T(3) and Glucose Coordinately Stimulate ChREBP-Mediated Ucp1 Expression in Brown Adipocytes From Male Mice

Increasing brown adipose tissue (BAT) activity is regarded as a potential treatment of obese, hyperglycemic patients with metabolic syndrome. Triiodothyronine (T(3)) is known to stimulate BAT activity by increasing mitochondrial uncoupling protein 1 (Ucp1) gene transcription, leading to increased thermogenesis and decreased body weight. Here we report our studies on the effects of T(3) and glucose in two mouse models and in mouse immortalized brown preadipocytes in culture. We identified carbohydrate response element binding protein (ChREBP) as a T(3) target gene in BAT by RNA sequencing and studied its effects in brown adipocytes. We found that ChREBP was upregulated by T(3) in BAT in both hyperglycemic mouse models. In brown preadipocytes, T(3) and glucose synergistically and dose dependently upregulated Ucp1 messenger RNA 1000-fold compared with low glucose concentrations. Additionally, we observed increased ChREBP and Ucp1 protein 11.7- and 19.9-fold, respectively, along with concomitant induction of a hypermetabolic state. Moreover, downregulation of ChREBP inhibited T(3) and glucose upregulation of Ucp1 100-fold, whereas overexpression of ChREBP upregulated Ucp1 5.2-fold. We conclude that T(3) and glucose signaling pathways coordinately regulate the metabolic state of BAT and suggest that ChREBP is a target for therapeutic regulation of BAT activity.