Thyroidal Regulation of Substrate Metabolism in Fasting Northern Elephant Seal Pups; FASTING, Re-defined

To a number of physiological and pathological human conditions, there are a variety of natural animal models that can be studied in an effort to obtain greater knowledge and insight into the progression of the disease, as well as enable more accurate and successful therapeutic strategies. The northern elephant seal, specifically the fasting pups, have been established as a powerful, natural model for a number of human diseases, including the onset and development of insulin resistance. Thyroidal regulation has been implicated to change or be changed during the progression of the disease. Therefore, the aim of this dissertation is to elucidate how the two are regulating one another, and specifically what the contributions of an active thyroidal system are, to the regulation of substrate metabolism, especially lipid. In the first chapter, we demonstrated that despite a prolonged fasting period, northern elephant seal pups do not down-regulate thyroid hormone-mediated events, but rather increase all components that would result in increased cellular metabolism. In the second chapter we showed that fasting duration increases the sensitivity of adipose TH-mediated mechanisms to insulin, some of which may be mediated by increased glucose. The third chapter underscored the physiological relevance of an increased thyroidal status, which very clearly is substantially up-regulated with fasting duration, as the thyroid gland evidently increases its production of thyroid hormones with fasting duration. The fourth chapter reveals the contribution of this perplexing physiological response to fasting and its capacity to not only drive lipid metabolism but also lead the system into a necessary state of insulin resistance. Evolution has led some species to develop unique adaptations to environmental influences and lifestyles that are fascinating, perplexing and, if only understood, bare solutions to widespread health issues. Elephant seals are such a species. Despite prolonged fasting their metabolism neither slows down nor reduces its sensitivity to stimulation, as is common, to avoid resource depletion. Instead we find the opposite. Increased thyroid hormone levels and dynamic response to thyroid gland stimulation reveal how the seals thrive on a fasting-driven body fat diet. These studies have the potential to elucidate new therapeutic targets for hormone treatment of human obesity and related metabolic dysfunctions