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

Exercise-induced ‘browning’ of adipose tissues

Global rates of obesity continue to rise and are necessarily the consequence of a long-term imbalance between energy intake and energy expenditure. This is the result of an expansion of adipose tissue due to both the hypertrophy of existing adipocytes and hyperplasia of adipocyte precursors. Exercise elicits numerous physiological benefits on adipose tissue, which are likely to contribute to the associated cardiometabolic benefits. More recently it has been demonstrated that exercise, through a range of mechanisms, induces a phenotypic switch in adipose tissue from energy storing white adipocytes to thermogenic beige adipocytes. This has generated the hypothesis that the process of adipocyte ‘browning’ may partially underlie the improved cardiometabolic health in physically active populations. Interestingly, ‘browning’ also occurs in response to various stressors and could represent an adaptive response. In the context of exercise, it is not clear whether the appearance of beige adipocytes is metabolically beneficial or whether they occur as a transient adaptive process to exercise-induced stresses. The present review discusses the various mechanisms (e.g. fatty acid oxidation during exercise, decreased thermal insulation, stressors and angiogenesis) by which the exercise-induced ‘browning’ process may occur

Resistance Exercise Training Improves Metabolic and Inflammatory Control in Adipose and Muscle Tissues in Mice Fed a High-Fat Diet

This study investigates whether ladder climbing (LC), as a model of resistance exercise, can reverse whole-body and skeletal muscle deleterious metabolic and inflammatory effects of high-fat (HF) diet-induced obesity in mice. To accomplish this, Swiss mice were fed for 17 weeks either standard chow (SC) or an HF diet and then randomly assigned to remain sedentary or to undergo 8 weeks of LC training with progressive increases in resistance weight. Prior to beginning the exercise intervention, HF-fed animals displayed a 47% increase in body weight (BW) and impaired ability to clear blood glucose during an insulin tolerance test (ITT) when compared to SC animals. However, 8 weeks of LC significantly reduced BW, adipocyte size, as well as glycemia under fasting and during the ITT in HF-fed rats. LC also increased the phosphorylation of AktSer473 and AMPKThr172 and reduced tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL1-β) contents in the quadriceps muscles of HF-fed mice. Additionally, LC reduced the gene expression of inflammatory markers and attenuated HF-diet-induced NADPH oxidase subunit gp91phox in skeletal muscles. LC training was effective in reducing adiposity and the content of inflammatory mediators in skeletal muscle and improved whole-body glycemic control in mice fed an HF diet