Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis

• DOI: 10.1016/j.cmet.2017.10.008
• Publication Date: 2017-11-16T20:03:11Z
• Authors: Joan Sanchez-Gurm...; Yuefeng Tang; Naja Zenius Jespe...; Martina Wallace; Camila Martinez C...; Sharvari Gujja; Huawei Li; Yvonne J.K. Edwards; Christian Wolfrum; Christian M. Metallo; Søren Nielsen; Camilla Scheele; David A. Guertin
• Keywords: Adult; Male; Adipose Tissue, White; Biochemistry; Diabetes Mellitus, Experimental; 03 medical and health sciences; Adipose Tissue, Brown; Journal Article; Adipocytes; Animals; Humans; Molecular Biology; Aged; Aged, 80 and over; 0303 health sciences; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Lipogenesis; Nuclear Proteins; Cell Biology; Middle Aged; Diet; Cellular and Molecular Physiology; Cold Temperature; Mice, Inbred C57BL; Gene Expression Regulation; Female; Energy Metabolism

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 that, in humans, DNL correlates with Ucp1 expression. The regulation and function of adipocyte DNL and its association with thermogenesis are not understood. We provide evidence suggesting that 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.