axillary fat — the smallest. The average intensity of the peaks was 0.4801010 and 0.639995, respectively. According to the results of gas chromatography, the largest amount of polyunsaturated fatty acids was noted in the subcutaneous fat samples: 20.199 in backfat fat, 21.749 in lateral and 20.436 in axillary fat compared to 18.636 in internal fat. Activation of beige cells in Kemerovo pigs under cold exposure, according to the authors, plays a crucial role in the heat balance, allowing them to tolerate cold without severe shivering. The study of the BeAT formation is of great practical importance for changing energy metabolism and increasing thermogenesis in newborn piglets by genome editing, as well as for improving the quality of pig’s fat.

Previous work has shown that dietary l-arginine (Arg) supplementation reduced white fat mass in obese rats. The present study was conducted with cell models to define direct effects of Arg on energy-substrate oxidation in hepatocytes, skeletal muscle cells, and adipocytes. BNL CL.2 mouse hepatocytes, C2C12 mouse myotubes, and 3T3-L1 mouse adipocytes were treated with different extracellular concentrations of Arg (0, 15, 50, 100 and 400 µM) or 400 µM Arg + 0.5 mM NG-nitro-l-arginine methyl ester (L-NAME; an NOS inhibitor) for 48 h. Increasing Arg concentrations in culture medium dose-dependently enhanced (P < 0.05) the oxidation of glucose and oleic acid to CO2 in all three cell types, lactate release from C2C12 cells, and the incorporation of oleic acid into esterified lipids in BNL CL.2 and 3T3-L1 cells. Arg at 400 µM also stimulated (P < 0.05) the phosphorylation of AMP-activated protein kinase (AMPK) in all three cell types and increased (P < 0.05) NO production in C2C12 and BNL CL.2 cells. The inhibition of NOS by L-NAME moderately reduced (P < 0.05) glucose and oleic acid oxidation, lactate release, and the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in BNL CL.2 cells, but had no effect (P > 0.05) on these variables in C2C12 or 3T3-L1 cells. Collectively, these results indicate that Arg increased AMPK activity and energy-substrate oxidation in BNL CL.2, C2C12, and 3T3-L1 cells through both NO-dependent and NO-independent mechanisms. [ABSTRACT FROM AUTHOR]

Background: Differentiation of Immortalized Human Bone Marrow Mesenchymal Stromal Cells - hTERT (iMSC3) into adipocytes is in vitro model of obesity. In our earlier study, rosiglitazone enhanced adipogenesis particularly the brown adipogenesis of iMSC3. In this study, the transcriptomic profiles of iMSC3 derived adipocytes with and without rosiglitazone were analyzed through mRNA sequencing. Results: A total of 1508 genes were differentially expressed between iMSC3 and the derived adipocytes without rosiglitazone treatment. GO and KEGG enrichment analyses revealed that rosiglitazone regulates PPAR and PI3K-Akt pathways. The constant rosiglitazone treatment enhanced the expression of Fatty Acid Binding Protein 4 (FABP4) which enriched GO terms such as fatty acid binding, lipid droplet, as well as white and brown fat cell differentiation. Moreover, the constant treatment upregulated several lipid droplets (LDs) associated proteins such as PLIN1. Rosiglitazone also activated the receptor complex PTK2B that has essential roles in beige adipocytes thermogenic program. Several uniquely expressed novel regulators of brown adipogenesis were also expressed in adipocytes derived with rosiglitazone: PRDM16, ZBTB16, HOXA4, and KLF15 in addition to other uniquely expressed genes. Conclusions: Rosiglitazone regulated several differentially regulated genes and non-coding RNAs that warrant further investigation about their roles in adipogenesis particularly brown adipogenesis. [ABSTRACT FROM AUTHOR]

The conversion of white adipocytes into brown adipocytes improves their thermogenesis and promotes energy consumption. Epigenetic modifications affect related genes and interfere with energy metabolism, and these are the basis of new ideas for obesity treatment. Neonatal mice show high levels of DNA hypermethylation in white adipose tissue early in life and low levels in brown adipose tissue. Thus, we considered that the regulation of DNA methylation may play a role in the conversion of white adipose to brown. We observed growth indicators, lipid droplets of adipocytes, brown fat specific protein, and miRNA-133a after treatment with 5-Aza-2′-deoxycytidine. The expression of Prdm16 and Ucp-1 in adipocytes was detected after inhibiting miRNA-133a. The results showed a decrease in total lipid droplet formation and an increased expression of the brown fat specific proteins Prdm16 and Ucp-1. This study indicated that 5-Aza-2′-deoxycytidine promotes white adipocyte browning following DNA demethylation, possibly via the modulation of miR-133a and Prdm16. [ABSTRACT FROM AUTHOR]

The prevalence and healthcare burden of obesity and its related metabolic disorders such as type 2 diabetes (T2D) are increasing rapidly. A better understanding of the pathogenesis of these diseases helps to find the therapeutic strategies. Mitochondria and endoplasmic reticulum (ER) are two important organelles involved in the maintenance of intracellular Ca2+ and ROS homeostasis. Their functional defects are thought to participate in the pathogenesis of insulin resistance or T2D. The proper structure and function of the mitochondria-associated ER membranes (MAMs) is required for efficient communication between the ER and mitochondria and defects in MAMs have been shown to play a role in metabolic syndrome and other diseases. However, the detailed mechanism to link MAMs dysfunction and pathogenesis of insulin resistance or T2D remains unclear. In the present study, we demonstrated that the proteins involved in .MAMs structure are upregulated and the formation of MAMs is increased during adipogenic differentiation of 3T3-L1 preadipocytes. Disruption of MAMs by knocking down GRP75, which is responsible for connecting ER and mitochondria, led to the impairment of differentiation and ROS accumulation in 3T3-L1 preadipocytes. Most importantly, the differentiated 3T3-L1 adipocytes with GRP75 knockdown displayed inactivation of insulin signaling pathway upon insulin stimulation. Moreover, GRP75 knockdown impaired thermogenesis and glucose utilization in brown adipocytes, the adipocytes with abundant mitochondria that regulate whole-body energy homeostasis. Taken together, our findings suggest that MAMs formation is essential for promoting mitochondrial function and maintaining a proper redox status to enable the differentiation of preadipocytes and normal functioning such as insulin signaling and thermogenesis in mature adipocytes.

Excess and dysfunctional adipose tissue plays an important role in metabolic diseases, including obesity, atherosclerosis and type 2 diabetes mellitus. In mammals, adipose tissue is categorized into two types: white and brown. Adult brown tissue is mainly composed of beige adipocytes, which dispose of stored energy as heat and have become increasingly popular as a therapeutic target for obesity. However, there is still a paucity of cell models that allow transdifferentiation of mature white adipocytes into beige adipocytes, as seen in vivo. Here, we describe a novel, ceiling culture-based model of human mature white adipocytes, which transdifferentiate into beige adipocytes under the mechanical force and hypoxia of ceiling culture. We also show that the use of rosiglitazone and rapamycin can modulate transdifferentiation, up and down regulating expression of beige adipocyte-specific genes, respectively. Rosiglitazone additionally facilitated the upregulation of fatty acid lipolysis and oxidation genes. Finally, these beige adipocytes derived from dedifferentiated adipocytes exhibited a progenitor-specific phenotype, with higher expression of mature adipocyte-specific genes than adipocyte-derived stem cells. Overall, we report a novel approach to conveniently cultivate beige adipocytes from white adipocytes in vitro, suitable for mechanistic studies of adipose biology and development of cell and drug therapies in the future.

As a central coordinator of physiologic metabolism, adipose tissue has long been appreciated as a highly plastic organ that dynamically responds to environmental cues. Once thought of as a homogenous storage depot, recent advances have enabled deep characterizations of the underlying structure and composition of adipose tissue depots. As the obesity and metabolic disease epidemics continue to accelerate due to modern lifestyles and an aging population, elucidation of the underlying mechanisms that control adipose and systemic homeostasis are of critical importance. Within the past decade, the emergence of deep cell profiling at tissue- and, recently, single-cell level has furthered our understanding of the complex dynamics that contribute to tissue function and their implications in disease development. Although many paradigm-shifting findings may lie ahead, profound advances have been made to forward our understanding of the adipose tissue niche in both health and disease. Now widely accepted as a highly heterogenous organ with major roles in metabolic homeostasis, endocrine signaling, and immune function, the study of adipose tissue dynamics has reached a new frontier. In this review, we will provide a synthesis of the latest advances in adipose tissue biology made possible by the use of single-cell technologies, the impact of epigenetic mechanisms on adipose function, and suggest what next steps will further our understanding of the role that adipose tissue plays in systemic physiology. [ABSTRACT FROM AUTHOR]

Averrhoa bilimbi is a fast-growing tree widely found in countries of tropical Asia. Due to easy accessibility and traditional knowledge, various parts of this plant are adopted as folk medicine and a natural health remedy. Recently, beneficial effects of bilimbi in combating obesity including its potential antihyperlipidemic and hypoglycemic activities have been discovered. This paper reports the successive extraction, partitioning and fractionation of bioactive compounds from the leaf of bilimbi that corresponds to brown adipocyte activation. In this study, the bilimbi crude ethanolic extract underwent bioassay-guided partitioning with increading polarity namely n-hexane ( n-Hex), ethyl acetate (EtOAc), n-butanol ( n-BuOH) and aqueous (H 2O). The n-hexane partition extract exhibited highest brown adipogenesis potential via adipomyocytes differentiation. Further fractionation of this active partition extract yielded 10 fractions. Gas chromatography-mass spectrometry (GC/MS was used to analyse the chemical constituents of active fractions.

As a central coordinator of physiologic metabolism, adipose tissue has long been appreciated as a highly plastic organ that dynamically responds to environmental cues. Once thought of as a homogenous storage depot, recent advances have enabled deep characterizations of the underlying structure and composition of adipose tissue depots. As the obesity and metabolic disease epidemics continue to accelerate due to modern lifestyles and an aging population, elucidation of the underlying mechanisms that control adipose and systemic homeostasis are of critical importance. Within the past decade, the emergence of deep cell profiling at tissue- and, recently, single-cell level has furthered our understanding of the complex dynamics that contribute to tissue function and their implications in disease development. Although many paradigm-shifting findings may lie ahead, profound advances have been made to forward our understanding of the adipose tissue niche in both health and disease. Now widely accepted as a highly heterogenous organ with major roles in metabolic homeostasis, endocrine signaling, and immune function, the study of adipose tissue dynamics has reached a new frontier. In this review, we will provide a synthesis of the latest advances in adipose tissue biology made possible by the use of single-cell technologies, the impact of epigenetic mechanisms on adipose function, and suggest what next steps will further our understanding of the role that adipose tissue plays in systemic physiology.

Averrhoa bilimbi is a fast-growing tree widely found in countries of tropical Asia. Due to easy accessibility and traditional knowledge, various parts of this plant are adopted as folk medicine and a natural health remedy. Recently, beneficial effects of bilimbi in combating obesity including its potential antihyperlipidemic and hypoglycemic activities have been discovered. This paper reports the successive isolation and purification of bioactive compounds from the leaf of bilimbi that corresponds to brown adipocyte activation. Bilimbi ethanolic extract underwent bioassay-guided partitioning and fractionation. The n-hexane partition exhibited highest brown adipogenesis potential via adipomyocytes differentiation. Further isolation of this active partition yielded 10 fractions. Active fractions with the highest brown adipogenesis potential were further evaluated via the adipomyocytes assay. Chemical structures of the constituents were elucidated by gas chromatography-mass spectrometry (GC-MS). Major phytocomponents in the n-hexane partition include hexadecanoic acid, phytol, 9-Octadecenoic acid (Z)- and squalene.

Regulating adipogenesis and lipogenesis in white adipose tissue (WAT) is an efficient strategy to reduce obesity. This study investigates whether garlic scape extract (GSE) has anti-adipogenic and anti-lipogenic effects and which stage of adipogenesis is critical for its effect using 3T3-L1 cells. 3T3-L1 cells that were treated with GSE during adipogenesis and differentiation exhibited reduced peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein a (Cebpa) and Cebpb, acetyl-CoA carboxylase, fatty acid synthase, sterol regulatory element binding protein 1c, diacylglycerol acyltransferase 1, and perilipin 1 genes. When the cells were treated with GSE during postdifferentiation or during preadipocytes, they showed less reduction and no change, respectively. Consistent with this, lipid accumulation was strongly reduced in the cells that were treated during adipogenesis and differentiation and to a lesser extent in the cells that were treated during preadipocytes and postdifferentiation. Phosphorylation on AMP-activated protein kinase (AMPK) and its downstream proteins was increased together with increased carnitine palmitoyl transferase 1α and phosphorylation on hormone-sensitive lipase in the cells that were treated with GSE during differentiation. In summary, GSE reduced intracellular lipid accumulation by suppressing adipogenic and lipogenic genes and proteins by possibly the activation of AMPK signaling pathway during adipocyte differentiation. This result indicates that garlic scape may have the potential to prevent obesity by regulating lipid metabolism in WAT. [ABSTRACT FROM AUTHOR]

The aim of this study was to elucidate mechanisms whereby bile acids exert beneficial metabolic effects, using the Cyp8b1−/- mouse as model. These mice are unable to synthesize cholic acid, resulting in increased synthesis of chenodeoxycholic acid and enlarged bile acid pool. Cyp8b1−/- mice were found to be protected against high-fat diet induced obesity. Bomb calorimetry measurements showed increased faecal energy output in Cyp8b1−/mice. Indirect calorimetry measurements demonstrated increased energy expenditure in Cyp8b1−/- mice. Meal tolerance tests revealed no differences in glucose disposal, but the insulin response was lower in Cyp8b1−/- mice. Intravenous glucose tolerance tests, as well as static incubations of isolated islets, showed no difference between the groups, whereas insulin tolerance tests demonstrated improved insulin sensitivity in Cyp8b1−/- mice. The genes encoding mitochondrial transcription factor A (TFAM) and type 2-iodothyronine deiodinase were upregulated in brown adipose tissue of Cyp8b1/- mice and Western blot analyses showed increased abundance of TFAM, and a trend towards increased abundance of UCP1. The upregulation of TFAM and UCP1 was accompanied by increased mitochondrial density, as shown by transmission electron microscopy. White adipocytes of Cyp8b1−/- mice exhibited increased responsiveness to both catecholamines and insulin in lipolysis experiments and increased insulin-stimulated lipogenesis. In conclusion, increased energy expenditure, mitochondrial density of brown adipocytes and faecal energy output may all contribute to the protection against diet-induced obesity of Cyp8b1−/- mice. Enhanced insulin sensitivity of Cyp8b1−/- mice is accompanied by increased hormonal responsiveness of white adipocytes.

Abstract Aims/Introduction Fat‐specific protein 27 (FSP27) α is the major isoform of FSP27 in white adipose tissue (WAT), and is essential for large unilocular lipid droplet (LD) formation in white adipocytes. In contrast, FSP27β is abundantly expressed in brown adipose tissue (BAT), and plays an important role in small multilocular LD formation. In FSP27 KO mice in which FSP27α and β are both depleted, WAT is characterized by multilocular LD formation, and by increased mitochondrial abundance and energy expenditure, whereas BAT conversely manifests large oligolocular LDs and reduced energy expenditure. Materials and Methods We investigated the effects of autophagy in WAT and BAT of wild type (WT) and FSP27 knockout (KO) mice. In addition, we examined the effects of FSP27α and FSP27β to the induction of autophagy in COS cells. Results Food deprivation induced autophagy in BAT of WT mice, as well as in WAT of FSP27 KO mice, suggesting that enhanced autophagy is characteristic of adipocytes with small multilocular LDs. Pharmacological inhibition of autophagy attenuated the fasting‐induced loss of LD area in adipocytes with small multilocular LDs (BAT of WT mice and WAT of FSP27 KO mice), without affecting that in adipocytes with large unilocular or oligolocular LDs (WAT of WT mice or in BAT of FSP27 KO mice). Overexpression of FSP27α inhibited autophagy induction by serum deprivation in COS cells, whereas that of FSP27β had no such effect. Conclusions The present results thus showed that FSP27α inhibits autophagy and might thereby contribute to the energy‐storage function of WAT.

The conversion of white adipocytes into brown adipocytes improves their thermogenesis and promotes energy consumption. Epigenetic modifications affect related genes and interfere with energy metabolism, and these are the basis of new ideas for obesity treatment. Neonatal mice show high levels of DNA hypermethylation in white adipose tissue early in life and low levels in brown adipose tissue. Thus, we considered that the regulation of DNA methylation may play a role in the conversion of white adipose to brown. We observed growth indicators, lipid droplets of adipocytes, brown fat specific protein, and miRNA-133a after treatment with 5-Aza-2′-deoxycytidine. The expression of Prdm16 and Ucp-1 in adipocytes was detected after inhibiting miRNA-133a. The results showed a decrease in total lipid droplet formation and an increased expression of the brown fat specific proteins Prdm16 and Ucp-1. This study indicated that 5-Aza-2′-deoxycytidine promotes white adipocyte browning following DNA demethylation, possibly via the modulation of miR-133a and Prdm16.

Averrhoa bilimbi is a fast-growing tree widely found in countries of tropical Asia. Due to easy accessibility and traditional knowledge, various parts of this plant are adopted as folk medicine and a natural health remedy. Recently, beneficial effects of bilimbi in combating obesity including its potential antihyperlipidemic and hypoglycemic activities have been discovered. This paper reports the successive isolation and purification of bioactive compounds from the leaf of bilimbi that corresponds to brown adipocyte activation. Bilimbi ethanolic extract underwent bioassay-guided partitioning and fractionation. The n-hexane partition exhibited highest brown adipogenesis potential via adipomyocytes differentiation. Further isolation of this active partition yielded 10 fractions. Active fractions with the highest brown adipogenesis potential were further evaluated via the adipomyocytes assay. Chemical structures of the constituents were elucidated by gas chromatography-mass spectrometry (GC-MS). Major phytocomponents in the n-hexane partition include hexadecanoic acid, phytol, 9-Octadecenoic acid (Z)- and squalene.

Lactate, a metabolite produced when the glycolytic flux exceeds mitochondrial oxidative capacities, is now viewed as a critical regulator of metabolism by acting as both a carbon and electron carrier and a signaling molecule between cells and tissues. In recent years, increasing evidence report its key role in white, beige, and brown adipose tissue biology, and highlights new mechanisms by which lactate participates in the maintenance of whole-body energy homeostasis. Lactate displays a wide range of biological effects in adipose cells not only through its binding to the membrane receptor but also through its transport and the subsequent effect on intracellular metabolism notably on redox balance. This study explores how lactate regulates adipocyte metabolism and plasticity by balancing intracellular redox state and by regulating specific signaling pathways. We also emphasized the contribution of adipose tissues to the regulation of systemic lactate metabolism, their roles in redox homeostasis, and related putative physiopathological repercussions associated with their decline in metabolic diseases and aging.

Lactate, a metabolite produced when the glycolytic flux exceeds mitochondrial oxidative capacities, is now viewed as a critical regulator of metabolism by acting as both a carbon and electron carrier and a signaling molecule between cells and tissues. In recent years, increasing evidence report its key role in white, beige, and brown adipose tissue biology, and highlights new mechanisms by which lactate participates in the maintenance of whole-body energy homeostasis. Lactate displays a wide range of biological effects in adipose cells not only through its binding to the membrane receptor but also through its transport and the subsequent effect on intracellular metabolism notably on redox balance. This study explores how lactate regulates adipocyte metabolism and plasticity by balancing intracellular redox state and by regulating specific signaling pathways. We also emphasized the contribution of adipose tissues to the regulation of systemic lactate metabolism, their roles in redox homeostasis, and related putative physiopathological repercussions associated with their decline in metabolic diseases and aging. [ABSTRACT FROM AUTHOR]

Abstract Background Brown adipocytes are known to promote energy expenditure and limit weight gain to combat obesity. Averrhoa bilimbi, locally called belimbing buluh (DBB), is mainly used as an ethnomedicine in the treatment of metabolic disorders including diabetes mellitus, hypertension and obesity. The present study aims to investigate the browning activity on white adipocytes by A. bilimbi leaf extract and to evaluate the potential mechanisms. Methods Ethanolic leaf extract of A. bilimbi was exposed to Myf5 lineage precursor cells to stimulate adipocyte differentiation. Protein expressions of brown adipocyte markers were determined through high content screening analysis and validated through western blotting. Mito Stress Test assay was conducted to evaluate the cellular oxygen consumption rate upon A. bilimbi treatment. Results A. bilimbi ethanolic leaf extract exhibited an adipogenesis effect similar to a PPARgamma agonist. It also demonstrated brown adipocyte differentiation in myoblastic Myf5-positive precursor cells. Expression of UCP1 and PRDM16 were induced. The basal metabolic rate and respiratory capacity of mitochondria were increased upon A. bilimbi treatment. Conclusions The findings suggest that Averrhoa bilimbi ethanolic leaf extract induces adipocyte browning through PRDM16 activation and enhances mitochondria activity due to UCP1 up-regulation.

Brown and brown‐like adipocytes (BBAs) control thermogenesis and are detected in adult humans. They express UCP1, which transforms energy into heat. They appear as promising cells to fight obesity. Deciphering the molecular mechanisms leading to the browning of human white adipocytes or the whitening of BBAs represents a goal to properly and safely control the pathways involved in these processes. Here, we analyzed how drugs endowed with therapeutic potential affect the differentiation of human adipose progenitor‐cells into BBAs and/or their phenotype. We showed that HIV‐protease inhibitors (PI) reduced UCP1 expression in BBAs modifying their metabolic profile and the mitochondria functionality. Lopinavir (LPV) was more potent than darunavir (DRV), a last PI generation. PPARγ and PGC‐1α were decreased in a PI or cell‐specific manner, thus altering UCP1's constitutive expression. In addition, LPV altered p38 MAPK phosphorylation, blunting then the β‐adrenergic responses. In contrast, low doses of resveratrol stimulated the activatable expression of UCP1 in a p38 MAPK‐dependent manner and counteracted the LPV induced loss of UCP1. This effect was independent of the resveratrol‐induced sirtuin‐1 expression. Altogether our results uncover how drugs impact crucial components of the networks regulating the expression of the thermogenic signature. They provide important information to control the relevant pathways involved in energy expenditure. [ABSTRACT FROM AUTHOR]

The aim of this study was to elucidate mechanisms whereby bile acids exert beneficial metabolic effects, using the Cyp8b1-/- mouse as model. These mice are unable to synthesize cholic acid, resulting in increased synthesis of chenodeoxycholic acid and enlarged bile acid pool. Cyp8b1-/- mice were found to be protected against high-fat diet induced obesity. Bomb calorimetry measurements showed increased faecal energy output in Cyp8b1-/mice. Indirect calorimetry measurements demonstrated increased energy expenditure in Cyp8b1-/- mice. Meal tolerance tests revealed no differences in glucose disposal, but the insulin response was lower in Cyp8b1-/- mice. Intravenous glucose tolerance tests, as well as static incubations of isolated islets, showed no difference between the groups, whereas insulin tolerance tests demonstrated improved insulin sensitivity in Cyp8b1-/- mice. The genes encoding mitochondrial transcription factor A (TFAM) and type 2-iodothyronine deiodinase were upregulated in brown adipose tissue of Cyp8b1-/- mice and Western blot analyses showed increased abundance of TFAM, and a trend towards increased abundance of UCP1. The upregulation of TFAM and UCP1 was accompanied by increased mitochondrial density, as shown by transmission electron microscopy. White adipocytes of Cyp8b1-/- mice exhibited increased responsiveness to both catecholamines and insulin in lipolysis experiments and increased insulin-stimulated lipogenesis. In conclusion, increased energy expenditure, mitochondrial density of brown adipocytes and faecal energy output may all contribute to the protection against diet-induced obesity of Cyp8b1-/- mice. Enhanced insulin sensitivity of Cyp8b1-/- mice is accompanied by increased hormonal responsiveness of white adipocytes. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Fat‐specific protein 27 (FSP27) α is the major isoform of FSP27 in white adipose tissue (WAT), and is essential for large unilocular lipid droplet (LD) formation in white adipocytes. In contrast, FSP27β is abundantly expressed in brown adipose tissue (BAT), and plays an important role in small multilocular LD formation. In FSP27 KO mice in which FSP27α and β are both depleted, WAT is characterized by multilocular LD formation, and by increased mitochondrial abundance and energy expenditure, whereas BAT conversely manifests large oligolocular LDs and reduced energy expenditure. Materials and Methods: We investigated the effects of autophagy in WAT and BAT of wild type (WT) and FSP27 knockout (KO) mice. In addition, we examined the effects of FSP27α and FSP27β to the induction of autophagy in COS cells. Results: Food deprivation induced autophagy in BAT of WT mice, as well as in WAT of FSP27 KO mice, suggesting that enhanced autophagy is characteristic of adipocytes with small multilocular LDs. Pharmacological inhibition of autophagy attenuated the fasting‐induced loss of LD area in adipocytes with small multilocular LDs (BAT of WT mice and WAT of FSP27 KO mice), without affecting that in adipocytes with large unilocular or oligolocular LDs (WAT of WT mice or in BAT of FSP27 KO mice). Overexpression of FSP27α inhibited autophagy induction by serum deprivation in COS cells, whereas that of FSP27β had no such effect. Conclusions: The present results thus showed that FSP27α inhibits autophagy and might thereby contribute to the energy‐storage function of WAT. [ABSTRACT FROM AUTHOR]

Obesity has become an ongoing global crisis, since it increases the risks of cardiovascular disease, type 2 diabetes, fatty liver, cognitive decline, and some cancers. Adipose tissue is closely associated with the disorder of lipid metabolism. Several efforts have been made toward the modulation of lipid accumulation, but have been hindered by poor efficiency of cellular uptake, low safety, and uncertain effective dosage. Herein, we design an Fe 3 O 4 microsphere-doped composite hydrogel (Fe 3 O 4 microspheres @chitosan/ β -glycerophosphate/collagen), termed as Fe 3 O 4 @Gel, as the magnetocaloric agent for magnetic hyperthermia therapy (MHT), aiming to promote lipolysis in white adipocytes. The experimental results show that the obtained Fe 3 O 4 @Gel displays a series of advantages, such as fast sol-gel transition, high biocompatibility, and excellent magneto-thermal performance. MHT, which is realized by Fe 3 O 4 @Gel subjected to an alternating magnetic field, leads to reduced lipid accumulation, lower triglyceride content, and increased mitochondrial activity in white adipocytes. This work shows that Fe 3 O 4 @Gel-mediated MHT can effectively promote lipolysis in white adipocytes in vitro , which provides a potential approach to treat obesity and associated metabolic disorders., (© 2024 IOP Publishing Ltd.)

Mitochondrial biogenesis is a key feature of energy expenditure and organismal energy balance. Genetic deletion of PARP1 or PARP2 was shown to induce mitochondrial biogenesis and energy expenditure. In line with that, PARP inhibitors were shown to induce energy expenditure in skeletal muscle. We aimed to investigate whether pharmacological inhibition of PARPs induces brown or beige adipocyte differentiation. SVF fraction of human pericardial adipose tissue was isolated and human adipose-derived mesenchymal stem cells (hADMSCs) were differentiated to white and beige adipocytes. A subset of hADMSCs were differentiated to white adipocytes in the presence of Olaparib, a potent PARP inhibitor currently in clinical use, to induce browning. Olaparib induced morphological changes (smaller lipid droplets) in white adipocytes that is a feature of brown/beige adipocytes. Furthermore, Olaparib induced mitochondrial biogenesis in white adipocytes and enhanced UCP1 expression. We showed that Olaparib treatment inhibited nuclear and cytosolic PAR formation, induced NAD+/NADH ratio and consequently boosted SIRT1 and AMPK activity and the downstream transcriptional program leading to increases in OXPHOS. Olaparib treatment did not induce the expression of beige adipocyte markers in white adipocytes, suggesting the formation of brown or brown-like adipocytes. PARP1, PARP2 and tankyrases are key players in the formation of white adipose tissue. Hereby, we show that PARP inhibition induces the transdifferentiation of white adipocytes to brown-like adipocytes suggesting that PARP activity could be a determinant of the differentiation of these adipocyte lineages. [ABSTRACT FROM AUTHOR]

The organisms of mammals are composed of organs cooperating as systems that are organized to perform functions which allow the survival of the individual and maintenance of the species. Thus, to reach the main goals of these functions we need systems that ensure nutrient uptake and distribution, thermogenesis, oxygen uptake and distribution, the discharge of toxic internal by-products, the defense from internal and external pathogens, gamete fertilization, and the fine-tuning of the activity of all the tissues composing the organs. Most of these activities also require interactions with the internal and external environment. The latter function is served by the nervous system and the others by the cardiovascular, respiratory, excretory, immune, reproductive and endocrine systems. Nutrient intake and distribution and thermoregulation are realized by the collaborative work of the adipose and the digestive organs. In this review I will outline data on adipose tissue anatomy and function which have been collected during the past 40 years. They provide a convergent body of evidence toward a new concept regarding the collaborative work between the adipose organ and the organs of the gastrointestinal tract, which constitute a system ensuring nutrient search, intake and distribution to the organism. Furthermore, the same system also seems to enable nutrient distribution to the offspring to ensure not only short-term but also long-term homeostasis. Arrows pointing to the brain indicate converging hormonal influences inducing a behavior that ensures survival (short-term homeostasis). Arrows pointing toward one another indicate reciprocal functional influences directed at ensuring functional collaboration to absorb (digestive organs) and store nutrients, whose aim is to support the organism (white adipocytes) and the offspring (pink adipocytes). The latter function ensures long-term homeostasis (species survival). Divergent arrows indicate system collaboration for thermogenesis, which also plays a role in meal interruption, especially in newborns. Image 1 [ABSTRACT FROM AUTHOR]

To explore the effect of histone H3K27me3 methyltransferase Ezh2 on the differentiation of white, brown and beige adipocytes in mice. Ezh2 whole body knockout mice (Ezh2flox/floxCAGcre) were constructed and induced by intraperitoneal injection of tamoxifen at the age of 6 weeks. The same litter, same sex and same genotype pseudoinduction mice (intraperitoneal injection of corn oil) were used as control. After induction completion, the morphology of adipocytes was observed under light microscope, and the expression of H3K27me3, Ezh2 and Ucp1 in adipose tissue was detected by Western Blot method. Realtime PCR was used to detect the expression of adipose differentiation-related genes (Ppar酌, Adipoq and Fabp4), brown adipocyte markers (Ucp1, Cidea and Prdm16) and beige adipocyte markers (CD137, Tmem26 and Tbx1) in different parts of adipose tissues. The cold tolerance of knockout mice was tested, and obesity was induced by high fat diet. The weight gain, glucose tolerance and insulin sensitivity of mice were observed after induction. The protein content of Ezh2 and H3K27me3 in Ezh2 knockout mice decreased, the lipid droplets of brown adipocytes in interscapular region were significantly smaller than those in control group, and the gene and protein expression of Ucp1 were significantly higher than those in control group (P<0.05); the differentiation of white adipocytes in Ezh2 knockout mice was poor, the differentiation of beige adipocytes increased, and the expression of Ucp1 and Tbx1 genes in beige adipocytes increased(P<0.05). Ezh2 knockout mice were better able to tolerate cold stimulation and resist obesity and insulin resistance induced by a high-fat diet. Ezh2 promotes the differentiation of white adipocytes and inhibits the differentiation of brown and beige adipocytes in vivo. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a complex disorder that is driven by inflammation and metabolic imbalances, resulting in extreme weight loss. Adipose tissue, a main player in cancer cachexia, is an essential metabolic and secretory organ consisting of both white adipose tissue (WAT) and brown adipose tissue. Its secretory products, including adipokines and cytokines, affect a wide variety of central and peripheral organs, such as the skeletal muscle, brain, pancreas, and liver. Therefore, a combination of metabolic alterations, and systemic inflammation dysregulation of both anti‐inflammatory and proinflammatory modulators contribute toward adipose tissue wasting in cancer cachexia. Growing evidence suggests that, during cancer cachexia, WAT undergoes a browning process, resulting in increased lipid mobilization and energy expenditure. In this review, we have summarized the characteristics of cancer cachexia and WAT browning. Furthermore, this review describes how adipose tissue becomes inflamed in cancer, shedding light on the combinatorial action of multiple secreted macromolecules, cytokines, hormones, and tumor mediators on adipose tissue dysfunction. We also highlight the inflammatory responses, energy utilization defects, and molecular mechanisms underlying the WAT dysfunction and browning in cancer cachexia. Further, the actual mechanisms behind the loss of adipose tissue are unknown, but have been attributed to increased adipocyte lipolysis, systemic inflammation, and apoptosis or reduced lipogenesis. The understanding of adipose tissue dysfunction in cancer cachexia will hopefully promote the development of new therapeutic approaches to prevent or treat this wasting syndrome. (a) The role of the adipose tissue and white adipose tissue (WAT) dysfunction in cancer cachexia, (b) the molecular mechanisms that lead to the WAT wasting and the transition to brown adipose tissue (BAT), (c) the importance of the crosstalk between fat and skeletal muscle in the pathogenesis of cancer cachexia and the role of several myokines, adipokines, and other mediators as drivers of cachexia are examined in this study. [ABSTRACT FROM AUTHOR]

Adipocytes play an essential role in maintaining energy homeostasis in mammals. The primary function of white adipose tissue (WAT) is to store energy; for brown adipose tissue (BAT), primary function is to release fats in the form of heat. Dysfunctional or excess WAT can induce metabolic disorders such as dyslipidemia, obesity, and diabetes. Preadipocytes or adipocytes from WAT possess sufficient plasticity as they can transdifferentiate into brown-like beige adipocytes. Studies in both humans and rodents showed that brown and beige adipocytes could improve metabolic health and protect from metabolic disorders. Brown fat requires activation via exposure to cold or β-adrenergic receptor (β-AR) agonists to protect from hypothermia. Considering the fact that the usage of β-AR agonists is still in question with their associated side effects, selective induction of WAT browning is therapeutically important instead of activating of BAT. Hence, a better understanding of the molecular mechanisms governing white adipocyte browning is vital. At the same time, it is also essential to understand the factors that define white adipocyte identity and inhibit white adipocyte browning. This literature review is a comprehensive and focused update on the epigenetic regulators crucial for differentiation and browning of white adipocytes.

Human adipose-derived stem cells (hASCs) can be isolated from fat tissue and have attracted interest for their potential therapeutic applications in metabolic disease. hASCs can be induced to undergo adipogenic differentiation in vitro by exposure to chemical agents or inductive growth factors. We investigated the effects and mechanism of differentiating hASC-derived white adipocytes into functional beige and brown adipocytes with isoliquiritigenin (ILG) treatment. Here, we showed that hASC-derived white adipocytes could promote brown adipogenesis by expressing both uncoupling protein 1 (UCP1) and PR/SET Domain 16 (PRDM16) following low-dose ILG treatments. ILG treatment of white adipocytes enhanced the expression of brown fat-specific markers, while the expression levels of c-Jun N-terminal kinase (JNK) signaling pathway proteins were downregulated. Furthermore, we showed that the inhibition of JNK phosphorylation contributed to white adipocyte differentiation into beige adipocytes, which was validated by the use of SP600125. We identified distinct regulatory effects of ILG dose responses and suggested that low-dose ILG induced the beige adipocyte potential of hASCs via JNK inhibition.

For more than three decades, numerous studies have demonstrated the function of p53 in cell cycle, cellular senescence, autophagy, apoptosis, and metabolism. Among diverse functions, the essential role of p53 is to maintain cellular homeostatic response to stress by regulating proliferation and apoptosis. Recently, adipocytes have been studied with increasing intensity owing to the increased prevalence of metabolic diseases posing a serious public health concern and because metabolic dysfunction can directly induce tumorigenesis. The prevalence of metabolic diseases has steadily increased worldwide, and a growing interest in these diseases has led to the focus on the role of p53 in metabolism and adipocyte differentiation with or without metabolic stress. However, our collective understanding of the direct role of p53 in adipocyte differentiation and function remains insufficient. Therefore, this review focuses on the newly discovered roles of p53 in adipocyte differentiation and function.

Aging is associated with progressive white adipose tissue (WAT) enlargement initiated early in life, but the molecular mechanisms involved remain unknown. Here we show that mitochondrial complex IV (CIV) activity and assembly are already repressed in white adipocytes of middle-aged mice and involve a HIF1A-dependent decline of essential CIV components such as COX5B. At the molecular level, HIF1A binds to the Cox5b proximal promoter and represses its expression. Silencing of Cox5b decreased fatty acid oxidation and promoted intracellular lipid accumulation. Moreover, local in vivo Cox5b silencing in WAT of young mice increased the size of adipocytes, whereas restoration of COX5B expression in aging mice counteracted adipocyte enlargement. An age-dependent reduction in COX5B gene expression was also found in human visceral adipose tissue. Collectively, our findings establish a pivotal role for CIV dysfunction in progressive white adipocyte enlargement during aging, which can be restored to alleviate age-dependent WAT expansion.

The article focuses on the translational value of morphology in the context of innovative therapies for diabetes, obesity, osteoporosis, and breast cancer, with a particular emphasis on the role of white and brown adipose tissues, transdifferentiation of adipocytes, and the link between obesity-related inflammation and type 2 diabetes, offering potential therapeutic strategies for these conditions.

Ca 2+ impacts a large array of cellular processes in every known cell type. In the white adipocyte, Ca 2+ is involved in regulation of metabolic processes such as lipolysis, glucose uptake and hormone secretion. Although the importance of Ca 2+ in control of white adipocyte function is clear, knowledge is still lacking regarding the control of dynamic Ca 2+ alterations within adipocytes and mechanisms inducing intracellular Ca 2+ changes remain elusive. Own work has recently demonstrated the existence of store-operated Ca 2+ entry (SOCE) in lipid filled adipocytes. We defined stromal interaction molecule 1 (STIM1) and the calcium release-activated calcium channel protein 1 (ORAI1) as the key players involved in this process and we showed that the transient receptor potential (TRP) channel TRPC1 contributed to SOCE. Here we have aimed to further characterised SOCE in the white adipocyte by use of single cell whole-cell patch clamp recordings. The electrophysiological measurements show the existence of a seemingly constitutively active current that is inhibited by known store-operated Ca 2+ channel (SOCC) blockers. We demonstrate that the mechanical force applied to the plasma membrane upon patching leads to an elevation of the cytoplasmic Ca 2+ concentration and that this elevation can be reversed by SOCC antagonists. We conclude that a mechanically activated current with properties similar to TRPC1 is present in white adipocytes. Activation of TRPC1 by membrane tension/stretch may be specifically important for the function of this cell type, since adipocytes can rapidly increase or decrease in size. [ABSTRACT FROM AUTHOR]

Lipolysis of stored triglycerides is stimulated via β-adrenergic receptor (β-AR)/3′,5′-cyclic adenosine monophosphate (cAMP) signaling and inhibited via phosphodiesterases (PDEs). In type 2 diabetes, a dysregulation in the storage/lipolysis of triglycerides leads to lipotoxicity. Here, we hypothesize that white adipocytes regulate their lipolytic responses via the formation of subcellular cAMP microdomains. To test this, we investigate real-time cAMP/PDE dynamics at the single-cell level in human white adipocytes with a highly sensitive florescent biosensor and uncover the presence of several receptor-associated cAMP microdomains where cAMP signals are compartmentalized to differentially regulate lipolysis. In insulin resistance, we also detect cAMP microdomain dysregulation mechanisms that promote lipotoxicity, but regulation can be restored by the anti-diabetic drug metformin. Therefore, we present a powerful live-cell imaging technique capable of resolving disease-driven alterations in cAMP/PDE signaling at the subcellular level and provide evidence to support the therapeutic potential of targeting these microdomains. [Display omitted] • Human white adipocytes exhibit β-AR/cAMP microdomains that facilitate regulation of lipolysis • In healthy adipocytes, lipolysis is predominantly mediated via β 1 -AR signaling • Insulin-resistant adipocytes switch to β 3 -AR-induced lipolysis due to loss of PDE3 coupling • PDE3 is essential for metformin to exert its anti-lipolytic action De Jong et al. apply state-of-the-art live-cell imaging in human white adipocytes, uncovering the presence of cAMP microdomains at the subcellular level that are required to regulate distinct β-AR subtype control of lipolysis. They identify mechanisms of pro-lipolytic remodeling within these microdomains in insulin-resistant adipocytes. [ABSTRACT FROM AUTHOR]

Visceral adiposity confers significant risk for developing metabolic disease in obesity whereas preferential expansion of subcutaneous white adipose tissue (WAT) appears protective. Unlike subcutaneous WAT, visceral WAT is resistant to adopting a protective thermogenic phenotype characterized by the accumulation of Ucp1+ beige/BRITE adipocytes (termed ‘browning’). In this study, we investigated the physiological consequences of browning murine visceral WAT by selective genetic ablation of Zfp423, a transcriptional suppressor of the adipocyte thermogenic program. Zfp423 deletion in fetal visceral adipose precursors (Zfp423loxP/loxP; Wt1-Cre), or adult visceral white adipose precursors (PdgfrbrtTA; TRE-Cre; Zfp423loxP/loxP), results in the accumulation of beige-like thermogenic adipocytes within multiple visceral adipose depots. Thermogenic visceral WAT improves cold tolerance and prevents and reverses insulin resistance in obesity. These data indicate that beneficial visceral WAT browning can be engineered by directing visceral white adipocyte precursors to a thermogenic adipocyte fate, and suggest a novel strategy to combat insulin resistance in obesity.

Recently, pharmacological activation of brown fat and induction of white fat browning (beiging) have been considered promising strategies to treat obesity. To search for natural products that could stimulate the process of browning in adipocytes, we evaluated the activity of trans-cinnamic acid (tCA), a class of cinnamon from the bark of Cinnamomum cassia, by determining genetic expression using real time reverse transcription polymerase chain reaction (RT-PCR) and protein expression by immunoblot analysis for thermogenic and fat metabolizing markers. In our study tCA induced brown like-phenotype in 3T3-L1 white adipocytes and activated HIB1B brown adipocytes. tCA increased protein content of brown-fat-specific markers (UCP1, PRDM16, and PGC-1α) and expression levels of beige-fat-specific genes (Cd137, Cidea, Cited1, Tbx1, and Tmen26) in 3T3-L1 white adipocytes, as well as brown-fat-specific genes (Lhx8, Ppargc1, Prdm16, Ucp1, and Zic1) in HIB1B brown adipocytes. Furthermore, tCA reduced expression of key adipogenic transcription factors C/EBPα and PPARγ in white adipocytes, but enhanced their expressions in brown adipocytes. In addition, tCA upregulates lipid catabolism. Moreover, mechanistic study revealed that tCA induced browning in white adipocytes by activating the β3-AR and AMPK signaling pathways. tCA can induce browning, increase fat oxidation, reduce adipogenesis and lipogenesis in 3T3-L1 adipocytes, and activate HIB1B adipocytes, suggesting its potential to treat obesity.