Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis.
Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis.
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DOI：
10.1016/j.cmet.2017.10.008
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发表时间：
2018-01-09
期刊：
影响因子：
29
通讯作者：
Guertin DA
中科院分区：
文献类型：
--
作者：
Sanchez-Gurmaches J;Tang Y;Jespersen NZ;Wallace M;Martinez Calejman C;Gujja S;Li H;Edwards YJK;Wolfrum C;Metallo CM;Nielsen S;Scheele C;Guertin DA
棕色脂肪组织(BAT)是代谢性疾病的治疗靶点，因此，了解其代谢回路具有重要的临床意义。许多关于蝙蝠的研究将轻度寒冷的啮齿动物与重度寒冷的啮齿动物进行比较。在这里，我们比较了中温和轻度冷适应小鼠的蝙蝠重塑，这两种情况与人类更相关。尽管BAT以分解代谢β氧化能力而闻名，但矛盾的是，我们发现编码ACly、ACSS2、Acc和Fasn的合成新体脂肪生成(DNL)基因是受温和寒冷上调最多的基因之一，在人类中，DNL与UCP1的表达相关。脂肪细胞DNL的调节和功能及其与产热的关系尚不清楚。我们提供的证据表明，AKT2通过刺激ChREBPβ转录活性在脂肪细胞中驱动DNL，寒冷诱导AKT2-ChREBP途径在蝙蝠中优化燃料储存和产热。这些数据提供了对脂肪细胞DNL调节和功能的洞察，并阐明了产热的代谢灵活性。Sanchez-Gurmaches等人。揭示了一种机制，即AKT信号和代谢通过棕色脂肪中的ChREBP相交，同时促进脂质合成和氧化，这是产热的一个矛盾而鲜为人知的特征。这条途径是最佳棕色脂肪功能所必需的，在人类中是保守的。
Brown adipose tissue (BAT) is a therapeutic target for metabolic diseases; thus, understanding its metabolic circuitry is clinically important. Many studies of BAT compare rodents mildly cold to those severely cold. Here, we compared BAT remodeling between thermoneutral and mild cold adapted mice, conditions more relevant to humans. Although BAT is renowned for catabolic β-oxidative capacity, we find paradoxically that the anabolic de novo lipogenesis (DNL) genes encoding ACLY, ACSS2, ACC, and FASN were among the most upregulated by mild cold, and in humans, DNL correlates with Ucp1 expression. The regulation and function of adipocyte DNL and its association with thermogenesis is not understood. We provide evidence suggesting AKT2 drives DNL in adipocytes by stimulating ChREBPβ transcriptional activity and that cold induces the AKT2-ChREBP pathway in BAT to optimize fuel storage and thermogenesis. These data provide insight into adipocyte DNL regulation and function and illustrate the metabolic flexibility of thermogenesis. Sanchez-Gurmaches et al. reveal a mechanism by which AKT signaling and metabolism intersect through ChREBP in brown fat to simultaneously promote lipid synthesis and oxidation, a paradoxical and poorly understood feature of thermogenesis. This pathway is required for optimum brown fat function and conserved in humans.
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