427 - Reduced Mitochondrial Oxidative Stress Impairs Brown Adipose Tissue-Mediated Thermogenesis in Mice

Abstract

Our recent work identified oxidative stress in adipocyte as a prerequisite for diet-induced thermogenesis and uncoupling protein 1 (UCP1) induction in white and brown adipose tissue of mice. To further confirm this observation, we used mice that overexpressed human catalase targeted to mitochondria (mCAT mice). Similar to the heart, catalase activity was significantly increased in brown adipose tissue (BAT) of mCAT mice compared to wild-type (WT) mice. WT and mCAT mice were fed high fat diet (HFD, 45% calories from fat) or normal chow diet (NCD, 4% calories from fat) for 20 weeks. Oxidative stress markers such as 4-hydroxynonenal and nitrotyrosine were only elevated in BAT of WT mice fed HFD. HFD induced similar weight gain and adiposity in WT and mCAT mice but mCAT mice produced less heat especially when housed at colder temperatures (15°C) or when given a beta-adrenergic agonist to activate thermogenesis. UCP1 expression in BAT was similarly induced by HFD in both WT and mCAT. However, mitochondrial uncoupling, as assessed by proton leak, was reduced in brown preadipocytes isolated from HFD-fed mCAT mice compared to those isolated from WT mice on HFD. To determine if the changes in BAT function affected whole body glucose and insulin homeostasis, we performed glucose and insulin tolerance tests. HFD similarly impaired glucose and insulin tolerance in WT and mCAT mice but induced adipose tissue inflammation only in WT mice. Taken together, these data suggest that oxidative stress is required for diet and cold-induced thermogenesis in mice.