Defective adaptive thermogenesis contributes to metabolic syndrome and liver steatosis in obese mice

Fatty liver diseases are complications of the metabolic syndrome associated with obesity, insulin resistance and low grade inflammation. Our aim was to uncover mechanisms contributing to hepatic complications in this setting. We used foz/foz mice prone to obesity, insulin resistance and progressive fibrosing non-alcoholic steatohepatitis (NASH). Foz/foz mice are hyperphagic but wild-type (WT)-matched calorie intake failed to protect against obesity, adipose inflammation and glucose intolerance. Obese foz/foz mice had similar physical activity level but reduced energy expenditure. Thermogenic adaptation to high-fat diet (HFD) or to cold exposure was severely impaired in foz/foz mice compared with HFD-fed WT littermates due to lower sympathetic tone in their brown adipose tissue (BAT). Intermittent cold exposure (ICE) restored BAT function and thereby improved glucose tolerance, decreased fat mass and liver steatosis. We conclude that failure of BAT adaptation drives the metabolic complications of obesity in foz/foz mice, including development of liver steatosis. Induction of endogenous BAT function had a significant therapeutic impact on obesity, glucose tolerance and liver complications and is a potential new avenue for therapy of non-alcoholic fatty liver disease (NAFLD)This work was supported by the Communaute franc ´ ¸aise de Belgique – Actions de Recherche Concertees [grant number 12/17- ´ 047]; the Fund for Scientific Medical Research [grant number PDR T.1067.14] and unrestricted research grants from Gilead Belgium, Janssens Pharmaceutica Belgium, and Roche Belgium. I.A.L. is senior research associate with the Belgian National Fund for Scientific Research (FNRS) and fellowship to V.L. has been supported by the Institut de Recherche experimentale et Clinique (IREC) at the ´ Universite catholique de Louvain, Brussels, Belgium. The behavior ´ platform was supported by the Programme d’Excellence Marshall, Wallonia regio and Universite catholique de Louvain (Diane conven- ´ tion)