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.

中文翻译：

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脂肪细胞中缺乏Gαi2蛋白可减轻饮食引起的肥胖。

目标

通常，肥胖是由于营养物质消耗的能量吸收与卡路里燃烧之间的不适当平衡造成的，这导致了脂肪量的病理性增加。肥胖是胰岛素抵抗和糖尿病的主要原因。抑制性G蛋白（Gα_我）形成，其参与脂肪组织功能的调节一个亚科。在这三个Gα_我成员，即Gα _I1，Gα _I2，Gα _I3中，Gα _I2，蛋白主要在脂肪组织中表达。然而，Gα的功能_I2亚型在脂肪组织和其对肥胖的发展的影响却知之甚少。

方法

通过使用AdipoqCreER ^T2小鼠，我们产生脂肪细胞特异性Gnai2缺陷小鼠来研究Gα _I2功能，特别是在白色和褐色脂肪细胞。给这些小鼠喂食对照饮食（CD）或高脂饮食（HFD）。检查小鼠的肥胖发展，胰岛素抵抗和葡萄糖耐量。我们检查了脂肪细胞的形态和白色脂肪组织中炎症的发展。最后，细胞内cAMP水平作为Gα的指标_我测定信令和甘油释放作为脂肪分解率的一个指标来验证Gα的影响_I2上棕色和白色脂肪细胞的信号传导途径。

结果

Gα的脂肪细胞特异性缺乏_I2显著减少饮食诱发的肥胖症，导致降低的脂肪质量，更小的脂肪细胞和白色相对于同窝对照脂肪组织下降炎症。同时，棕色脂肪细胞的耗氧量和体内测得的能量消耗显着增加。此外，与相应的对照组相比，HFD喂养的脂肪细胞特异性Gnai2缺陷型小鼠的葡萄糖耐量和胰岛素敏感性得到改善。在不存在的Gα _I2，细胞内脂肪细胞cAMP水平的肾上腺素能刺激的增加，其与脂肪分解增加和能量消耗相关。

结论

我们的结论是脂肪细胞Gα _I2是饮食引起的肥胖脂肪细胞脂质含量，导致能量消耗增加一个cAMP依赖的方式抑制脂肪细胞脂肪分解的主要调节。