Uncoupling protein 1 and the capacity for nonshivering thermogenesis are components of the glucose homeostatic system

Abstract

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.

The metabolic effects of mirabegron are mediated primarily by β3‐adrenoceptors

“…The presence of UCP1 is essential for this effect at least in lean mice housed at sub‐thermoneutral temperatures. It has been recently reported that UCP1 knockout mice exhibit lower glucose uptake in thermogenic tissues with compensatory increases in WAT and skeletal muscle in an oral glucose tolerance test 44 . Our results imply that these compensatory mechanisms, if further induced by mirabegron in UCP1 knockout mice, are unable to significantly affect postprandial glucose uptake in these tissues to result in substantial increases in glucose tolerance.…”

Brown adipose tissue lipoprotein and glucose disposal is not determined by thermogenesis in uncoupling protein 1-deficient mice

“…It is known that BAT of cold-exposed Ucp1 -/displays mitochondrial dysfunction, ER stress and inflammation (37,38,76), processes that have been implicated in the development of insulin resistance (37) and reduced cellular glucose uptake (77)(78)(79)(80). In line with an alteration in insulin sensitivity, it has been found that when fed a high fat diet Ucp1 -/mice display impaired glucose clearance (81). Thus, the lower glucose uptake, as well as the associated reduction of lipogenic enzymes, in BAT of acute and chronically activated Ucp1 -/mice (Figures 3 and 4) may be explained by insulin resistance.…”

Regulation of adipocyte thermogenesis: mechanisms controlling obesity

“…It has been reported that Ucp1 À/À mice have impaired adrenergic activation of metabolic rate following four weeks of high fat feeding and that their relative increase in body weight is greater than wild-type animals at thermoneutrality whether fed chow or high fat diet [85]. However, independent investigators have reported that body weight regulation in Ucp1 À/À mice is identical to wild-type animals fed a high fat diet at thermoneutrality [86,91,[94][95][96]. Moreover, severe loss of UCP1 protein in BAT because of other genetic manipulations also does not result in obesity at thermoneutrality [97][98][99][100][101][102].…”