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首页> 美国卫生研究院文献>Endocrinology >Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice
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Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice

机译：减少的ATGL介导的脂肪细胞脂解对肥胖相关的胰岛素抵抗和雄性小鼠炎症的影响。

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Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.
机译：越来越多的证据表明，肥胖中脂肪细胞脂解的调节受损会促进代谢组织的促炎性免疫细胞浸润，这一过程被认为有助于胰岛素抵抗的发展和恶化。为了在体内测试该假设，我们产生了脂肪甘油三酸酯脂肪酶（ATGL）的脂肪细胞特异性缺失的小鼠，甘油三酸酯脂肪酶是催化三酰甘油水解的限速酶。与以前的模型相比，脂联素驱动的Cre表达被用于靶向ATGL缺失。然后表征所得的脂肪细胞特异性ATGL基因敲除（AAKO）小鼠的代谢和免疫表型。瘦和饮食诱导的肥胖AAKO小鼠脂肪细胞（AT）和肝脏中的脂肪细胞脂解，血清脂质，全身脂质氧化以及过氧化物酶体增殖物激活受体α靶基因的表达降低。这些变化在24周龄之前并未增加AAKO小鼠的整体体重或脂肪量，部分原因是参与脂质吸收，合成和脂肪形成的基因表达减少。 AAKO小鼠的全身葡萄糖和胰岛素耐受性得到改善，这主要归因于增强的肝胰岛素信号传导，同时饮食引起的肝脂肪变性以及肝免疫细胞浸润和活化显着降低。相反，尽管脂肪细胞ATGL的缺失降低了急性脂解刺激对AT免疫细胞的浸润，但不足以缓解甚至加剧由饮食引起的肥胖引起的AT慢性炎症变化，甚至可能加剧。

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