ATF4 Deletion in Brown Adipocytes Attenuates Diet-Induced Insulin Resistance in Male Mice Independently of Weight Gain

Expression of the activating transcription factor 4 (ATF4) in thermogenic adipocytes is required to maintain core body temperature and systemic metabolic homeostasis in models of mitochondrial stress. We have recently shown that ATF4 is required for thermoregulation in response to cold stress in mice, establishing a role for ATF4 in regulating brown adipose tissue (BAT) function during physiological stress. In the present study, we investigated the role of ATF4 in thermogenic adipocytes in regulating glucose metabolism and energy homeostasis during diet-induced obesity (DIO). To this end, we generated mice with selective Atf4 deletion in BAT (ATF4 BKO). After 12 weeks of high-fat-feeding, ATF4 BKO mice had similar weight gain and total fat mass relative to wild-type mice. Accordingly, no changes in food intake, locomotor activity, or energy expenditure were detected between genotypes. Nonetheless, diet-induced glucose intolerance and insulin resistance were attenuated in ATF4 BKO mice, which correlated with reduced markers of inflammation and increased levels of glucose transporters in BAT. Taken together, our results indicate that Atf4 deficiency in BAT during DIO improves glucose homeostasis and insulin sensitivity in mice without affecting energy homeostasis. Mechanistically, our data suggest ATF4 deletion leads to repressed inflammation in BAT of obese mice, while likely increasing glucose uptake and utilization, thereby contributing to overall improvement in glucose homeostasis.