TRB3 Inhibits Brown Adipocyte Differentiation and Function by Suppressing Insulin Signaling

Abstract Brown adipocytes play important roles in the regulation of energy homeostasis by uncoupling protein 1-mediated non-shivering thermogenesis. Recent studies suggest that brown adipocytes as novel therapeutic targets for combating obesity and associated diseases, such as type II diabetes. However, the molecular mechanisms underlying brown adipocyte differentiation and function are not fully understood. We employed previous findings obtained through proteomic studies performed to assess proteins displaying altered levels during brown adipocyte differentiation. Here, we performed assays to determine the functional significance of their altered levels during brown adipogenesis and development. We identified isocitrate dehydrogenase 1 (IDH1) as upregulated during brown adipocyte differentiation, with subsequent investigations revealing that ectopic expression of IDH1 inhibited brown adipogenesis, whereas suppression of IDH1 levels promoted differentiation of brown adipocytes. Additionally, Idh1 overexpression resulted in increased levels of intracellular α-ketoglutarate (α-KG) and inhibited the expression of genes involved in brown adipogenesis. Exogenous treatment with α-KG reduced brown adipogenesis during the early phase of differentiation, and ChIP analysis revealed that IDH1-mediated α-KG reduced trimethylation of histone H3 lysine 4 in the promoters of genes associated with brown adipogenesis. Furthermore, administration of α-KG decreased adipogenic gene expression by modulating histone methylation in brown adipose tissues of mice. These results suggested that the IDH1–α-KG axis plays an important role in regulating brown adipocyte differentiation and might represent a therapeutic target for treating metabolic diseases.

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The mineralocorticoid receptor: a new player controlling energy homeostasis

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0033 ◽

2013 ◽

Vol 15 (2) ◽

Cited By ~ 1

Author(s):

Emmanuelle Kuhn ◽

Marc Lombès

Keyword(s):

Mineralocorticoid Receptor ◽

Energy Homeostasis ◽

Adipocyte Differentiation ◽

Therapeutic Potential ◽

Control Point ◽

Brown Adipocyte ◽

Transgenic Mouse Models ◽

Electrolyte Homeostasis ◽

Potential Impact ◽

And Function

AbstractNumerous studies have demonstrated the interaction that exists between adipocyte differentiation, energy balance and factors involved in fluid and electrolyte homeostasis, such as the renin-angiotensin-aldosterone system. More specifically, a potential impact of aldosterone on the function of several organs implicated in the control of energy homeostasis, such as adipose tissue, liver, skeletal muscle or pancreas, has been recently described. In addition, the mineralocorticoid receptor (MR, NR3C2), a transcription factor, was shown to play a crucial role on white and brown adipocyte differentiation and function, mediating the effects of both mineralocorticoid and glucocorticoid hormones on adipose tissues. Transgenic mouse models as well as pharmacological inactivation of MR signaling provided compelling evidence that MR is an important control point for energy homeostasis. Herein, we review recent findings on the involvement of aldosterone but also of MR on energy metabolism and discuss the therapeutic potential of manipulating MR signaling for the management of metabolic disorders in humans.

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Brown Adipocyte Differentiation and Function in Energy Metabolism

Adipose Tissue ◽

10.1201/9781498712644-9 ◽

2001 ◽

pp. 92-106

Keyword(s):

Energy Metabolism ◽

Adipocyte Differentiation ◽

Brown Adipocyte ◽

And Function

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Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Is Not Required for Brown Adipogenesis but Regulates Brown Adipose Tissue Development and Function

Molecular and Cellular Biology ◽

10.1128/mcb.01120-15 ◽

2016 ◽

Vol 36 (15) ◽

pp. 2027-2038 ◽

Cited By ~ 12

Author(s):

Hongyi Zhou ◽

Stephen M. Black ◽

Tyler W. Benson ◽

Neal L. Weintraub ◽

Weiqin Chen

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Adipocyte Differentiation ◽

Whole Body ◽

Brown Adipocyte ◽

Endoplasmic Reticulum Membrane ◽

Brown Adipocytes ◽

White Adipocyte ◽

Brown Adipose ◽

And Function

Brown adipose tissue (BAT) plays a unique role in regulating whole-body energy homeostasis by dissipating energy through thermogenic uncoupling. Berardinelli-Seip congenital lipodystrophy (BSCL) type 2 (BSCL2; also known as seipin) is a lipodystrophy-associated endoplasmic reticulum membrane protein essential for white adipocyte differentiation. Whether BSCL2 directly participates in brown adipocyte differentiation, development, and function, however, is unknown. We show that BSCL2 expression is increased during brown adipocyte differentiation. Its deletion does not impair the classic brown adipogenic program but rather induces premature activation of differentiating brown adipocytes through cyclic AMP (cAMP)/protein kinase A (PKA)-mediated lipolysis and fatty acid and glucose oxidation, as well as uncoupling. cAMP/PKA signaling is physiologically activated during neonatal BAT development in wild-type mice and greatly potentiated in mice with genetic deletion ofBscl2in brown progenitor cells, leading to reduced BAT mass and lipid content during neonatal brown fat formation. However, prolonged overactivation of cAMP/PKA signaling during BAT development ultimately causes apoptosis of brown adipocytes through inflammation, resulting in BAT atrophy and increased overall adiposity in adult mice. These findings reveal a key cell-autonomous role for BSCL2 in controlling BAT mass/activity and provide novel insights into therapeutic strategies targeting cAMP/PKA signaling to regulate brown adipocyte function, viability, and metabolic homeostasis.

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2044-P: Histone Methyltransferase DOT1L Regulates Brown Adipocyte Differentiation and Thermogenesis

Diabetes ◽

10.2337/db19-2044-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 2044-P

Author(s):

LIN SHUAI ◽

JIA LI ◽

JINGYA LI

Keyword(s):

Adipocyte Differentiation ◽

Histone Methyltransferase ◽

Brown Adipocyte

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A Synergistic Anti-Diabetic Effect by Ginsenosides Rb1 and Rg3 through Adipogenic and Insulin Signaling Pathways in 3T3-L1 Cells

Applied Sciences ◽

10.3390/app11041725 ◽

2021 ◽

Vol 11 (4) ◽

pp. 1725

Author(s):

Hee-Do Hong ◽

Sun-Il Choi ◽

Ok-Hwan Lee ◽

Young-Cheul Kim

Keyword(s):

Transcription Factors ◽

Insulin Signaling ◽

Adipocyte Differentiation ◽

Red Ginseng ◽

Inhibitory Effects ◽

Rt Pcr ◽

High Concentration ◽

Expression Of Genes ◽

The Individual ◽

Maximal Expression

Although ginsenosides Rb1 and Rg3 have been identified as the significant ginsenosides found in red ginseng that confer anti-diabetic actions, it is unclear whether insulin-sensitizing effects are mediated by the individual compounds or by their combination. To determine the effect of ginsenosides Rb1 and Rg3 on adipocyte differentiation, 3T3-L1 preadipocytes were induced to differentiate the standard hormonal inducers in the absence or presence of ginsenosides Rb1 or Rg3. Additionally, we determined the effects of Rb1, Rg3, or their combination on the expression of genes related to adipocyte differentiation, adipogenic transcription factors, and the insulin signaling pathway in 3T3-L1 cells using semi-quantitative RT-PCR. Rb1 significantly increased the expression of CEBPα, PPARγ, and aP2 mRNAs. However, Rg3 exerted its maximal stimulatory effect on these genes at 1 μM concentration, while a high concentration (50 μM) showed inhibitory effects. Similarly, treatment with Rb1 and Rg3 (1 μM) increased the expression of IRS-1, Akt, PI3K, GLUT4, and adiponectin. Importantly, co-treatment of Rb1 and Rg3 (9:1) induced the maximal expression levels of these mRNAs. Our data indicate that the anti-diabetic activity of red ginseng is, in part, mediated by synergistic actions of Rb1 and Rg3, further supporting the significance of minor Rg3.

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Growth factor regulation of uncoupling protein-1 mRNA expression in brown adipocytes

AJP Cell Physiology ◽

10.1152/ajpcell.01396.2000 ◽

2002 ◽

Vol 282 (1) ◽

pp. C105-C112 ◽

Cited By ~ 22

Author(s):

Bibian García ◽

Maria-Jesús Obregón

Keyword(s):

Growth Factor ◽

Adipocyte Differentiation ◽

Uncoupling Protein ◽

Brown Adipocyte ◽

Mrna Levels ◽

Uncoupling Protein 1 ◽

Brown Adipocytes ◽

Proliferation And Differentiation ◽

Epidermal Growth ◽

Continuous Presence

To study the effect of the mitogens epidermal growth factor (EGF), acidic and basic fibroblast growth factors (aFGF and bFGF), and vasopressin on brown adipocyte differentiation, we analyzed the expression of uncoupling protein-1 (UCP-1) mRNA. Quiescent brown preadipocytes express high levels of UCP-1 mRNA in response to triiodothyronine (T3) and norepinephrine (NE). The addition of serum or the mitogenic condition aFGF + vasopressin + NE or EGF + vasopressin + NE decreases UCP-1 mRNA. A second addition of mitogens further decreases UCP-1 mRNA. Treatment with aFGF or bFGF alone increases UCP-1 mRNA, whereas the addition of EGF or vasopressin dramatically reduces UCP-1 mRNA levels. The continuous presence of T3 increases UCP-1 mRNA levels in cells treated with EGF, aFGF, or bFGF. The effect of T3 on the stimulation of DNA synthesis also was tested. T3 inhibits the mitogenic activity of aFGF and bFGF. In conclusion, mitogens like aFGF or bFGF allow brown adipocyte differentiation, whereas EGF and vasopressin inhibit the differentiation process. T3 behaves as an important hormone that regulates both brown adipocyte proliferation and differentiation.

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Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00344.2014 ◽

2015 ◽

Vol 308 (2) ◽

pp. E130-E143 ◽

Cited By ~ 40

Author(s):

Amicia D. Elliott ◽

Alessandro Ustione ◽

David W. Piston

Keyword(s):

Metabolic Disease ◽

Pancreatic Islets ◽

Insulin Signaling ◽

Glucagon Secretion ◽

Critical Component ◽

Signaling Mechanisms ◽

Independent Mechanism ◽

Glucagon Suppression ◽

Phosphodiesterase 3B ◽

And Function

The dysregulation of glucose-inhibited glucagon secretion from the pancreatic islet α-cell is a critical component of diabetes pathology and metabolic disease. We show a previously uncharacterized [Ca2+]i-independent mechanism of glucagon suppression in human and murine pancreatic islets whereby cAMP and PKA signaling are decreased. This decrease is driven by the combination of somatostatin, which inhibits adenylyl cyclase production of cAMP via the Gαi subunit of the SSTR2, and insulin, which acts via its receptor to activate phosphodiesterase 3B and degrade cytosolic cAMP. Our data indicate that both somatostatin and insulin signaling are required to suppress cAMP/PKA and glucagon secretion from both human and murine α-cells, and the combination of these two signaling mechanisms is sufficient to reduce glucagon secretion from isolated α-cells as well as islets. Thus, we conclude that somatostatin and insulin together are critical paracrine mediators of glucose-inhibited glucagon secretion and function by lowering cAMP/PKA signaling with increasing glucose.

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