Beige-like Adipocytes Research Articles

Regulation of mitotic clonal expansion and thermogenic pathway are involved in the antiadipogenic effects of cyanidin-3-O-glucoside.

Introduction: Obesity is a metabolic disease with an increase both in cell size (hypertrophy) and in cell number (hyperplasia) following differentiation of new adipocytes. Adipogenesis is a well-orchestrated program in which mitotic clonal expansion (MCE) occurs in the early step followed by the late terminal differentiation one. Methods: Aim of the study was to evaluate the in vitro effects of cyanidin-3-O-glucoside (C3G), an anthocyanin present in many fruits and vegetables, in the early or late phase of 3T3-L1 preadipocytes differentiation. Results: C3G exposure in the early phase of adipogenesis process induced a more marked reduction of CCAAT/enhancer-binding protein-β (C/EBPβ), peroxisome proliferator-activated receptor γ (PPAR-ɣ) and fatty acid synthase (Fasn) expression than late phase exposure and these effects were associated to a reduced MCE with cell cycle arrest at G0/G1 phase via p21 expression. Furthermore, C3G exposure during the early phase activated AMP-activated protein kinase (AMPK) pathway better than in the late phase promoting the enhancement of beige-like adipocytes. In fact, C3G induced thermogenic biomarkers uncoupling protein-1 (Ucp1) and peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (Pgc1) and these effects were more evident during early phase exposure. Conclusion: Our data demonstrate that C3G reduces the terminal adipogenic process affecting the early phase of differentiation and inducing a thermogenic program.

Induction of beige-like adipocyte markers and functions in 3T3-L1 cells by Clk1 and PKCβII inhibitory molecules.

Excessive dietary intake of fat results in its storage in white adipose tissue (WAT). Energy expenditure through lipid oxidation occurs in brown adipose tissue (BAT). Certain WAT depots can undergo a change termed beiging where markers that BAT express are induced. Little is known about signalling pathways inducing beiging. Here, inhibition of a signalling pathway regulating alternative pre‐mRNA splicing is involved in adipocyte beiging. Clk1/2/4 kinases regulate splicing by phosphorylating factors that process pre‐mRNA. Clk1 inhibition by TG003 results in beige‐like adipocytes highly expressing PGC1α and UCP1. SiRNA for Clk1, 2 and 4, demonstrated that Clk1 depletion increased UCP1 and PGC1α expression, whereas Clk2/4 siRNA did not. TG003‐treated adipocytes contained fewer lipid droplets, are smaller, and contain more mitochondria, resulting in proton leak increases. Additionally, inhibition of PKCβII activity, a splice variant regulated by Clk1, increased beiging. PGC1α is a substrate for both Clk1 and PKCβII kinases, and we surmised that inhibition of PGC1α phosphorylation resulted in beiging of adipocytes. We show that TG003 binds Clk1 more than Clk2/4 through direct binding, and PGC1α binds to Clk1 at a site close to TG003. Furthermore, we show that TG003 is highly specific for Clk1 across hundreds of kinases in our activity screen. Hence, Clk1 inhibition becomes a target for induction of beige adipocytes.

Beiging Modulates Inflammatory Adipogenesis in Salt-Treated and MEK6-Transfected Adipocytes.

To investigate whether the beiging process changes the interactive effects of salt and MEK6 gene on inflammatory adipogenesis, the salt treatment (NaCl 50 mM) and MEK6 transfection of Tg(+/+) cells were performed with white adipocytes (WAT) and beige-like-adipocytes (BLA). BLA induced by T3 were confirmed by UCP-1 expression and the MEK6 protein was 3.5 times higher in MEK6 transfected WAT than the control. The adipogenic genes, PPAR-γ and C/EBP-α, were 1.5 times more highly expressed in the salt-treated groups than the non-salt-treated groups, and adipogenesis was greatly increased in Tg(+/+) WAT compared to non-transfected Tg(−/−). The adipogenesis induced by salt treatment and MEK6 transfection was significantly reduced in BLA. The inflammatory adipocytokines, TNF-α, IL-1β, and IL-6, were increased in the salt-treated Tg(+/+) WAT, but an anti-inflammation biomarker, the adiponectin/leptin ratio, was reduced in Tg(+/+), to tenth of that in Tg(−/−). However, the production of adipocytokines in WAT was strongly weakened in BLA, although a combination of salt and MEK6 transfection had the most significant effects on inflammation in both WAT and BLA. Oxygen consumption in mitochondria was maximized in salt-treated and MEK6 transfected WAT, but it was decreased by 50% in BLA. In conclusion, beiging controls the synergistic effects of salt and MEK6 on adipogenesis, inflammation, and energy expenditure.

Compromised browning plasticity of primary subcutaneous adipocytes derived from overweight Chinese adults

PurposePeople with obesity have a compromised browning capacity of adipose tissue when faced with sympathetic stimuli. This study aimed to determine whether norepinephrine treatment can enhance the induction of precursor cells from human white adipose tissue to differentiate into adipocytes that express key markers of beige adipocytes, and if there is a difference in this capacity between normal weight and overweight individuals.MethodsStromal vascular cells derived from subcutaneous white adipose tissue of normal weight and overweight groups were induced to differentiation, with or without norepinephrine, into adipocytes. Oxygen consumption rate, lipolysis, the expression of uncoupling protein 1 and other thermogenic genes were compared between different adiposity and treatment groups.ResultsPeroxisome proliferator activated receptor γ- coactivator-1 alpha (PGC-1 α) and uncoupling protein 1 gene expression increased significantly in the normal weight group, but not in the overweight group, with norepinephrine treatment. The increments of lipolysis and oxygen consumption rate were also higher in adipocytes from the normal weight group with norepinephrine treatment, as compared with those of the overweight group. PR domain containing protein 16 (PRDM 16) gene expression was higher in the normal weight group compared with that in the overweight group, while there were no significant changes found with norepinephrine treatment in either the normal weight or overweight group.ConclusionsAdipogenic precursor cells derived from overweight individuals were less prone to differentiate into beige-like adipocytes when facing sympathetic stimuli than normal weight ones, resulting in the compromised sympathetic-induced browning capacity in subcutaneous white adipose tissue in overweight individuals, which occurred before the onset of overt obesity.

The Effects of C3G and D3G Anthocyanin-Rich Black Soybean on Energy Metabolism in Beige-like Adipocytes.

Various mechanisms of obesity prevention have been identified; however, the roles of brown or beige fat as regulators of the energy balance are unclear. The effects of anthocyanin-rich black soybean, Glycine max (L.) Merr., testa (ABS) extracts on the energy balance were investigated by comparing beige-like adipocytes (BLA) and white adipocytes (WAT). ABS extracts reduced peroxisome proliferator-activated receptor gamma protein expression and triglyceride accumulation in WAT and BLA without inducing nuclear damage. The biomarkers of fat degradation (phospho-AMPKα and ATGL) or glycerol secretion in the medium and β-oxidation of fatty acids (CPT2) in the ABS-treated BLA were increased compared to those in WAT. ABS extracts significantly increased the expression of thermogenesis markers (UCP1 and CIDEA) and biomarkers related to mitochondrial activation (cytochrome c and NRF1) in BLA. In the primary cell culture of brown adipocytes (BAT) from rats fed ABS, the expression levels of PGC1-α, cytochrome c, and UCP1 proteins were increased compared to those in BAT from nonfed rats. A reduction in the NAD/NADH ratio was consistently associated with an increase in the oxygen consumption rate and basal/maximal respiration rate in ABS-treated BLA. Anthocyanins promote beiging in the body, contribute to the prevention of obesity, and are potentially useful functional materials.

Purified Gymnemic Acids from Gymnema inodorum Tea Inhibit 3T3-L1 Cell Differentiation into Adipocytes.

Gymnema inodorum (GI) is an indigenous medicinal plant and functional food in Thailand that has recently helped to reduce plasma glucose levels in healthy humans. It is renowned for the medicinal properties of gymnemic acid and its ability to suppress glucose absorption. However, the effects of gymnemic acids on adipogenesis that contribute to the accumulation of adipose tissues associated with obesity remain unknown. The present study aimed to determine the effects of gymnemic acids derived from GI tea on adipogenesis. We purified and identified GiA-7 and stephanosides C and B from GI tea that inhibited adipocyte differentiation in 3T3-L1 cells. These compounds also suppressed the expression of peroxisome proliferator-activated receptor gamma (Pparγ)-dependent genes, indicating that they inhibit lipid accumulation and the early stage of 3T3-L1 preadipocyte differentiation. Only GiA-7 induced the expression of uncoupling protein 1 (Ucp1) and pparγ coactivator 1 alpha (Pgc1α), suggesting that GiA-7 induces mitochondrial activity and beige-like adipocytes. This is the first finding of stephanosides C and B in Gymnema inodorum. Our results suggested that GiA-7 and stephanosides C and B from GI tea could help to prevent obesity.

1966-P: Induction of Beige Adipocyte Markers in 3T3-L1 Cells by Clk1 and PKCbetaII Inhibitors

Excessive dietary intake of fat results in its storage in white adipose tissue (WAT), whereas energy expenditure by lipid oxidation occurs in brown adipose tissue. A third type of fat is beige, and it is observed in WAT depots. Certain WAT can undergo beiging. Numerous factors have roles in beiging. However, little is known about the signaling pathways inducing pre-adipocytes to become beige adipocytes. Known participants are activators of PPARgamma, PGC1alpha, and PRDM16 that induce UCP1-containing mitochondria upon cold exposure. We found a signaling pathway that regulates alternative pre-mRNA splicing is also involved in beiging when it is inhibited. Clk1 kinase phosphorylates proteins with serine and arginine rich domains. Clk1 inhibition by 50 nM TG003 during differentiation of 3T3-L1 adipocytes (post day 3) results in beige-like adipocytes demonstrating increased PGC1alpha and UCP1 mRNA and proteins. TG003 inhibits Clk1, 2, and 4. We demonstrate using siRNA for Clk1, 2, and 4, that Clk1 inhibition increased UCP1, PGC1alpha and PPARgamma mRNA whereas Clk1 and 4 siRNA did not. TG003-treated adipocytes contained fewer lipid droplets and more mitochondria which resulted in significant proton leak. In addition to TG003, CG53353, a PKCbetaII inhibitor, also increased mitochondria number and decreased lipid droplet size. PKCbetaII is an mRNA splice variant regulated by Clk1. Others previously showed that TG003 treatment of mice on high fat diets (HFD) resulted in weight loss, and PKCbeta(I+II) knockout mice did not gain weight on HFD. Using bioinformatics, we determined that PGC1alpha was a substrate for Clk1 and PKCbetaII. PGC1alpha was shown to be phosphorylated by Clk2 previously. Hence, we believe that inhibition of Clk1 and PKCbetaII phosphorylation of PGC1alpha results in upregulation of UCP1 expression in adipocytes. This newly identified pathway supports a role for Clk1 and PKCbetaII as potential targets for inhibition to treat weight loss in obesity. Disclosure A. Patel: None. T. Dobbins: None. S. Kong: None. N.A. Patel: None. D.R. Cooper: None. Funding U.S. Department of Veterans Affairs (5|01BX003689)

Expression and Secretion of an Atrial Natriuretic Peptide in Beige-Like 3T3-L1 Adipocytes.

The browning of white adipose tissue (beige adipocytes) stimulates energy expenditure. Omega-3 fatty acids have been shown to induce thermogenic action in adipocytes via G-protein coupled receptor 120 (GPR120). Atrial natriuretic peptide (ANP) is a peptide hormone that plays the role of maintaining normal blood pressure in kidneys to inhibit Na+ reuptake. Recently, ANP was found to induce adipocyte browning by binding to NPR1, an ANP receptor. However, the expression of ANP in adipocytes has not yet been studied. Therefore, in this study, we investigate the expression of ANP in beige-like adipocytes induced by docosahexaenoic acids (DHA), T3, or a PPAR agonist, rosiglitazone. First, we found that brown adipocyte-specific genes were upregulated in beige-like adipocytes. DHA promoted ANP expression in beige-like cells, whereas DHA-induced ANP expression was abolished by GPR120 knockout. ANP secretion of beige-like adipocytes was increased via PKC/ERK1/2 signaling in the GPR120 pathway. Furthermore, ANP secreted from beige-like adipocytes acted on HEK-293 cells, the recipient cells, leading to increased cGMP activity. After the NPR1 knockdown of HEK-293 cells, cGMP activity was not changed. Taken together, our findings indicate that beige-like adipocytes induce ANP secretion, which may contribute to improving obesity-associated metabolic disease.

Catechins and Caffeine Promote Lipid Metabolism and Heat Production Through the Transformation of Differentiated 3T3-L1 Adipocytes from White to Beige Adipocytes.

To elucidate effects of catechins and caffeine on lipid metabolism in adipocytes and identify the mechanism of action, differentiated 3T3-L1 adipocytes were incubated in culture media containing catechins at 1, 2.5, 5, and 10 µg/mL and caffeine at 50 and 100 µg/mL, singly or in combination, for 8 days. Intracellular lipid accumulation and glycerol-3-phosphate dehydrogenase activity were strongly suppressed by catechins and caffeine combination treatment. The mRNA expression of PPARɤ, GLUT4, HSL, UCP-1, and TMEM26 were significantly increased in the combined groups. These findings suggest that the combined treatment inhibited lipid synthesis and improved lipid metabolism in adipocytes. Moreover, it was indicated that the differentiated 3T3-L1 adipocytes could be transformed from white adipocytes to beige-like adipocytes by catechins and caffeine, and accordingly that this transformation could promote calorigenic action. PRACTICAL APPLICATION: In this study, we revealed that the combined treatment of catechins and caffeine inhibited lipid synthesis and improved lipid metabolism in adipocytes. Moreover, the treatment may contribute to the transforming from white adipocytes to beige-like adipocytes, which could strongly promote calorigenic action.

Non-invasive in vivo imaging of UCP1 expression in live mice via near-infrared fluorescent protein iRFP720.

Uncoupling protein 1 (UCP1) is a mitochondrial protein that is expressed in both brown and beige adipocytes. UCP1 uncouples the mitochondrial electron transport chain from ATP synthesis to produce heat via non-shivering thermogenesis. Due to their ability to dissipate energy as heat and ameliorate metabolic disorders, UCP1-expressing adipocytes are considered as a potential target for anti-obesity treatment. To monitor the expression of UCP1 in live mice in a non-invasive manner, we generated the Ucp1-iRFP720 knock-in (Ucp1-iRFP720 KI) mice, in which the gene encoding a near-infrared fluorescent protein iRFP720 is inserted into the Ucp1 gene locus. Using the heterozygous Ucp1-iRFP720 KI mice, we observed robust iRFP fluorescence in the interscapular region where brown adipose tissue is located. Moreover, the iRFP fluorescence was clearly observable in inguinal white adipose tissues in live mice administered with β3-adrenergic receptor agonist CL316,243. We also found that the homozygous Ucp1-iRFP720 KI mice, which are deficient in UCP1, displayed prominent iRFP fluorescence in the inguinal regions at the standard housing temperature. Consistent with this, the mice exhibited expanded populations of beige-like adipocytes in inguinal white adipose tissue, in which the Ucp1 promoter was dramatically activated. Thus, the Ucp1-iRFP720 KI mice provide a convenient model for non-invasive in vivo imaging of UCP1 expression in both brown and beige adipocytes in live mice.

The Beige Adipocyte as a Therapy for Metabolic Diseases.

Adipose tissue is traditionally categorized into white and brown relating to their function and morphology. The classical white adipose tissue builds up energy in the form of triglycerides and is useful for preventing fatigue during periods of low caloric intake and the brown adipose tissue more energetically active, with a greater number of mitochondria and energy production in the form of heat. Since adult humans possess significant amounts of active brown fat depots and its mass inversely correlates with adiposity, brown fat might play an important role in human obesity and energy homeostasis. New evidence suggests two types of thermogenic adipocytes with distinct developmental and anatomical features: classical brown adipocytes and beige adipocytes. Beige adipocyte has recently attracted special interest because of its ability to dissipate energy and the possible ability to differentiate themselves from white adipocytes. The presence of brown and beige adipocyte in human adults has acquired attention as a possible therapeutic intervention for metabolic diseases. Importantly, adult human brown appears to be mainly composed of beige-like adipocytes, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, such as atherosclerosis, arterial hypertension and diabetes mellitus type 2. Because many epigenetics changes can affect beige adipocyte differentiation from adipose progenitor cells, the knowledge of the circumstances that affect the development of beige adipocyte cells may be important to new pathways in the treatment of metabolic diseases. New molecules have emerged as possible therapeutic targets, which through the impulse to develop beige adipocytes can be useful for clinical studies. In this review will discuss some recent observations arising from the unique physiological capacity of these cells and their possible role as ways to treat obesity and diabetes mellitus type 2.

Sargahydroquinoic acid, a major compound in Sargassum serratifolium (C. Agardh) C. Agardh, widely activates lipid catabolic pathways, contributing to the formation of beige-like adipocytes

Abstract Sargassum serratifolium (C. Agardh) C. Agardh, a marine brown alga, has been consumed as food and traditional medicine in Asia. Previous study showed that the meroterpenoid-rich fraction of an ethanolic extract of Sargassum serratifolium (C. Agardh) C. Agardh (MES) stimulated adipose tissue browning and inhibited diet-induced obesity and metabolic syndrome. Sargahydroquinoic acid (SHQA) is a major component in MES. It is investigated whether SHQA is a contributor for the anti-obesity effect of MES and whether SHQA directly acts on adipocytes using 3T3-L1 differentiated under the classical and beige adipocyte-inducing conditions. Interestingly, SHQA notably reduced lipid accumulation despite the upregulation of adipogenic transcription factor PPARγ in adipocytes differentiated under both conditions. Western blotting and protein-ligand docking simulation further revealed that SHQA also activates PPARα and AMPKα, lipid-catabolic proteins. Thus, it is further focused on the signaling pathways mediated by these proteins. SHQA markedly elevated lipolysis and mitochondria number, but paradoxically reduced ATP production. When uncoupled metabolic signaling was examined, SHQA significantly increased UCP1-positive adipocytes as well as beige adipocyte markers. In conclusion, SHQA may activate PPARγ, PPARα, and AMPKα, contributing to the stimulation of lipid catabolic pathways and adipocyte browning. Therefore, SHQA may be used as a novel pharmaceutical agent to combat obesity and associated metabolic syndrome.

An immune-beige adipocyte communication via nicotinic acetylcholine receptor signaling.

Beige adipocytes have been recently shown to regulate energy dissipation when activated, and help organisms defend against hypothermia and obesity. Prior reports indicate beige-like adipocytes exist in adult humans and may present novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of activated beige adipocytes, we uncovered that the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) is induced in subcutaneous fat during the activation of these cells, and that acetylcholine-producing immune cells within this tissue regulate this signaling pathway via paracrine mechanisms. CHRNA2 functions selectively in uncoupling protein 1 (Ucp1)+ beige adipocytes, increasing thermogenesis through a cAMP and PKA pathway. Furthermore, this signaling via CHRNA2 is conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromises the cold-induced thermogenic response selectively in subcutaneous fat and exacerbates high-fat diet-induced obesity and associated metabolic disorders, indicating that even partial loss of beige fat regulation in vivo leads to detrimental consequences. Our results reveal a beige-selective immune-adipose interaction mediated through CHRNA2 and identify a novel function of nicotinic acetylcholine receptors (nAChRs) in energy metabolism. These findings may lead to identification of therapeutic targets to counteract human obesity.

Low temperature exposure induces browning of bone marrow stem cell derived adipocytes in vitro

Brown and beige adipocytes are characterised as expressing the unique mitochondrial uncoupling protein (UCP)1 for which the primary stimulus in vivo is cold exposure. The extent to which cold-induced UCP1 activation can also be achieved in vitro, and therefore perform a comparable cellular function, is unknown. We report an in vitro model to induce adipocyte browning using bone marrow (BM) derived mesenchymal stem cells (MSC), which relies on differentiation at 32 °C instead of 37 °C. The low temperature promoted browning in adipogenic cultures, with increased adipocyte differentiation and upregulation of adipogenic and thermogenic factors, especially UCP1. Cells exhibited enhanced uncoupled respiration and metabolic adaptation. Cold-exposed differentiated cells showed a marked translocation of leptin to adipocyte nuclei, suggesting a previously unknown role for leptin in the browning process. These results indicate that BM-MSC can be driven to forming beige-like adipocytes in vitro by exposure to a reduced temperature. This in vitro model will provide a powerful tool to elucidate the precise role of leptin and related hormones in hitherto functions in the browning process.

Magnolol promotes thermogenesis and attenuates oxidative stress in 3T3-L1 adipocytes

The aim of this study was to explore the browning and antioxidative effects of magnolol in 3T3-L1 adipocytes, as recruitment of beige-like adipocytes (browning) by natural compounds is being considered as a promising strategy to fight against obesity. Magnolol-induced browning effect was evaluated by determining the expression levels of specific marker genes and proteins using real-time polymerase chain reaction and immunoblotting, respectively. Induction of thermogenesis and suppression of oxidative stress in 3T3-L1 adipocytes were further validated by immunofluorescence. Magnolol significantly enhanced expression of a core set of brown fat-specific marker genes (Ucp1, Cd137, Prdm16, Cidea, and Tbx1) and proteins (UCP1, PRDM16, and PGC-1α). Increased expression of UCP1 and other brown fat-specific markers contributed to the browning of 3T3-L1 adipocytes possibly via activation of the AMPK, PPARγ, and protein kinase A (PKA) pathways. In addition, magnolol up-regulated key fatty acid oxidation and lipolytic markers (CPT1, ACSL1, SIRT1, and PLIN) and down-regulated lipogenic markers (FAS and SREBP1). Magnolol also reduced the production and release of reactive oxygen species. The current data suggest possible roles for magnolol in browning of white adipocytes, augmentation of lipolysis, and thermogenesis, as well as repression of oxidative stress and lipogenesis. Thus, magnolol may be explored as a potentially promising therapeutic agent for the prevention of obesity and other metabolic disorders.

Distinctive effects of licarin A on lipolysis mediated by PKA and on formation of brown adipocytes from C3H10T1/2 mesenchymal stem cells

Obesity increases with the positive energy imbalance and correlates with increased risks for metabolic diseases. Promotion of white adipose tissue beiging has received considerable attention due to possible usefulness for preventing obesity and the comorbidities. Licarin A (LA) is a compound derived from Mexican medicinal plant Aristolochia taliscana. Here, we report that LA stimulates the development of brown-like and beige-like adipocytes from C3H10T1/2 mesenchymal stem cells with phenotypic shifts to formation of smaller lipid droplets. LA also markedly induced the expression of proteins characteristic of brown-like adipocytes in C3H10T1/2 mesenchymal stem cells. LA induced uncoupling protein 1 (Ucp1) and expression of other thermogenic genes in C3H10T1/2 mesenchymal stem cells via a mechanism involving protein kinase A (PKA). LA treatment also inhibited expression of white-adipocyte–specific genes. Moreover, LA treatment promoted lipolysis via PKA mediated pathway. Our findings inaugurate a new role of LA as an inducer of brown-like adipocytes formation with lipolytic properties, which in future might be studied in vivo as a potential anti-obesity agent.

Now UCP(rotein), Now You Don’t: UCP1 Is Not Mandatory for Thermogenesis

Adipocyte-targeted therapies could potentially combat obesity and metabolic disorders; however, our understanding of adipogenesis and the characterization of the various adipose tissues are incomplete. In this issue, Bertholet etal. (2017) report the existence of two types of heat-producing beige-like adipocytes, those with and those without the mitochondrial uncoupling protein 1 (UCP1).

Zfp423 Maintains White Adipocyte Identity through Suppression of the Beige Cell Thermogenic Gene Program

The transcriptional regulators Ebf2 and Prdm16 establish and maintain the brown and/or beige fat cell identity. However, the mechanisms operating in white adipocytes to suppress the thermogenic gene program and maintain an energy-storing phenotype are less understood. Here, we report that the transcriptional regulator Zfp423 is critical for maintaining white adipocyte identity through suppression of the thermogenic gene program. Zfp423 expression is enriched in white versus brown adipocytes and suppressed upon cold exposure. Doxycycline-inducible inactivation of Zfp423 in mature adipocytes, combined with β-adrenergic stimulation, triggers a conversion of differentiated adiponectin-expressing inguinal and gonadal adipocytes into beige-like adipocytes; this reprogramming event is sufficient to prevent and reverse diet-induced obesity and insulin resistance. Mechanistically, Zfp423 acts in adipocytes to inhibit the activity of Ebf2 and suppress Prdm16 activation. These data identify Zfp423 as a molecular brake on adipocyte thermogenesis and suggest a therapeutic strategy to unlock the thermogenic potential of white adipocytes in obesity.

Biology of Beige Adipocyte and Possible Therapy for Type 2 Diabetes and Obesity.

All mammals own two main forms of fat. The classical white adipose tissue builds up energy in the form of triglycerides and is useful for preventing fatigue during periods of low caloric intake and the brown adipose tissue instead of inducing fat accumulation can produce energy as heat. Since adult humans possess significant amounts of active brown fat depots and their mass inversely correlates with adiposity, brown fat might play an important role in human obesity and energy homeostasis. New evidence suggests two types of thermogenic adipocytes with distinct developmental and anatomical features: classical brown adipocytes and beige adipocytes. Beige adipocyte has recently attracted special interest because of its ability to dissipate energy and the possible ability to differentiate itself from white adipocytes. Importantly, adult human brown adipocyte appears to be mainly composed of beige-like adipocytes, making this cell type an attractive therapeutic target for obesity and obesity-related diseases. Because many epigenetic changes can affect beige adipocyte differentiation, the knowledge of the circumstances that affect the development of beige adipocyte cells may be important for therapeutic strategies. In this review we discuss some recent observations arising from the great physiological capacity of these cells and their possible role as ways to treat obesity and diabetes mellitus type 2.

Engineering Fat Cell Fate to Fight Obesity and Metabolic Diseases.

All mammals harbor two types of adipose tissues that serve distinct physiological functions: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT functions mainly in the storage of excess energy, while BAT specializes in dissipating energy in the form of heat and functions as a defense against hypothermia and obesity. Since adult humans possess significant amounts of active BAT depots and it's mass inversely correlates with adiposity, BAT plays an important role in human obesity and energy homeostasis.New evidence suggests two types of thermogenic adipocytes with distinct developmental and anatomical features: classical brown adipocytes and beige adipocytes. Classical brown adipocytes are located mainly in dedicated BAT depots of rodents and infants. Beige adipocytes, on the other hand, reside mainly in subcutaneous WAT where they arise postnatally in response to certain external cues, such as chronic cold exposure and long-term treatment with PPAR- agonists, a process often referred to as the "browning" of WAT. Importantly, adult human BAT appears to be mainly composed of beige-like adipocytes, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, such as insulin resistance and type2 diabetes. I will review recent progress in the molecular control of brown and beige adipocyte development and discuss emerging questions.(Presented at the 1912th Meeting, December 21, 2015).