Date on Master's Thesis/Doctoral Dissertation

5-2014

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Degree Program

Physiology and Biophysics, PhD

Committee Chair

Bhatnagar, Aruni

Subject

Nitric oxide--Therapeutic use; Nitric oxide--Physiological effect; Obesity--Treatment

Abstract

Obesity is a strong risk factor for developing type 2 diabetes and cardiovascular disease and has quickly reached epidemic proportions with few tangible and safe treatment options. While it is generally accepted that the primary cause of obesity is energy imbalance, i.e., more calories are consumed than are utilized, understanding how caloric balance is regulated has proven a challenge. Molecular processes and pathways that directly regulate energy metabolism represent promising targets for therapy. In particular, nitric oxide (NO) is emerging as a central regulator of energy metabolism and body composition. NO bioavailability is decreased in animal models of obesity and in obese and insulin resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. Additionally, deletion of eNOS (the source of NO in the vasculature) is associated with adiposity, insulin resistance and impaired fatty acid oxidation. The role of eNOS in regulating metabolism, however, is not well understood. We propose that decreased vascular-derived NO bioavailability during nutrient excess is a critical development that leads to metabolic dysregulation. The studies presented here show that obesity induces severe metabolic changes in adipose tissue including profound decreases in eNOS abundance. Overexpression of eNOS prevents obesity and its related metabolic alterations while causing significant changes in energy expenditure and systemic metabolism. Our findings reveal potent anti-obesogenic effects of NO and demonstrate a significant role for NO in regulating metabolism.

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