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

TY - JOUR

T1 - Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis

AU - Sanchez-Gurmaches, Joan

AU - Tang, Yuefeng

AU - Jespersen, Naja Zenius

AU - Wallace, Martina

AU - Martinez Calejman, Camila

AU - Gujja, Sharvari

AU - Li, Huawei

AU - Edwards, Yvonne J K

AU - Wolfrum, Christian

AU - Metallo, Christian M

AU - Nielsen, Søren

AU - Scheele, Camilla

AU - Guertin, David A

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2018/1/9

Y1 - 2018/1/9

N2 - 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. 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.

AB - 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. 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.

KW - Journal Article

U2 - 10.1016/j.cmet.2017.10.008

DO - 10.1016/j.cmet.2017.10.008

M3 - Journal article

C2 - 29153407

SN - 1550-4131

VL - 27

SP - 195-209.e6

JO - Cell Metabolism

JF - Cell Metabolism

IS - 1

ER -