An essential role for Tbx15 in the differentiation of brown and “brite” but not white adipocytes

2012 ◽  
Vol 303 (8) ◽  
pp. E1053-E1060 ◽  
Author(s):  
Valentina Gburcik ◽  
William P. Cawthorn ◽  
Jan Nedergaard ◽  
James A. Timmons ◽  
Barbara Cannon
Keyword(s):  
Adipose Tissue ◽  
Brown Adipocyte ◽  
Marker Genes ◽  
Phenotypic Marker ◽  
White Adipocytes ◽  
Pparγ Agonist ◽  
Brown Adipose ◽  
Beige Adipocytes

The transcription factor Tbx15 is expressed predominantly in brown adipose tissue and in those white adipose depots that are capable of giving rise to brown-in-white (“brite”/“beige”) adipocytes. Therefore, we have investigated a possible role here of Tbx15 in brown and brite adipocyte differentiation in vitro. Adipocyte precursors were isolated from interscapular and axilliary brown adipose tissues, inguinal white (“brite”) adipose tissue, and epididymal white adipose tissue in 129/Sv mouse pups and differentiated in culture. Differentiation was enhanced by chronic treatment with the PPARγ agonist rosiglitazone plus the sympathetic neurotransmitter norepinephrine. Using short interfering RNAs (siRNA) directed toward Tbx15 in these primary adipocyte cultures, we decreased Tbx15 expression >90%. This resulted in reduced expression levels of adipogenesis markers (PPARγ, aP2). Importantly, Tbx15 knockdown reduced the expression of brown phenotypic marker genes (PRDM16, PGC-1α, Cox8b/Cox4, UCP1) in brown adipocytes and even more markedly in inguinal white adipocytes. In contrast, Tbx15 knockdown had no effect on white adipocytes originating from a depot that is not brite competent in vivo (epididymal). Therefore, Tbx15 may be essential for the development of the adipogenic and thermogenic programs in adipocytes/adipomyocytes capable of developing brown adipocyte features.

The PPARγ agonist rosiglitazone enhances rat brown adipose tissue lipogenesis from glucose without altering glucose uptake

2009 ◽  
Vol 296 (5) ◽  
pp. R1327-R1335 ◽  
Author(s):  
William T. Festuccia ◽  
Pierre-Gilles Blanchard ◽  
Véronique Turcotte ◽  
Mathieu Laplante ◽  
Meltem Sariahmetoglu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Glucose Uptake ◽  
Mrna Levels ◽  
Pparγ Agonist ◽  
Brown Adipose ◽  
Lipin 1 ◽  
The Impact

We investigated the mechanisms whereby peroxisome proliferator-activated receptor-γ (PPARγ) agonism affects glucose and lipid metabolism in brown adipose tissue (BAT) by studying the impact of PPARγ activation on BAT glucose uptake and metabolism, lipogenesis, and mRNA levels plus activities of enzymes involved in triacylglycerol (TAG) synthesis. Interscapular BAT of rats treated or not with rosiglitazone (15 mg·kg−1·day−1, 7 days) was evaluated in vivo for glucose uptake and lipogenesis and in vitro for glucose metabolism, gene expression, and activities of glycerolphosphate acyltransferase (GPAT), phosphatidate phosphatase-1 (PAP or lipin-1), and diacylglycerol acyltransferase (DGAT). Rosiglitazone increased BAT mass without affecting whole tissue glucose uptake. BAT glycogen content (−80%), its synthesis from glucose (−50%), and mRNA levels of UDP-glucose pyrophosphorylase (−40%), which generates UDP-linked glucose for glycogen synthesis, were all reduced by rosiglitazone. In contrast, BAT TAG-glycerol synthesis in vivo and glucose incorporation into TAG-glycerol in vitro were stimulated by the agonist along with the activities and mRNA levels of glycerol 3-phosphate-generating phosphoenolpyruvate carboxykinase and glycerokinase. Furthermore, rosiglitazone markedly increased the activities of GPAT and DGAT but not those of lipin-1-mediated PAP-1, enzymes involved in the sequential acylation of glycerol 3-phosphate and TAG synthesis. Because an adequate supply of fatty acids is essential for BAT nonshivering thermogenesis, the enhanced ability of BAT to synthesize TAG under PPARγ activation may constitute an important mechanism by which lipid substrates are stored in preparation for an eventual thermogenic activation.

Role of bone morphogenetic protein 4 in the differentiation of brown fat-like adipocytes

2014 ◽  
Vol 306 (4) ◽  
pp. E363-E372 ◽  
Author(s):  
Ruidan Xue ◽  
Yun Wan ◽  
Shuo Zhang ◽  
Qiongyue Zhang ◽  
Hongying Ye ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Uncoupling Protein ◽  
Brown Fat ◽  
Brown Adipocyte ◽  
White Adipocyte ◽  
Brown Adipose ◽  
And Function ◽  
Brown Adipogenesis

There are two different types of fat present in mammals: white adipose tissue, the primary site of energy storage, and brown adipose tissue, which is specializes in energy expenditure. Factors that specify the developmental fate and function of brown fat are poorly understood. Bone morphogenic proteins (BMPs) play an important role in adipogenesis. While BMP4 is capable of triggering commitment of stem cells to the white adipocyte lineage, BMP7 triggers commitment of progenitor cells to a brown adipocyte lineage and activates brown adipogenesis. To investigate the differential effects of BMPs on the development of adipocytes, C3H10T1/2 pluripotent cells were pretreated with BMP4 and BMP7, followed by different adipogenic induction cocktails. Both BMP4 and BMP7 unexpectedly activated a full program of brown adipogenesis, including induction of the brown fat-defining marker uncoupling protein-1 (UCP1), increasing the expression of early regulators of brown fat fate PRDM16 (PR domain-containing 16) and induction of mitochondrial biogenesis and function. Implantation of BMP4-pretreated C3H10T1/2 cells into nude mice resulted in the development of adipose tissue depots containing UCP1-positive brown adipocytes. Interestingly, BMP4 could also induce brown fat-like adipocytes in both white and brown preadipocytes, thereby decreasing the classical brown adipocyte marker Zic1 and increasing the recently identified beige adipocyte marker TMEM26. The data indicate an important role for BMP4 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro and offers a potentially new therapeutic approach for the treatment of obesity.

scholarly journals Brown and beige adipose tissue regulate systemic metabolism to resist diet-induced obesity through metabolite signals in an inter-organ signaling axis

2020 ◽  
Author(s):  
Anna Whitehead ◽  
Fynn Krause ◽  
Amy Moran ◽  
Jason Scragg ◽  
Ben McNally ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipocyte ◽  
Oxidative Energy Metabolism ◽  
Obesity And Diabetes ◽  
Brown Adipose ◽  
Endocrine Organs ◽  
Beige Adipose Tissue

Abstract Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an inter-organ signaling network. Using a metabolomic approach we identified 3-methyl-2-oxovaleric acid (MOVA), 5-oxoproline (5OP), and β-hydroxyisobutyric acid (BHIBA) as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. MOVA, 5OP and BHIBA induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. MOVA and 5OP signal through cAMP-PKA-p38 MAPK and BHIBA via mTOR. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. In humans, plasma and adipose tissue MOVA, 5OP and BHIBA concentrations are correlated with markers of adipose browning and inversely associated with BMI. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk.

scholarly journals HIF3A Inhibition Triggers Browning of White Adipocytes via Metabolic Rewiring

2022 ◽  
Vol 9 ◽  
Author(s):  
Francesca Cuomo ◽  
Carmela Dell’Aversana ◽  
Teresa Chioccarelli ◽  
Veronica Porreca ◽  
Francesco Manfrevola ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Metabolism ◽  
Metabolic Diseases ◽  
Cell Metabolism ◽  
Expression Patterns ◽  
White Adipocytes ◽  
Brown Adipose ◽  
Gene And Protein Expression

Maintenance of energy balance between intake and expenditure is a prerequisite of human health, disrupted in severe metabolic diseases, such as obesity and type 2 diabetes (T2D), mainly due to accumulation of white adipose tissue (WAT). WAT undergoes a morphological and energetic remodelling toward brown adipose tissue (BAT) and the BAT activation has anti-obesity potential. The mechanisms or the regulatory factors able to activate BAT thermogenesis have been only partially deciphered. Identifying novel regulators of BAT induction is a question of great importance for fighting obesity and T2D. Here, we evaluated the role of Hif3α in murine pre-adipocyte 3T3-L1 cell line, a versatile and well characterized biological model of adipogenesis, by gain- and loss-of function approaches and in thermogenesis-induced model in vivo. HIF3A is regulated by inflammation, it modulates lypolysis in adipose tissue of obese adults, but its role in energy metabolism has not previously been investigated. We characterized gene and protein expression patterns of adipogenesis and metabolic activity in vitro and mechanistically in vivo. Overexpression of Hif3α in differentiating adipocytes increases white fat cells, whereas silencing of Hif3α promotes “browning” of white cells, activating thermogenesis through upregulation of Ucp1, Elovl3, Prdm16, Dio2 and Ppargc1a genes. Investigating cell metabolism, Seahorse Real-Time Cell Metabolism Analysis showed that silencing of Hif3α resulted in a significant increase of mitochondrial uncoupling with a concomitant increase in acetyl-CoA metabolism and Sirt1 and Sirt3 expression. The causal Hif3α/Ucp1 inverse relation has been validated in Cannabinoid receptor 1 (CB1) knockout, a thermogenesis-induced model in vivo. Our data indicate that Hif3α inhibition triggers “browning” of white adipocytes activating the beneficial thermogenesis rewiring energy metabolism in vitro and in vivo. HIF3A is a novel player that controls the energy metabolism with potential applications in developing therapy to fight metabolic disorders, as obesity, T2D and ultimately cancer.

scholarly journals TAF7L modulates brown adipose tissue formation

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Haiying Zhou ◽  
Bo Wan ◽  
Ivan Grubisic ◽  
Tommy Kaplan ◽  
Robert Tjian
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Core Promoter ◽  
Uncoupling Protein ◽  
Dna Looping ◽  
Chromatin Interactions ◽  
Brown Adipose ◽  
Important Regulator

Brown adipose tissue (BAT) plays an essential role in metabolic homeostasis by dissipating energy via thermogenesis through uncoupling protein 1 (UCP1). Previously, we reported that the TATA-binding protein associated factor 7L (TAF7L) is an important regulator of white adipose tissue (WAT) differentiation. In this study, we show that TAF7L also serves as a molecular switch between brown fat and muscle lineages in vivo and in vitro. In adipose tissue, TAF7L-containing TFIID complexes associate with PPARγ to mediate DNA looping between distal enhancers and core promoter elements. Our findings suggest that the presence of the tissue-specific TAF7L subunit in TFIID functions to promote long-range chromatin interactions during BAT lineage specification.

scholarly journals JAZF1 heterozygous knockout mice show altered adipose development and metabolism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jain Jeong ◽  
Soyoung Jang ◽  
Song Park ◽  
Wookbong Kwon ◽  
Si-Yong Kim ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Knockout Mice ◽  
Metabolic Disorders ◽  
Adipocyte Differentiation ◽  
Zinc Finger Protein ◽  
Tissue Mass ◽  
In Vivo Models ◽  
Brown Adipose

Abstract Background Juxtaposed with another zinc finger protein 1 (JAZF1) is associated with metabolic disorders, including type 2 diabetes mellitus (T2DM). Several studies showed that JAZF1 and body fat mass are closely related. We attempted to elucidate the JAZF1 functions on adipose development and related metabolism using in vitro and in vivo models. Results The JAZF1 expression was precisely regulated during adipocyte differentiation of 3T3-L1 preadipocyte and mouse embryonic fibroblasts (MEFs). Homozygous JAZF1 deletion (JAZF1-KO) resulted in impaired adipocyte differentiation in MEF. The JAZF1 role in adipocyte differentiation was demonstrated by the regulation of PPARγ—a key regulator of adipocyte differentiation. Heterozygous JAZF1 deletion (JAZF1-Het) mice fed a normal diet (ND) or a high-fat diet (HFD) had less adipose tissue mass and impaired glucose homeostasis than the control (JAZF1-Cont) mice. However, other metabolic organs, such as brown adipose tissue and liver, were negligible effect on JAZF1 deficiency. Conclusion Our findings emphasized the JAZF1 role in adipocyte differentiation and related metabolism through the heterozygous knockout mice. This study provides new insights into the JAZF1 function in adipose development and metabolism, informing strategies for treating obesity and related metabolic disorders.

scholarly journals Betatrophin knockdown induces beiging and mitochondria biogenesis of white adipocytes

2020 ◽  
Vol 245 (1) ◽  
pp. 93-100 ◽  
Author(s):  
Zhe-Zhen Liao ◽  
Xiao-Yan Qi ◽  
Ya-Di Wang ◽  
Jiao-Yang Li ◽  
Qian-Qian Gu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Ampk Signaling ◽  
White Adipocytes ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
Mitochondria Biogenesis ◽  
Paracrine Actions ◽  
White Fat

Remodeling of energy-storing white fat into energy-consuming beige fat has led to a promising new approach to alleviate adiposity. Several studies have shown adipokines can induce white adipose tissue (WAT) beiging through autocrine or paracrine actions. Betatrophin, a novel adipokine, has been linked to energy expenditure and lipolysis but not clearly clarified. Here, we using high-fat diet-induced obesity to determine how betatrophin modulate beiging and adiposity. We found that betatrophin-knockdown mice displayed less white fat mass and decreased plasma TG and NEFA levels. Consistently, inhibition of betatrophin leads to the phenotype change of adipocytes characterized by increased mitochondria contents, beige adipocytes and mitochondria biogenesis-specific markers both in vivo and in vitro. Of note, blocking AMP-activated protein kinase (AMPK) signaling pathway is able to abolish enhanced beige-like characteristics in betatrophin-knockdown adipocytes. Collectively, downregulation of betatrophin induces beiging in white adipocytes through activation of AMPK signaling pathway. These processes suggest betatrophin as a latent therapeutic target for obesity.

Abstract 339: Impaired Periaortic Adipocyte Differentiation in Angiotensin AT1 Receptor-Deficient Mice: Possible Role in Proinflammatory Phenotypic Modulation of Perivascular Adipose Tissue

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Daisuke Irie ◽  
Hiroyuki Yamada ◽  
Taku Kato ◽  
Hiroyuki Kawahito ◽  
Kouji Ikeda ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Adipocyte Differentiation ◽  
At1 Receptor ◽  
Brown Adipocyte ◽  
Marker Genes ◽  
Interscapular Brown Adipose Tissue ◽  
Perivascular Adipose Tissue ◽  
Expression Levels ◽  
Brown Adipose ◽  
Differentiation Marker

[BACKGROUND] The angiotensin II type 1 (AT1) receptor in visceral white adipose tissue (WAT) is closely implicated in lipid metabolism and energy homeostasis. Recently, perivascular adipose tissue (PVAT) has been shown to play a crucial role in the development of atherosclerosis; however, the effects of AT1 on PVAT properties and their functional relevance in atherogenesis remain undefined. [METHOD AND RESULT] We examined the fat depot-specific difference of adipose tissue among epididymal WAT, PVAT surrounding thoracic aorta, and interscapular brown adipose tissue (BAT) in 8-week-old apoE deficient (apoE-/-) mice. The expression levels of brown adipocyte marker genes (UCP-1, PGC-1α, Elovl3, PPARα, and Cidea) were significantly higher in BAT and PVAT compared with WAT (P<0.01). White adipocyte marker genes (Igfbp3, DPT, Tcf21, and Hoxc9), which were hardly expressed in BAT, showed a moderate expression levels in PVAT, suggesting that PVAT has a strikingly different phenotype from the classical WAT and BAT. We next examined the properties of PVAT in 8-week-old apoE-/-/AT1 receptor deficient (Agtr1-/-) mice. After 4 weeks of western diet, the expression levels of adipocyte differentiation maker genes (PPARγ, FABP4, c/EBPα) were markedly increased in apoE -/- PVAT (P<0.05), which was completely diminished in apoE-/-/Agtr1 -/- PVAT (P<0.01). To investigate the effect of AT1 on the periaortic adipocyte differentiation, we performed primary culture of preadipocyte from stromal vascular fraction in Agtr1 -/- and Agtr1+/+ PVAT. The mRNA expressions of adipocyte differentiation marker genes (PPARγ, FABP4, and c/EBPα) were time-dependently increased in Agtr1+/+ adipocyte. In contrast, FABP4 and c/EBPα mRNA expressions were markedly inhibited in Agtr1 -/- adipocyte, whereas PPARγ did not differ between the two groups during differentiation, suggesting that AT1 is essentially implicated in the terminal differentiation of periaortic adipocyte. [CONCLUSION] Our findings demonstrate that AT1 regulates the expression levels of late stage of adipocyte-differentiation marker genes in PVAT, suggesting that AT1-mediated modulation of periaortic adipocyte differentiation could be a novel therapeutic target for the prevention of atherosclerosis.

scholarly journals Dopamine receptor D1- and D2-agonists do not spark brown adipose tissue thermogenesis in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Francesca-Maria Raffaelli ◽  
Julia Resch ◽  
Rebecca Oelkrug ◽  
K. Alexander Iwen ◽  
Jens Mittag
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Dopamine Receptor ◽  
Ex Vivo ◽  
Potential Target ◽  
D2 Agonist ◽  
Obesity And Diabetes ◽  
Brown Adipose

AbstractBrown adipose tissue (BAT) thermogenesis is considered a potential target for treatment of obesity and diabetes. In vitro data suggest dopamine receptor signaling as a promising approach; however, the biological relevance of dopamine receptors in the direct activation of BAT thermogenesis in vivo remains unclear. We investigated BAT thermogenesis in vivo in mice using peripheral administration of D1-agonist SKF38393 or D2-agonist Sumanirole, infrared thermography, and in-depth molecular analyses of potential target tissues; and ex vivo in BAT explants to identify direct effects on key thermogenic markers. Acute in vivo treatment with the D1- or D2-agonist caused a short spike or brief decrease in BAT temperature, respectively. However, repeated daily administration did not induce lasting effects on BAT thermogenesis. Likewise, neither agonist directly affected Ucp1 or Dio2 mRNA expression in BAT explants. Taken together, the investigated agonists do not seem to exert lasting and physiologically relevant effects on BAT thermogenesis after peripheral administration, demonstrating that D1- and D2-receptors in iBAT are unlikely to constitute targets for obesity treatment via BAT activation.

scholarly journals Lsd1 prevents age-programed loss of beige adipocytes

2017 ◽  
Vol 114 (20) ◽  
pp. 5265-5270 ◽  
Author(s):  
Delphine Duteil ◽  
Milica Tosic ◽  
Dominica Willmann ◽  
Anastasia Georgiadi ◽  
Toufike Kanouni ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Peroxisome Proliferator ◽  
Fat Cell ◽  
White Adipocyte ◽  
White Adipocytes ◽  
Age Related ◽  
Beige Adipocytes ◽  
Beige Fat ◽  
And Function

Aging is accompanied by major changes in adipose tissue distribution and function. In particular, with time, thermogenic-competent beige adipocytes progressively gain a white adipocyte morphology. However, the mechanisms controlling the age-related transition of beige adipocytes to white adipocytes remain unclear. Lysine-specific demethylase 1 (Lsd1) is an epigenetic eraser enzyme positively regulating differentiation and function of adipocytes. Here we show that Lsd1 levels decrease in aging inguinal white adipose tissue concomitantly with beige fat cell decline. Accordingly, adipocyte-specific increase of Lsd1 expression is sufficient to rescue the age-related transition of beige adipocytes to white adipocytes in vivo, whereas loss of Lsd1 precipitates it. Lsd1 maintains beige adipocytes by controlling the expression of peroxisome proliferator-activated receptor α (Ppara), and treatment with a Ppara agonist is sufficient to rescue the loss of beige adipocytes caused by Lsd1 ablation. In summary, our data provide insights into the mechanism controlling the age-related beige-to-white adipocyte transition and identify Lsd1 as a regulator of beige fat cell maintenance.

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