Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity
Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity
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DOI：
10.15252/embj.201899182
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发表时间：
2018-11-15
期刊：
影响因子：
11.4
通讯作者：
Sumara, Grzegorz
中科院分区：
文献类型：
--
作者：
Loeffler, Mona C.;Mayer, Alexander E.;Sumara, Grzegorz
营养过重与能量消耗减少相结合会导致肥胖和糖尿病。肥胖导致荷尔蒙失衡，其中之一是激活G蛋白偶联受体，利用二酰甘油(DAG)作为第二信使。蛋白激酶D_1(PKD_1)是一种DAG效应器，它整合了多种营养和激素输入，但其在脂肪细胞中的生理作用尚不清楚。在这里，我们表明，PKD1促进脂肪生成，并抑制线粒体碎裂，生物发生，呼吸，和能量消耗依赖的AMP激活的蛋白激酶(AMPK)的方式。此外，由于能量消耗增加，脂肪细胞中缺乏PKD1的小鼠对饮食诱导的肥胖具有抵抗力。脂肪细胞的褐变促进能量消耗，并抵消肥胖。在CCAAT/增强子结合蛋白(C/EBP)-α和增量依赖的方式中，PKD1的缺失一直促进β3-肾上腺素能受体(ADRB3)的表达，从而导致脂肪细胞和皮下脂肪组织中米色标志物的表达增加。最后，脂肪细胞中PKD1的缺失改善了胰岛素敏感性，改善了肝脏脂肪变性。因此，脂肪细胞中PKD1的缺失通过几种互补机制增加能量消耗，可能是治疗肥胖及其相关并发症的一种有吸引力的策略。
Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others activates G protein-coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector, which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet-induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the beta 3-adrenergic receptor (ADRB3) in a CCAAT/enhancer binding protein (C/EBP)-alpha- and delta-dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis. Thus, depletion of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.