scholarly journals GADD45α drives brown adipose tissue formation through upregulating PPARγ in mice

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Wenjing You ◽  
Ziye Xu ◽  
Ye Sun ◽  
Teresa G. Valencak ◽  
Yizhen Wang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Mrna Level ◽  
Cellular Level ◽  
Metabolic Dysfunction ◽  
Tissue Formation ◽  
Brown Adipocytes ◽  
Brown Adipose ◽  
Transcriptomics Data ◽  
Underlying Mechanisms

Abstract Stress can lead to obesity and metabolic dysfunction, but the underlying mechanisms are unclear. Here we identify GADD45α, a stress-inducible histone folding protein, as a potential regulator for brown adipose tissue biogenesis. Unbiased transcriptomics data indicate a positive correlation between adipose Gadd45a mRNA level and obesity. At the cellular level, Gadd45a knockdown promoted proliferation and lipolysis of brown adipocytes, while Gadd45a overexpression had the opposite effects. Consistently, using a knockout (Gadd45a−/−) mouse line, we found that GADD45α deficiency inhibited lipid accumulation and promoted expression of thermogenic genes in brown adipocytes, leading to improvements in insulin sensitivity, glucose uptake, energy expenditure. At the molecular level, GADD45α deficiency increased proliferation through upregulating expression of cell cycle related genes. GADD45α promoted brown adipogenesis via interacting with PPARγ and upregulating its transcriptional activity. Our new data suggest that GADD45α may be targeted to promote non-shivering thermogenesis and metabolism while counteracting obesity.

Abstract 12631: Peripheral Gamma-aminobutyric Acid(gaba) Signaling in Brown Adipose Tissue Induces Metabolic Dysfunction in Obesity

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Ryutaro Ikegami ◽  
Ippei Shimizu ◽  
Takeshi Sato ◽  
Shuang Jiao ◽  
Yohko Yoshida ◽  
...  
Keyword(s):  
Nervous System ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Mitochondrial Function ◽  
Aminobutyric Acid ◽  
Mitochondrial Calcium ◽  
Metabolic Dysfunction ◽  
Gamma Aminobutyric Acid ◽  
Brown Adipose ◽  
Gaba Signaling

Accumulating evidence suggests that adult humans possess active brown adipose tissue (BAT) that may contribute significantly to systemic metabolism because of its high energy consumption capacity. Recently, we demonstrated that metabolic stress induced BAT hypoxia and impaired mitochondrial function, leading to the development of BAT “whitening” and systemic metabolic dysfunction in murine obese models. Various neurotransmitters are known to be involved in the maintenance of BAT homeostasis. Among them, the gamma-aminobutyric acid (GABA) signaling in the central nervous system is well accepted to have anti-obesity effects through the activation of the sympathetic nervous system. Here we show the previously unknown role of peripheral GABA signaling in the development of systemic metabolic dysfunction in obesity. We generated an obese model by imposing a high fat/high sucrose (HFHS) diet on C57BL/6NCr mice. Mass spectrometry analysis demonstrated a significant increase in GABA level in BAT of the dietary obese model. Addition of GABA into drinking water induced BAT whitening, reduced the thermogenic response upon cold tolerance test, and promoted systemic metabolic dysfunction in the obese mice. Mitochondrial calcium is important for the maintenance of mitochondrial homeostasis, whereas calcium overload is reported to inhibit mitochondrial function. Treatment of BAT cells with GABA markedly increased mitochondrial calcium level, promoted the production of reactive oxygen species (ROS), and inhibited mitochondrial respiration. These results indicate that peripheral GABA contributes to the development of systemic metabolic dysfunction by inhibiting BAT function in obesity. The inhibition of peripheral GABA signaling would become a new therapeutic target for obesity and diabetes.

scholarly journals Changes in uncoupling protein and GLUT4 glucose transporter expressions in interscapular brown adipose tissue of diabetic rats: relative roles of hyperglycaemia and hypoinsulinaemia

1993 ◽  
Vol 291 (1) ◽  
pp. 109-113 ◽  
Author(s):  
R Burcelin ◽  
J Kande ◽  
D Ricquier ◽  
J Girard
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Time Course ◽  
Glucose Transporter ◽  
Uncoupling Protein ◽  
Mrna Level ◽  
Diabetic Rats ◽  
Plasma Insulin Concentration ◽  
Interscapular Brown Adipose Tissue ◽  
Brown Adipose

We have studied the time course and relative effects of hypoinsulinaemia and hyperglycaemia on concentrations of uncoupling protein (UCP) and glucose transporter (GLUT4) and their mRNAs in brown adipose tissue (BAT) during the early phase of diabetes induced by streptozotocin. Two days after intravenous injection of streptozotocin, plasma insulin concentration was at its lowest and glycaemia was higher than 22 mmol/l. After 3 days, a 60% decrease in BAT UCP mRNA concentration and a 36% decrease in UCP was observed. Concomitantly, there was an 80% decrease in GLUT4 mRNA and a 44% decrease in GLUT4 levels. When hyperglycaemia was prevented by infusing phlorizin into diabetic rats, BAT UCP mRNA and protein levels were further decreased (respectively 90% and 60% lower than in control rats). In contrast, the marked decreases in GLUT4 mRNA and protein concentrations in BAT were similar in hyperglycaemic and normoglycaemic diabetic rats. Infusion of physiological amounts of insulin restored normoglycaemia in diabetic rats, and BAT UCP and GLUT4 mRNA and protein concentrations were maintained at the level of control rats. When insulin infusion was stopped, a 75% decrease in BAT UCP mRNA level and a 75% decrease in GLUT4 mRNA level were observed after 24 h, but UCP and GLUT4 concentrations did not decrease. This study shows that insulin plays an important role in the regulation of UCP and GLUT4 mRNA and protein concentrations in BAT. Hyperglycaemia partially prevents the rapid decrease in concentration of UCP and its mRNA observed in insulinopenic diabetes whereas it did not affect the decrease in GLUT4 mRNA and protein concentration. It is suggested that UCP is produced by a glucose-dependent gene.

scholarly journals Peroxisome Proliferator-Activated Receptors-α and -γ, and cAMP-Mediated Pathways, Control Retinol-Binding Protein-4 Gene Expression in Brown Adipose Tissue

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1162-1173 ◽  
Author(s):  
Meritxell Rosell ◽  
Elayne Hondares ◽  
Sadahiko Iwamoto ◽  
Frank J. Gonzalez ◽  
Martin Wabitsch ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Retinol Binding Protein ◽  
Peroxisome Proliferator ◽  
Brown Adipocytes ◽  
Retinol Binding Protein 4 ◽  
White Adipocytes ◽  
Brown Adipose ◽  
Rbp4 Gene

Retinol binding protein-4 (RBP4) is a serum protein involved in the transport of vitamin A. It is known to be produced by the liver and white adipose tissue. RBP4 release by white fat has been proposed to induce insulin resistance. We analyzed the regulation and production of RBP4 in brown adipose tissue. RBP4 gene expression is induced in brown fat from mice exposed to cold or treated with peroxisome proliferator-activated receptor (PPAR) agonists. In brown adipocytes in culture, norepinephrine, cAMP, and activators of PPARγ and PPARα induced RBP4 gene expression and RBP4 protein release. The induction of RBP4 gene expression by norepinephrine required intact PPAR-dependent pathways, as evidenced by impaired response of the RBP4 gene expression to norepinephrine in PPARα-null brown adipocytes or in the presence of inhibitors of PPARγ and PPARα. PPARγ and norepinephrine can also induce the RBP4 gene in white adipocytes, and overexpression of PPARα confers regulation by this PPAR subtype to white adipocytes. The RBP4 gene promoter transcription is activated by cAMP, PPARα, and PPARγ. This is mediated by a PPAR-responsive element capable of binding PPARα and PPARγ and required also for activation by cAMP. The induction of the RBP4 gene expression by norepinephrine in brown adipocytes is protein synthesis dependent and requires PPARγ-coactivator-1-α, which acts as a norepinephine-induced coactivator of PPAR on the RBP4 gene. We conclude that PPARγ- and PPARα-mediated signaling controls RBP4 gene expression and releases in brown adipose tissue, and thermogenic activation induces RBP4 gene expression in brown fat through mechanisms involving PPARγ-coactivator-1-α coactivation of PPAR signaling.

scholarly journals Eicosapentaenoic acid regulates brown adipose tissue metabolism in high-fat-fed mice and in clonal brown adipocytes

2017 ◽  
Vol 39 ◽  
pp. 101-109 ◽  
Author(s):  
Mandana Pahlavani ◽  
Fitia Razafimanjato ◽  
Latha Ramalingam ◽  
Nishan S. Kalupahana ◽  
Hanna Moussa ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Eicosapentaenoic Acid ◽  
Brown Adipose Tissue ◽  
High Fat ◽  
Brown Adipocytes ◽  
Adipose Tissue Metabolism ◽  
Tissue Metabolism ◽  
Brown Adipose

Transient overexpression of Pparγ2 and C/ebpα in mesenchymal stem cells induces brown adipose tissue formation

2013 ◽  
Vol 8 (3) ◽  
pp. 295-308 ◽  
Author(s):  
Dmitriy Sheyn ◽  
Gadi Pelled ◽  
Wafa Tawackoli ◽  
Susan Su ◽  
Shiran Ben-David ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Tissue Formation ◽  
Brown Adipose ◽  
Transient Overexpression

scholarly journals MORPHOLOGY OF HUMAN ADIPOSE TISSUE

2020 ◽  
Vol 20 (2) ◽  
pp. 171-175
Author(s):  
A.P. Stepanchuk
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Subcutaneous Adipose Tissue ◽  
Endocrine Function ◽  
Metabolic Complications ◽  
Brown Adipocytes ◽  
Tissue Samples ◽  
Brown Adipose ◽  
Subcutaneous Adipose ◽  
Interscapular Region

The risk of developing metabolic complications in obesity depends on the topography of excess adipose tissue. Adipose tissue is the main source of energy and also performs an endocrine function secreting substances that affect the sensitivity of tissues to insulin. The article describes the characteristics of histological preparations of adipose tissue samples taken from the omentum of middle-aged human cadavers with no confirmed diseases of the digestive system and of subcutaneous adipose tissue samples from interscapular region in the human dead foetuses. Microscopy of sections of adipose tissue from the omentum and subcutaneous adipose tissue from the interscapular region of the foetus revealed that it consisted of lobes and microvessels. Lobes of adipose tissue of a human large omentum consist of polygonal white adipocytes containing in their cytoplasm a nucleus displaced to the periphery and a fat drop. The subcutaneous adipose tissue taken from the interscapular region of the foetus consists of brown adipocytes with a nucleus located in the centre of the cytoplasm and surrounded by numerous fat droplets. Brown adipocytes when compared with white adipocyted are smaller and rounded in shape. Brown adipose tissue predominates in women than in men. Brown adipose tissue is not active all the time, but only at low ambient temperatures. In women, brown adipocytes are more saturated with mitochondria than in men. Adipose tissue of a human omentum can be a source of graft implant for restoring abdominal organ defects during extensive surgical operations.

scholarly journals Interscapular brown adipose tissue denervation does not promote the oxidative activity of inguinal white adipose tissue in male mice

2018 ◽  
Vol 315 (5) ◽  
pp. E815-E824 ◽  
Author(s):  
Sébastien M. Labbé ◽  
Alexandre Caron ◽  
William T. Festuccia ◽  
Roger Lecomte ◽  
Denis Richard
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Glucose Uptake ◽  
White Adipose Tissue ◽  
Oxidative Activity ◽  
Substrate Uptake ◽  
Adrenergic Stimulation ◽  
Brown Adipocytes ◽  
Apparent Lack ◽  
Brown Adipose

Brown adipose tissue (BAT) thermogenesis is a key controller of energy metabolism. In response to cold or other adrenergic stimuli, brown adipocytes increase their substrate uptake and oxidative activity while uncoupling ATP synthesis from the mitochondrial respiratory chain activity. Brown adipocytes are found in classic depots such as in the interscapular BAT (iBAT). They can also develop in white adipose tissue (WAT), such as in the inguinal WAT (iWAT), where their presence has been associated with metabolic improvements. We previously reported that the induction of oxidative metabolism in iWAT is low compared with that of iBAT, even after sustained adrenergic stimulation. One explanation to this apparent lack of thermogenic ability of iWAT is the presence of an active iBAT, which may prevent the full activation of iWAT. In this study, we evaluated whether iBAT denervation-induced browning of white fat enhanced the thermogenic activity of iWAT following cold acclimation, under beta-3 adrenergic stimulation (CL 316,243). Following a bilateral denervation of iBAT, we assessed energy balance, evaluated the oxidative activity of iBAT and iWAT using 11C-acetate, and quantified the dynamic glucose uptake of those tissues using 2-deoxy-2-[18F]- fluoro-d-glucose. Our results indicate that despite portraying marked browning and mildly enhanced glucose uptake, iWAT of cold-adapted mice does not exhibit significant oxidative activity following beta-3 adrenergic stimulation in the absence of a functional iBAT. The present results suggest that iWAT is not readily recruitable as a thermogenic organ even when functional iBAT is lacking.

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