Aerobic Thermogenesis in mtDNA Mutator Mice : Fibroblast Growth Factor 21 at the Nexus of Mitochondrial Stress and Metabolic Adaptation

The functional state of the mitochondrion, the organelle responsible for generating the cellular fuel source adenosine triphosphate, is intricately linked with systemic metabolic fitness, but the precise details of the connection between mitochondria and metabolism are only beginning to become fleshed out. This dissertation investigates the mechanisms through which mitochondria non -autonomously relay signals of energetic stress to peripheral tissues capable of mediating adaptive changes in metabolism. To accomplish these studies, states of mitochondrial stress were modeled in pre-progeroid polymerase gamma mtDNA mutator (POLG) mice challenged with a high-fat diet, in lean and metabolically-perturbed obese mice administered drugs that interact with mitochondrial- dependent pathways, as well as in cultured cells treated with mitochondrial poisons. Paradoxically, high-fat diet feeding appeared to ameliorate metabolic defects present in young POLG mice, mitigating their pre-programmed adaptive starvation-like response to apparent mitochondrial defects. In addition to having complete resistance to diet-induced obesity, these mice displayed a striking diet-induced increase in mitochondrial biogenesis in brown adipose tissue, resulting in increased oxygen consumption and thermogenesis. Mechanistically, this response can be linked to induction of fibroblast growth factor 21 (FGF21), a hepatic-derived endocrine hormone believed to mediate a metabolic response to caloric restriction, but also interestingly an established marker of mitochondrial disease. Moreover, compounds that activate the mitochondrial unfolded protein stress response corrected some metabolic defects and symptoms of progeria exclusively in aging POLG mice. In addition, chemical compounds that uncouple the electron transport chain as well as the widely used biguanide class of anti- diabetic drugs induced FGF21 and promoted oxidative metabolism in both cultured cells and diet-induced obese mice in a manner similar to the HFD-induced phenotype observable in POLG mice. Comprehensively, the studies described in this dissertation provide new mechanistic insight into the multi-faceted functions of FGF21, and implicate this hormone as an adaptive metabolic mediator of mitochondrial stress signal