Hepatic AKT orchestrates adipose tissue thermogenesis via FGF21-dependent and -independent mechanisms

Organismal stressors such as cold exposure require a systemic response to maintain body temperature. Brown adipose tissue (BAT) is a key thermogenic tissue in mammals that protects against hypothermia in response to cold exposure. Defining the complex interplay of multiple organ systems in this response is fundamental to our understanding of adipose tissue thermogenesis. In this study, we identify a role for hepatic insulin signaling via AKT in the adaptive response to cold stress and show that liver AKT is an essential cell-nonautonomous regulator of adipocyte lipolysis and BAT function. Mechanistically, inhibition of forkhead box O1 (FOXO1) by AKT controls BAT thermogenesis by enhancing catecholamine-induced lipolysis in the white adipose tissue (WAT) and increasing circulating fibroblast growth factor 21 (FGF21). Our data identify a role for hepatic insulin signaling via the AKT-FOXO1 axis in regulating WAT lipolysis, promoting BAT thermogenic capacity, and ensuring a proper thermogenic response to acute cold exposure. [Display omitted] •Hepatic AKT is activated in response to cold exposure and β3 adrenergic stimulation•Lack of AKT in liver leads to cold sensitivity•Hepatic AKT signaling via FOXO1 induces FGF21 expression•FOXO1 cell-nonautonomously regulates adipose tissue thermogenesis Maintaining body temperature upon cold stress is necessary for mammalian survival. Sostre-Colón et al. show that hepatic insulin action via AKT-FOXO1 regulates the thermogenic response, providing fundamental knowledge of the liver’s response to cold exposure and to our understanding of the inter-organ communication that mobilizes energy for heat production.