Uncoupling protein 1 and the capacity for non-shivering thermogenesis are components of the glucose homeostatic system.

Uncoupling protein 1 (Ucp1) provides nonshivering thermogenesis (NST) fueled by the dissipation of energy from macronutrients in brown and brite adipocytes. The availability of thermogenic fuels is facilitated by the uptake of extracellular glucose. This conjunction renders thermogenic adipocytes in brown and white adipose tissue (WAT) a potential target against obesity and glucose intolerance. We employed wild-type (WT) and Ucp1-ablated mice to elucidate this relationship. In three experiments of similar setup, Ucp1-ablated mice fed a high-fat diet (HFD) had either reduced or similar body mass gain, food intake, and metabolic efficiency compared with WT mice, challenging the hypothesized role of this protein in the development of diet-induced obesity. Despite the absence of increased body mass, oral glucose tolerance was robustly impaired in Ucp1-ablated mice in response to HFD. Postprandial glucose uptake was attenuated in brown adipose tissue but enhanced in subcutaneous WAT of Ucp1-ablated mice. These differences were explainable by expression of the insulin-responsive member 4 of the facilitated glucose transporter family and fully in line with the capacity for NST in these very tissues. Thus, the postprandial glucose uptake of adipose tissues serves as a surrogate measure for Ucp1-dependent and independent capacity for NST. Collectively, our findings corroborate Ucp1 as a modulator of adipose tissue glucose uptake and systemic glucose homeostasis but challenge its hypothesized causal effect on the development of obesity.