Medical Student Research Fellowship for Summer 2010
Mentor: Deborah Clegg
Department: Internal Medicine/Clinical Nutrition
Room number: K5.252
Mail Code: 8854
Phone number: 214-648-3401
Project title: Estrogen and peripheral regulation of body weight
Animal subjects IRB approved project number: A34722-01; 2008-2010
Project Type animal-based research, and/or basic research
Brief Description of Project: Estrogen and Peripheral Regulation of Body Weight
Females are protected against metabolic perturbations known to cause the Metabolic Syndrome and insulin resistance (IR) when compared to males. In the United States, approximately 4000 women enter menopause each day, and these individuals are at increased risk for developing obesity, IR, and diabetes. Estrogen replacement therapy is an established way to reduce these risks. However, due to ubiquitous expression of estrogen receptors (ERs), especially in peripheral tissues, the metabolic benefits provided by estrogen are often associated with increased risk of heart disease and breast cancer. Disruption of estrogen (E2) signaling by estrogen receptor (ER)-? ablation yields an obese, glucose intolerant phenotype in rodents and humans. Together these findings support a role for E2 and ER? in preventing obesity and in maintaining insulin sensitivity (IS); however, the molecular mechanisms and tissue specific sites conferring ER? activity are unknown. We have developed an exciting and novel mouse model with which we can study the effects of ER? specifically in adipocytes. To this end we have employed the ER? floxed mouse crossed to a mouse that expresses CRE recombinase under the control of the adiponectin promoter. Our lab has also developed a technique where by we can manipulate gene expression in a fat pad specific way. Finally, we have produced mouse embryo fibroblasts from these mice (both ER?lox/lox/Adipo-CRE and ER?lox/lox) of which we have differentiated to adipocytes. These data together, strongly suggest that reduced ER? in adipose tissue, moreover specifically in the adipocytes themselves has profound effects on adipose tissue function. Therefore, we are in the process of investigating the critical sites of estrogen action for protecting women from the Metabolic Syndrome may be at the level of adipose tissue. Students will be exposed to transgenic mice, metabolically phenotyping mice, molecular analysis of tissues, and cell culture - all focusing on the important role of estrogen in mediating obesity.
Brief Description of Project: The Role of Estrogen in Mediating Body Weight,
Reproduction, Energy Expenditure, Glucose Homeostasis in the Central Nervous
Recent observations from our own and other labs have demonstrated that the ovarian steroid estrogen, acting at specific estrogen receptor-? (ER?) in distinct regions of the in the central nervous system (CNS), is responsible for normal body weight regulation. The ventral hypothalamus (VMH) contains two key nuclei, the arcuate (ARC ) which contains populations of neurons that regulate food intake and body weight, and the ventral medial nucleus (VMN), which alone has not been found to have a prominent role in the regulation of food intake and body weight but does influence energy expenditure. When portions of both the VMN and the ARC are destroyed in a typical VMH lesion, animals, and especially female animals, eat more, burn less energy and become obese. Further, animals devoid of ER? are obese. The mechanisms by which the estrogen/ER? system regulates energy homeostasis, however, are yet fully understood. To tackle this issue, we first generated mice lacking E? in different regions in the CNS. Students will be exposed to transgenic mice and metabolic phenotyping of the mice. We also have in vitro hypothalamic cell lines where we can manipulate estrogen/testosterone and determine its impact on neuronal function.
Previous Research Activities or Publications with Medical Students: