The mineralocorticoid receptor: a new player controlling energy homeostasis

2013 ◽  
Vol 15 (2) ◽  
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.

scholarly journals SUN-587 IDH1-Dependent Alpha-KG Regulates Brown Fat Differentiation and Function by Modulating Histone Methylation

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Won Kon Kim ◽  
Baek-Soo Han
Keyword(s):  
Histone Methylation ◽  
Molecular Mechanisms ◽  
Adipocyte Differentiation ◽  
Uncoupling Protein ◽  
Ectopic Expression ◽  
Brown Adipocyte ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
And Function ◽  
Brown Adipogenesis

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.

scholarly journals The brown adipocyte protein CIDEA promotes lipid droplet fusion via a phosphatidic acid-binding amphipathic helix

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
David Barneda ◽  
Joan Planas-Iglesias ◽  
Maria L Gaspar ◽  
Dariush Mohammadyani ◽  
Sunil Prasannan ◽  
...  
Keyword(s):  
Phosphatidic Acid ◽  
Lipid Droplet ◽  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Adipocyte Differentiation ◽  
Neutral Lipids ◽  
Brown Adipocyte ◽  
Amphipathic Helix ◽  
Tight Coupling ◽  
Brown Adipocytes

Maintenance of energy homeostasis depends on the highly regulated storage and release of triacylglycerol primarily in adipose tissue, and excessive storage is a feature of common metabolic disorders. CIDEA is a lipid droplet (LD)-protein enriched in brown adipocytes promoting the enlargement of LDs, which are dynamic, ubiquitous organelles specialized for storing neutral lipids. We demonstrate an essential role in this process for an amphipathic helix in CIDEA, which facilitates embedding in the LD phospholipid monolayer and binds phosphatidic acid (PA). LD pairs are docked by CIDEA trans-complexes through contributions of the N-terminal domain and a C-terminal dimerization region. These complexes, enriched at the LD–LD contact site, interact with the cone-shaped phospholipid PA and likely increase phospholipid barrier permeability, promoting LD fusion by transference of lipids. This physiological process is essential in adipocyte differentiation as well as serving to facilitate the tight coupling of lipolysis and lipogenesis in activated brown fat.

scholarly journals Tribbles 3 inhibits brown adipocyte differentiation and function by suppressing insulin signaling

2016 ◽  
Vol 470 (4) ◽  
pp. 783-791 ◽  
Author(s):  
Ha-Won Jeong ◽  
Ran Hee Choi ◽  
Jamie L. McClellan ◽  
Gerardo G. Piroli ◽  
Norma Frizzell ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
Adipocyte Differentiation ◽  
Brown Adipocyte ◽  
And Function

scholarly journals TRB3 Inhibits Brown Adipocyte Differentiation and Function by Suppressing Insulin Signaling

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Ha‐Won Jeong ◽  
Ran Hee Choi ◽  
Jamie McClellan ◽  
Yu‐Hua Tseng ◽  
Laurie Goodyear ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
Adipocyte Differentiation ◽  
Brown Adipocyte ◽  
And Function

scholarly journals DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation

2021 ◽  
Author(s):  
Lin Shuai ◽  
Bo-Han Li ◽  
Hao-Wen Jiang ◽  
Lin Yang ◽  
Jia Li ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Adipocyte Differentiation ◽  
Metabolic Diseases ◽  
Diet Induced Obesity ◽  
Beige Adipocytes ◽  
Thermogenic Adipocytes ◽  
And Function ◽  
H3k79 Methylation

Brown and beige adipocytes are characterized as thermogenic adipocytes and have great potential for treating obesity and associated metabolic diseases. Here, we identify a conserved mammalian lysine 79 of histone H3 (H3K79) methyltransferase, disruptor of telomeric silencing -1 like (DOT1L), as a new epigenetic regulator that controls thermogenic adipocyte differentiation and function. We show that deletion of DOT1L in thermogenic adipocytes potently protects mice from diet-induced obesity, improves glucose homeostasis, alleviates hepatic steatosis, and facilitates adaptive thermogenesis<i> in vivo</i>. Loss of DOT1L in primary preadipocytes significantly promotes brown and beige adipogenesis and thermogenesis<i> in vitro</i>. Mechanistically, DOT1L epigenetically regulates the BAT-selective gene program through modulating H3K79 methylation, in particular H3K79me2 modification. Thus, our study demonstrates that DOT1L exerts an important role in energy homeostasis by regulating thermogenic adipocyte differentiation and function.

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

2016 ◽  
Vol 36 (15) ◽  
pp. 2027-2038 ◽  
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.

Expression and function of the human mineralocorticoid receptor: lessons from transgenic mouse models

2004 ◽  
Vol 217 (1-2) ◽  
pp. 127-136 ◽  
Author(s):  
Damien Le Menuet ◽  
Say Viengchareun ◽  
Martine Muffat-Joly ◽  
Maria-Christina Zennaro ◽  
Marc Lombès
Keyword(s):  
Transgenic Mouse ◽  
Mouse Models ◽  
Mineralocorticoid Receptor ◽  
Transgenic Mouse Models ◽  
And Function

scholarly journals DOT1L Regulates Thermogenic Adipocyte Differentiation and Function via Modulating H3K79 Methylation

2021 ◽  
Author(s):  
Lin Shuai ◽  
Bo-Han Li ◽  
Hao-Wen Jiang ◽  
Lin Yang ◽  
Jia Li ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Adipocyte Differentiation ◽  
Metabolic Diseases ◽  
Diet Induced Obesity ◽  
Beige Adipocytes ◽  
Thermogenic Adipocytes ◽  
And Function ◽  
H3k79 Methylation

Brown and beige adipocytes are characterized as thermogenic adipocytes and have great potential for treating obesity and associated metabolic diseases. Here, we identify a conserved mammalian lysine 79 of histone H3 (H3K79) methyltransferase, disruptor of telomeric silencing -1 like (DOT1L), as a new epigenetic regulator that controls thermogenic adipocyte differentiation and function. We show that deletion of DOT1L in thermogenic adipocytes potently protects mice from diet-induced obesity, improves glucose homeostasis, alleviates hepatic steatosis, and facilitates adaptive thermogenesis<i> in vivo</i>. Loss of DOT1L in primary preadipocytes significantly promotes brown and beige adipogenesis and thermogenesis<i> in vitro</i>. Mechanistically, DOT1L epigenetically regulates the BAT-selective gene program through modulating H3K79 methylation, in particular H3K79me2 modification. Thus, our study demonstrates that DOT1L exerts an important role in energy homeostasis by regulating thermogenic adipocyte differentiation and function.

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