Dataset Information

Lack of G?_i2 proteins in adipocytes attenuates diet-induced obesity.

ABSTRACT:

Objectives

Typically, obesity results from an inappropriate balance between energy uptake from nutrient consumption and burning of calories, which leads to a pathological increase in fat mass. Obesity is a major cause of insulin resistance and diabetes. Inhibitory G proteins (G?_i) form a subfamily that is involved in the regulation of adipose tissue function. Among the three G?_i members, i.e. G?_i1, G?_i2, G?_i3, the G?_i2, protein is predominantly expressed in adipose tissue. However, the functions of the G?_i2 isoform in adipose tissue and its impact on the development of obesity are poorly understood.

Methods

By using AdipoqCreER^T2 mice, we generated adipocyte-specific Gnai2-deficient mice to study G?_i2 function, specifically in white and brown adipocytes. These mice were fed either a control diet (CD) or a high fat diet (HFD). Mice were examined for obesity development, insulin resistance and glucose intolerance. We examined adipocyte morphology and the development of inflammation in the white adipose tissue. Finally, intracellular cAMP levels as an indicator of G?_i signaling and glycerol release as an indicator of lipolysis rates were measured to verify the impact of G?_i2 on the signaling pathway in brown and white adipocytes.

Results

An adipocyte-specific deficiency of G?_i2 significantly reduced diet-induced obesity, leading to decreased fat masses, smaller adipocytes and decreased inflammation in the white adipose tissue relative to littermate controls. Concurrently, oxygen consumption of brown adipocytes and in vivo measured energy expenditure were significantly enhanced. In addition, glucose tolerance and insulin sensitivity of HFD-fed adipocyte-specific Gnai2-deficient mice were improved compared to the respective controls. In the absence of G?_i2, adrenergic stimulation of intracellular adipocyte cAMP levels was increased, which correlated with increased lipolysis and energy expenditure.

Conclusion

We conclude that adipocyte G?_i2 is a major regulator of adipocyte lipid content in diet-induced obesity by inhibiting adipocyte lipolysis in a cAMP-dependent manner resulting in increased energy expenditure.

SUBMITTER: Leiss V

PROVIDER: S-EPMC7306590 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Lack of Gαi2 proteins in adipocytes attenuates diet-induced obesity.

Leiss Veronika V Schönsiegel Annika A Gnad Thorsten T Kerner Johannes J Kaur Jyotsna J Sartorius Tina T Machann Jürgen J Schick Fritz F Birnbaumer Lutz L Häring Hans-Ulrich HU Pfeifer Alexander A Nürnberg Bernd B

Molecular metabolism 20200530

<h4>Objectives</h4>Typically, obesity results from an inappropriate balance between energy uptake from nutrient consumption and burning of calories, which leads to a pathological increase in fat mass. Obesity is a major cause of insulin resistance and diabetes. Inhibitory G proteins (Gαi) form a subfamily that is involved in the regulation of adipose tissue function. Among the three Gαi members, i.e. Gαi1, Gαi2, Gαi3, the Gαi2, pr ...[more]

PMID: 32480042

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Project description:P2Y2, a G protein-coupled receptor (R), is expressed in all organs involved in the development of obesity and insulin resistance. To explore the role of it in diet-induced obesity, we fed male P2Y2-R whole body knockout (KO) and wild type (WT) mice (B6D2 genetic background) with regular diet (CNT; 10% calories as fat) or high-fat diet (HFD; 60% calories as fat) with free access to food and water for 16 weeks, and euthanized them. Adjusted for body weights (BW), KO mice consumed modestly, but significantly more HFD vs. WT mice, and excreted well-formed feces with no taint of fat or oil. Starting from the 2nd week, HFD-WT mice displayed significantly higher BW with terminal mean difference of 22% vs. HFD-KO mice. Terminal weights of white adipose tissue (WAT) were significantly lower in the HFD-KO vs. HFD-WT mice. The expression of P2Y2-R mRNA in WAT was increased by 2-fold in HFD-fed WT mice. Serum insulin, leptin and adiponectin levels were significantly elevated in the HFD-WT mice, but not in the HFD-KO mice. When induced in vitro, preadipocytes derived from KO mice fed regular diet did not differentiate and mature as robustly as those from the WT mice, as assessed by cellular expansion and accumulation of lipid droplets. Blockade of P2Y2-R by AR-C118925 in preadipocytes derived from WT mice prevented differentiation and maturation. Under basal conditions, KO mice had significantly higher serum triglycerides and showed slightly impaired lipid tolerance as compared to the WT mice. HFD-fed KO mice had significantly better glucose tolerance (GTT) as compared to HFD-fed WT mice. Whole body insulin sensitivity and mRNA expression of insulin receptor, IRS-1 and GLUT4 in WAT was significantly higher in HFD-fed KO mice vs. HFD-fed WT mice. On the contrary, the expression of pro-inflammatory molecules MCP-1, CCR2, CD68, and F4/80 were significantly higher in the WAT of HFD-fed WT vs. HFD-fed KO mice. These data suggest that P2Y2-R plays a significant role in the development of diet-induced obesity by promoting adipogenesis and inflammation, and altering the production of adipokines and lipids and their metabolism in adipose tissue, and thereby facilitates HFD-induced insulin resistance.

Dataset Information

Lack of G?_i2 proteins in adipocytes attenuates diet-induced obesity.

Objectives

Methods

Results

Conclusion

Publications

Lack of Gα<sub>i2</sub> proteins in adipocytes attenuates diet-induced obesity.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Lack of G?i2 proteins in adipocytes attenuates diet-induced obesity.

Objectives

Methods

Results

Conclusion

Publications

Lack of Gα<sub>i2</sub> proteins in adipocytes attenuates diet-induced obesity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Lack of G?_i2 proteins in adipocytes attenuates diet-induced obesity.