High-Fat Diet Enhances Triglyceride Recycling, Impairs UCP1-Mediated Thermogenic Activity, and Causes Insulin Resistance in Rat Brown Adipocytes

Brown adipose tissue (BAT) is rich in uncoupling protein 1 (UCP1) and dissipates energy through thermogenesis. However, even though BAT mass and its UCP1 content increase under conditions of diet-induced obesity (DIO), marked expansion of the WAT is not prevented, suggesting impairment of BAT-mediated diet-induced thermogenesis (DIT) in obesity. Thus, the objective of this study was to investigate the metabolic and molecular mechanisms that regulated BAT thermogenesis in DIO. To accomplish this, rats were fed a high-fat diet (HFD) for eight weeks. Subsequently, glucose and fat metabolism and the molecular mechanisms underlying these processes were assessed in BAT adipocytes. Despite increasing BAT mass (1.3-fold), UCP1 content (2.1-fold), and isoproterenol (Iso)-induced lipolysis (1.6-fold), HFD reduced UCP1-mediated glucose (62%) and fatty acid (57%) oxidation, and abrogated insulin-stimulated glucose uptake in BAT adipocytes. Furthermore, phosphoenolpyruvate carboxykinase (PEPCK) and glycerol kinase (GyK) contents, as well as glycerol and palmitate incorporation into lipids were all significantly increased (1.8-fold, 2.1-fold, 2-fold, and 1.7-fold, respectively) in HFD BAT. This coincided with 3.6- and 3.7-fold elevations in lipoprotein lipase (LPL) and cluster of differentiation 36 (CD36), respectively, in HFD BAT adipocytes. Morphological analysis also revealed that these adipocytes were more unilocular in appearance. Altogether, these findings provide novel evidence that HFD suppresses UCP1-mediated thermogenesis, shifts metabolism toward triglyceride recycling, and induces insulin resistance in BAT adipocytes. These adaptive responses to chronic HFD are consistent with a mechanism that attenuates the contribution of BAT to DIT and favors the growth of adipose tissue and the development of obesity. Thus reversal of these adaptive metabolic responses of brown adipocytes to DIO could be of therapeutic value for obesity and its related metabolic disorders.