Hepatic Glucokinase Modulates Obesity Predisposition by Regulating BAT Thermogenesis via Neural Signals

SummaryConsidering the explosive increase in obesity worldwide, there must be an unknown mechanism(s) promoting energy accumulation under conditions of overnutrition. We identified a feed-forward mechanism favoring energy storage, originating in hepatic glucokinase (GK) upregulation. High-fat feeding induced hepatic GK upregulation, and hepatic GK overexpression dose-dependently decreased adaptive thermogenesis by downregulating thermogenesis-related genes in brown adipose tissue (BAT). This intertissue (liver-to-BAT) system consists of the afferent vagus from the liver and sympathetic efferents from the medulla and antagonizes anti-obesity effects of leptin on thermogenesis. Furthermore, upregulation of endogenous GK in the liver by high-fat feeding was more marked in obesity-prone than in obesity-resistant strains and was inversely associated with BAT thermogenesis. Hepatic GK overexpression in obesity-resistant mice promoted weight gain, while hepatic GK knockdown in obesity-prone mice attenuated weight gain with increased adaptive thermogenesis. Thus, this intertissue energy-saving system may contribute to determining obesity predisposition.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (195 K)Download as PowerPoint slideHighlights► High-fat feeding rapidly upregulates hepatic GK particularly in obesity-prone mice ► Hepatic GK induction suppresses BAT thermogenesis and antagonizes leptin's effects ► This intertissue (liver-to-BAT) thrifty system is mediated by a neuronal pathway ► Hepatic GK induction contributes to determining obesity predisposition