T₃ 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 (T₃) 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 T₃ and glucose in two mouse models and in mouse immortalized brown preadipocytes in culture. We identified carbohydrate response element binding protein (ChREBP) as a T₃ target gene in BAT by RNA sequencing and studied its effects in brown adipocytes. We found that ChREBP was upregulated by T₃ in BAT in both hyperglycemic mouse models. In brown preadipocytes, T₃ 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 T₃ and glucose upregulation of Ucp1 100-fold, whereas overexpression of ChREBP upregulated Ucp1 5.2-fold. We conclude that T₃ and glucose signaling pathways coordinately regulate the metabolic state of BAT and suggest that ChREBP is a target for therapeutic regulation of BAT activity.