CHCHD10 Modulates Thermogenesis of Adipocytes by Regulating Lipolysis
CHCHD10 Modulates Thermogenesis of Adipocytes by Regulating Lipolysis
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CHCHD10 通过调节脂肪分解来调节脂肪细胞的产热
DOI：
10.2337/db21-0999
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发表时间：
2022-09-01
期刊：
影响因子：
7.7
通讯作者：
Liu, Yang
中科院分区：
文献类型：
--
作者：
Ding, Meng;Ma, Yin-jun;Liu, Yang
棕色和米色脂肪细胞以一种不颤抖的产热方式消耗能量，对代谢稳态产生有益的影响。CHCHD10是一种核编码的线粒体蛋白，参与了眉骨组织的形成；然而，它在生热脂肪细胞中的作用尚不清楚。我们发现CHCHD10是一种新的脂肪细胞产热调节因子。在人和小鼠的脂肪组织中，CHCHD10在PPARγ-PGC1α激活的热源性脂肪细胞中显著上调，并与UCP1的表达呈正相关。我们建立了脂肪细胞特异性Chchd10基因敲除小鼠(Chchd10-AKO)，发现在禁食状态下，耗尽CHCHD10会导致UCP1依赖的产热和能量消耗受损，而在进食状态下没有影响。CHCHD10缺乏可破坏脂肪细胞的脂解作用，而通过ATGL过表达而增强的脂解作用可恢复Chchd10-AKO小鼠的脂肪细胞产热。Chchd10的过度表达一直以来都能激活产热脂肪细胞。从机制上讲，CHCHD10缺乏导致线粒体脊的解体，导致线粒体氧化磷酸化复合体组装受损，进而抑制ATP的生成。三磷酸腺苷的减少通过减少ATGL的新生蛋白质合成，从而抑制脂肪细胞的产热，从而导致脂解下调。因此，Chchd10-AKO小鼠容易患上高脂饮食诱导的代谢紊乱。总之，我们的发现揭示了CHCHD10在调节脂肪细胞的脂肪分解和生热程序中的重要作用。
Brown and beige adipocytes dissipate energy in a nonshivering thermogenesis manner, exerting beneficial effects on metabolic homeostasis. CHCHD10 is a nuclear-encoded mitochondrial protein involved in cristae organization; however, its role in thermogenic adipocytes remains unknown. We identify CHCHD10 as a novel regulator for adipocyte thermogenesis. CHCHD10 is dramatically upregulated during thermogenic adipocyte activation by PPAR gamma-PGC1 alpha and positively correlated with UCP1 expression in adipose tissues from humans and mice. We generated adipocyte-specific Chchd10 knockout mice (Chchd10-AKO) and found that depleting CHCHD10 leads to impaired UCP1-dependent thermogenesis and energy expenditure in the fasting state, with no effect in the fed state. Lipolysis in adipocytes is disrupted by CHCHD10 deficiency, while augmented lipolysis through ATGL overexpression recovers adipocyte thermogenesis in Chchd10-AKO mice. Consistently, overexpression of Chchd10 activates thermogenic adipocytes. Mechanistically, CHCHD10 deficiency results in the disorganization of mitochondrial cristae, leading to impairment of oxidative phosphorylation complex assembly in mitochondria, which in turn inhibits ATP generation. Decreased ATP results in downregulation of lipolysis by reducing nascent protein synthesis of ATGL, thereby suppressing adipocyte thermogenesis. As a result, Chchd10-AKO mice are prone to develop high-fat diet-induced metabolic disorders. Together, our findings reveal an essential role of CHCHD10 in regulating lipolysis and the thermogenic program in adipocytes.