Center for Human Nutrition, Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine , St. Louis, Missouri.
Department of Ophthalmology, Washington University School of Medicine , St. Louis, Missouri.
Am J Physiol Endocrinol Metab. 2018 Oct 1;315(4):E520-E530. doi: 10.1152/ajpendo.00057.2018. Epub 2018 Apr 10.
Mitochondrial dysfunction in adipose tissue is involved in the pathophysiology of obesity-induced systemic metabolic complications, such as type 2 diabetes, insulin resistance, and dyslipidemia. However, the mechanisms responsible for obesity-induced adipose tissue mitochondrial dysfunction are not clear. The aim of present study was to test the hypothesis that nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin-3 (SIRT3) in adipocytes plays a critical role in adipose tissue mitochondrial biology and obesity. We first measured adipose tissue SIRT3 expression in obese and lean mice. Next, adipocyte-specific mitochondrial Sirt3 knockout (AMiSKO) mice were generated and metabolically characterized. We evaluated glucose and lipid metabolism in adult mice fed either a regular-chow diet or high-fat diet (HFD) and in aged mice. We also determined the effects of Sirt3 deletion on adipose tissue metabolism and mitochondrial biology. Supporting our hypothesis, obese mice had decreased SIRT3 gene and protein expression in adipose tissue. However, despite successful knockout of SIRT3, AMiSKO mice had normal glucose and lipid metabolism and did not change metabolic responses to HFD-feeding and aging. In addition, loss of SIRT3 had no major impact on putative SIRT3 targets, key metabolic pathways, and mitochondrial function in white and brown adipose tissue. Collectively, these findings suggest that adipocyte SIRT3 is dispensable for maintaining normal adipose tissue mitochondrial function and whole body metabolism. Contrary to our hypothesis, loss of SIRT3 function in adipocytes is unlikely to contribute to the pathophysiology of obesity-induced metabolic complications.
脂肪组织中线粒体功能障碍与肥胖引起的全身代谢并发症的病理生理学有关，如 2 型糖尿病、胰岛素抵抗和血脂异常。然而，导致肥胖引起的脂肪组织中线粒体功能障碍的机制尚不清楚。本研究旨在验证这样一个假设，即在脂肪细胞中，烟酰胺腺嘌呤二核苷酸（NAD）依赖性去乙酰化酶 SIRT3 对于脂肪组织中线粒体生物学和肥胖起着关键作用。我们首先测量了肥胖和瘦小鼠的脂肪组织 SIRT3 表达。接下来，生成了脂肪细胞特异性线粒体 Sirt3 敲除（AMiSKO）小鼠并对其进行了代谢特征分析。我们评估了常规饮食或高脂肪饮食（HFD）喂养的成年小鼠以及老年小鼠的葡萄糖和脂质代谢情况。我们还确定了 Sirt3 缺失对脂肪组织代谢和线粒体生物学的影响。支持我们的假设，肥胖小鼠的脂肪组织中 SIRT3 基因和蛋白表达降低。然而，尽管 SIRT3 成功敲除，AMiSKO 小鼠的葡萄糖和脂质代谢正常，并且对 HFD 喂养和衰老的代谢反应没有改变。此外，SIRT3 的缺失对白色和棕色脂肪组织中的假定 SIRT3 靶标、关键代谢途径和线粒体功能没有重大影响。总的来说，这些发现表明脂肪细胞 SIRT3 对于维持正常脂肪组织线粒体功能和全身代谢是可有可无的。与我们的假设相反，脂肪细胞中 SIRT3 功能的缺失不太可能导致肥胖引起的代谢并发症的病理生理学变化。
