Type of Document Dissertation Author Posey, Kelly Ann URN etd-07312009-144804 Title The role of dietary fat in hypothalamic insulin and leptin resistance and the pathogenesis of obesity Degree PhD Department Molecular Physiology and Biophysics Advisory Committee
Advisor Name Title Alan Cherrington Committee Chair Larry Swift Committee Member Maureen Gannon Committee Member Owen McGuinness Committee Member Richard O'Brien Committee Member Keywords
- energy homeostasis
Date of Defense 2009-07-21 Availability unrestricted AbstractMOLECULAR PHYSIOLOGY AND BIOPHYSICS
THE ROLE OF DIETARY FAT IN HYPOTHALAMIC INSULIN AND LEPTIN RESISTANCE AND THE PATHOGENESIS OF OBESITY
KELLY ANN POSEY
Dissertation under the direction of Kevin D. Niswender, M.D., PhD.
Obesity has rapidly become a worldwide epidemic with a seemingly uncontrollable increase in prevalency. Yet, abundant evidence indicates that body weight is a tightly regulated physiological variable such that caloric intake is closely matched to energy expenditure over time to maintain a stable body weight and adiposity. The regulation of body adiposity can be modeled as a classical endocrine feedback loop in which the peripheral adiposity signals, insulin and leptin, convey the status of energy stores to the hypothalamus and coordinately regulate food intake and energy expenditure to promote the stability of adipose stores. Conversely, typical human obesity is characterized by hypothalamic resistance to the adiporegulatory effects of insulin and leptin and represents a state of dysregulated energy homeostasis.
Although many factors are implicated in the development of obesity, dietary fat remains one of the most potent predictors of obesity. Therefore, I sought to elucidate potential mechanisms involved in the development of high-fat diet-induced hypothalamic insulin and leptin resistance and whether it contributes to the onset of obesity. My overall hypothesis is that dietary fat per se and not excess caloric intake contributes, either directly or indirectly, to the development of hypothalamic insulin and leptin resistance resulting in impaired regulation of body fat and the development of obesity.
Results from these studies support a model in which cellular exposure to excess nutrients, particularly saturated fat, triggers cellular inflammation and insulin resistance that in turn contributes to impaired energy homeostasis and obesity. While insulin and leptin both function as adiposity negative feedback signals, studies performed at the onset of obesity suggest that the development of high-fat diet-induced hypothalamic insulin and leptin resistance are temporally and mechanistically distinct.
This body of work extends previous findings and describes potential mechanisms involved in the development of high-fat diet-induced hypothalamic insulin and leptin resistance and obesity. Further elucidation of the mechanisms involved in hypothalamic resistance and the distinct functional roles of these adiposity hormones will aid in the development of therapeutic treatments to curb the obesity epidemic.
Approved: ______________________________________ Date: _____________
Filename Size Approximate Download Time (Hours:Minutes:Seconds)
28.8 Modem 56K Modem ISDN (64 Kb) ISDN (128 Kb) Higher-speed Access Finalthesis.pdf 1.00 Mb 00:04:39 00:02:23 00:02:05 00:01:02 00:00:05