The global increase in obesity and its associated metabolic complications such as type II diabetes is a major concern for the public health. Current pharmaceutical obesity interventions are few and often have limited efficacy. An interesting target for obesity treatment is increasing energy expenditure. Brown adipose tissue (BAT) has the ability to dissipate energy as heat in the process of non-shivering thermogenesis. This unique feature of BAT is conferred by the presence of the mitochondrial uncoupling protein 1, which can disengage the mitochondrial proton gradient from ATP production releasing the stored energy as heat. Physiologically the process is activated by cold exposure but can also be mimicked by stimulation with β-adrenergic agonists.
Finding specific inducers of BAT activity requires detailed knowledge of the signaling cascades governing β-adrenergic stimulated thermogenesis. The first part of this thesis explores this by identifying and investigating two novel kinase regulators of brown adipocyte function. Study 1 demonstrates that spleen tyrosine kinase is a hitherto undescribed regulator of brown adipocyte differentiation and activation. Study 2 identifies glycogen synthase kinase 3 as a negative regulator of the canonical p38 mitogen-activated protein kinase signaling cascade. Thus both studies add novel regulatory layers to the growing understanding of brown adipocyte signal transduction.
Activated BAT also exerts great influence on whole body glucose homeostasis, of great interest for diabetes treatment. The second part of this thesis explores this by investigating glycolytic flux in activated brown adipocytes. Study 3 identifies hypoxia-inducible factor 1α as an important regulator of glycolytic gene expression in brown adipocytes. Study 4 establishes that glycolytic flux is important for β-adrenergically induced oxygen consumption, and highlights that glucose oxidation serves multiple purposes in brown adipocytes. Together the studies describe novel aspects of glucose consumption adding to the understanding of substrate oxidation in activated brown adipocytes. Taken together the research presented in this thesis describes novel aspects of BAT physiology, adding to the growing understanding of brown adipocyte activation and fuel preferences.