Pharmacological and Cold-Induced Alterations in Glucose and Fat Utilization: Implications for Tissue-Specific and Whole-Body Energy Metabolism

This dissertation presents two possible approaches to enhancing glucose utilization, improving insulin sensitivity and reducing fat mass that could have therapeutic value for the treatment of obesity and type 2 diabetes (T2D). The results of my first study showed that suppressing the import of long-chain fatty acids into the mitochondria improved glucose homeostasis while also reducing fat mass. A reduction in lipogenesis in the white adipose tissue (WAT) explained the reduction in fat mass as lipolysis was also reduced. Subsequent studies examined the effects that activation of cold-induced thermogenesis would have on whole-body and tissue-specific metabolism. I confirmed that cold exposure increases UCP1 content (induces browning) in the subcutaneous (Sc) inguinal (Ing) WAT, but it did not enhance substrate oxidation in this fat depot. Instead, cold acclimation activated a futile cycle of lipolysis and lipogenesis that contributed to increasing energy expenditure within this fat depot. This futile cycle was not activated in the epididymal (Epid) fat, confirming that cold induced a fat depot-specific browning adaptive response. I then studied the hormone fibroblast growth factor 21 (FGF21) as a factor that could explain this depot-specific difference. FGF21 content and secretion was enhanced in the Sc Ing WAT, but not the Epid WAT depot. The downstream signaling pathway was also only activated in the Sc Ing WAT depot, suggesting that FGF21 could be involved in the depot-specific browning that I observed. Additional studies showed that muscles rich in both type I and type II fibers enhanced their FA oxidation following cold exposure. However it was only muscles rich in type I fibers that enhanced expression of the glucose transporter Glut4 while also reducing phosphorylation of glycogen synthase, leading to an increase in glycogen synthesis rate and glycogen content after cold acclimation. Liver glycogen content was reduced following cold acclimation, while gluconeogenesis was enhanced in this organ. Despite a cold-induced increase in food intake and endogenous glucose production, and reduction in plasma insulin, circulating glucose remained unchanged. These results show that activation of cold-induced thermogenesis can enhance insulin sensitivity and could be a viable alternative treatment for diseases such as obesity and T2D.