Obesity is a serious health risk. The seven leading causes of death in the U.S. accounting for 80% of all mortality are incontrovertibly associated with obesity. The difficulty seen in treatment of obesity may lie in the lack of under-standing of the basic mechanisms of adipose cell development. The information regarding the hormonal and paracrine/autocrine regulation of adipose cell differentiation is incomplete. In vivo, adipose cells develop in concert with other cell types to form mature adipose tissue. The stromal-vascular model used here morphologically and biochemically mimics in utero adipose tissue development. Part of this success may be linked to the potential for local control through paracrine and autocrine factors from the different cell proposed research. These advances include the development of monoclonal antibodies against cell surface and cytometric antigens expressed during porcine adipocyte differentiation and the adaption of flow cytometric procedures to quantify lipid free preadipocytes and the associated expression of a developmentally regulated cell surface antigens. The obese pig has a size advantage over other animal models. We have utilized a line of pigs which have been genetically selected to have over two times as much body fat as contemporary pigs. When extreme differences exist between experimental and control subjects, it permits easier identification of the regulatory events which are important for in vivo development of adipose cells.
The specific aims of this proposal are to identify the function and mode of action of primary endocrine factors in prenatal adipose tissue development, using the fetal pig as an animal model. The first series of experiments will test the hypothesis that primary endocrine regulation is multifaceted, i.e., involving preadipocyte and adipocyte differentiation and vascular development, and that this regulation is mediated locally via soluble and insoluble factors. The approach used includes quantitative and qualitative analysis of preadipocytes in stromal-vascular (S-V) cultures derived from hormone treated hypophysectomized (hypoxed) pig fetuses. These experiments will address the following questions: Which hormone or combination will restore the hypox-induced deficit in preadipocyte (S-V) development? and What paracrine/autocrine factor(s) would be associated with normalization of preadipocyte development? Another facet of these studies is the qualitative evaluation of paracrine/autocrine factors in vivo will be correlated with cellular and metabolic changes induced with the various hormone treatments. These studies will provide the first definitive and physiologically relevant understanding of major endocrine factors in prenatal adipose tissue development. The second series of experiments will test the hypothesis that several traits or """"""""markers"""""""" of pre-obese pig fetuses are indeed genetically linked to an altered profile of primary endocrine factors. To test this hypothesis we will utilize embryo transfer technology to switch embryos from obese to lean dams and vice versa. The absence of maternal effects would establish the genetic nature of these characteristics of preobese fetuses.
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