MOLECULAR 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: _____________
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07312009-144804 |
| Date | 03 August 2009 |
| Creators | Posey, Kelly Ann |
| Contributors | Alan Cherrington, Richard O'Brien, Owen McGuinness, Maureen Gannon, Larry Swift |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-07312009-144804/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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