Lack of Gαi2 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 (Gα_i) form a subfamily that is involved in the regulation of adipose tissue function. Among the three Gα_i members, i.e. Gα_i1, Gα_i2, Gα_i3, the Gα_i2, protein is predominantly expressed in adipose tissue. However, the functions of the Gα_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 Gα_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 Gα_i signaling and glycerol release as an indicator of lipolysis rates were measured to verify the impact of Gα_i2 on the signaling pathway in brown and white adipocytes.

Results: An adipocyte-specific deficiency of Gα_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 Gα_i2, adrenergic stimulation of intracellular adipocyte cAMP levels was increased, which correlated with increased lipolysis and energy expenditure.

Conclusion: We conclude that adipocyte Gα_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.

Keywords: Adipocytes; G proteins; Gnai2; High fat diet; Insulin; Obesity; White adipose tissue; brown adipose tissue.