Student Theses and Dissertations

Date of Award

2008

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Friedman Laboratory

Abstract

Obesity is rapidly increasing in prevalence, and has become one of the leading contributors to poor health in the world. Increased body weight by necessity must be a result of increased nutrient intake relative to total energy expenditure. While many have focused on the importance of caloric consumption in determining weight, it is increasingly clear that differences in energy expenditure, basal metabolic rates and/or adaptive thermogenesis are also important variables that contribute to human obesity. The experiments in this thesis start off by demonstrating that a significant portion of leptin-mediated weight loss is the result of an increase in energy expenditure caused by the hormone. They then go on to take a closer look at three candidate organs in which such changes in caloric expenditure are likely to be occurring. Our study finds that leptin treatment of ob/ob mice reduces the basal metabolic rate, uncoupled respiration (i.e. leak), and non-mitochondrial respiration of primary hepatocytes. We show that this is due to changes in the substrate oxidation system in liver mitochondria as well as changes in mitochondrial structure, and volume density. These changes are directly caused by leptin, and are not downstream of the hormone’s correction of hepatic steatosis. We next explored the proteomic and lipidomic modifications underlying the changes discussed above. Leptin-mediated changes in three components of the 1mitochondrial respiratory chain can account for the aforementioned metabolic effects of the hormone in the liver. Dramatic alterations in levels of the enzyme ELOVL5 might be responsible for the hepatic steatosis exhibited with leptin deficiency, and for its correction with leptin treatment. Furthermore, differences in mitochondrial cardiolipin levels may also be associated with the observed leptin-mediated changes in the liver. Finally, we show a trend that leptin may be altering the levels of reactive oxygen species in hepatic mitochondria. Having completed a thorough investigation into leptin-mediated changes in the liver, we moved on to the other two candidate organs, the heart and skeletal muscle. Our results show that leptin clearly modulates mitochondrial respiration in these tissues, though we cannot yet say exactly how it does so. In conclusion, this thesis illustrates the effects of leptin levels on the liver, and details the mechanisms by which the hormone induces change down to the proteomic level. It also shows clear leptin-mediated effects in skeletal muscle and the heart, and sets the stage for further investigation into the role of these tissues in leptin induced weight loss.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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