Ablation of uncoupling protein 1 causes opposing changes of glucose uptake in brown and brite fat compatible with regulation of Glut 4 gene expression

Abstract

BackgroundRecruitment and activation of uncoupling protein 1 – dependent thermogenesis in brown and brite fat is a candidate mechanism to promote negative energy balance and improve systemic glucose homeostasis. Non‐shivering thermogenesis mediated by UCP1 is mainly sustained by fatty acid oxidation and to lesser extent by glucose. Glucose supply, however, is essential to run serial and parallel metabolic pathways involved in thermogenesis, including glycolysis, glyceroneogenesis, anabolic bolstering of the citric acid cycle and de novo lipogenesis. Norepinephrine release in the cold stimulates glucose uptake via GLUT1 to support thermogenesis, while insulin stimulates uptake via GLUT4 for the storage of glycogen and triglyceride. It is unclear, however, whether glucose uptake depends on the presence of UCP1.ObjectiveWe aimed to quantify the effect of UCP1 ablation on insulin sensitivity, glucose tolerance and glucose uptake in brown and brite adipose tissues of mice fed either low, intermediate or high fat diets.MethodsWe assessed insulin sensitivity and oral glucose tolerance, and measured 2‐deoxyglucose uptake in different brown and white fat depots of UCP1‐KO and WT mice (B6 and 129 background) housed at thermoneutral temperature. Mice were fed low, intermediate and high fat diets. Transcriptomes of interscapular brown fat and inguinal brite fat were sequenced (RNA‐SEQ) and subjected to bioinformatic analysis.Results and DiscussionIn UCP1‐KO mice fed intermediate and high fat diets, body weight trajectories and body fat mass were rather unchanged or decreased. They rather showed reduced metabolic efficiency when fed the high fat diet, thus challenging a role of UCP1‐dependent thermogenesis in diet‐induced obesity resistance. Oral glucose tolerance, when analyzed as incremental area under the curve, was robustly impaired in UCP1‐KO mice fed intermediate and high fat diets, whereas insulin sensitivity was unchanged. In WT mice, brown fat showed the highest mass‐specific glucose uptake, with total uptake in the interscapular brown fat depot attaining up to 70% of the amount of glucose uptake measured in liver. Glucose uptake in UCP1‐KO mice was reduced in different brown fat depots, irrespective of diet. In contrast, glucose uptake was increased in inguinal brite fat of UCP1‐KO mice fed low fat diet. This increase was attenuated in mice fed intermediate or high fat diets. These differential genotype effects on glucose uptake in brown and brite fat were strongly associated with corresponding changes in Glut4 expression. Our results demonstrate a role of UCP1 in post‐prandial glucose homeostasis, most likely due to the reduced uptake into brown fat. Increased glucose uptake in inguinal brite fat of UCP1‐KO further corroborates the recruitment of alternative UCP1‐independent thermogenic capacity. We conclude that UCP1 is a modulator of adipose tissue glucose uptake and systemic glucose homeostasis.Support or Funding InformationThis work was supported by the EU FP7 project DIABAT (HEALTH‐F2‐2011‐278373), the Deutsche Forschungsgemeinschaft (KL973/13‐1, NUTRIBRITE) and the Else Kröner‐Fresenius Stiftung (EKFS).