Although obesity ranks as one of the outstanding public health problems in the United States and often occurs among members of the same kindred, much is still unknown about the genetic factors of the genetic- environmental interactions which lead to its development and its extraordinary recidivism. A clearly articulated need of the research community studying obesity, is the necessity for criteria to distinguish between the obesities, both in humans and animal models. The importance of hereditary factors in producing obesity in humans is unclear, although it is well known that there is a familial pattern in obesity. Recently, adoptive studies, which included biologic as well as adoptive parents, indicate that obesity is more highly heritable than previously thought. The experiments proposed in this request are directed toward increasing our understanding of obesities by controlling nutritional conditions and examining cellular/genetic components, testing our """"""""LPL"""""""" hypothesis. the long term objectives of this renewal proposal are to advance our understanding of the genetic basic of obesity and to provide useful prognosticators of its development in humans.
The specific aims i nclude: (1) Preparation of a """"""""bank"""""""" of adipose tissue mRNA derived from well controlled, nutritionally defined groups of rats from 3 genotypes: homozygous obese (fafa), heterozygous lean (Fafa) and homozygous lean (FaFA). Such a """"""""bank"""""""" will facilitate screening of specific cDNA probes that now exist, and new ones as they become available. Probes can be screened relative to gene dosage and independent of many other variables, such as age of animal feeding state, type of diet, adipocyte size and a number of related plasma metabolic variables. This """"""""bank"""""""" will facilitate our proposed studies and also provide a resource for other investigators interested in examining the molecular basis of adipose tissue metabolism and genetic obesity. (2) Using banked mRNA, we will pursue our initial observations on LPL mRNA expression and regulation of LPL activity in vivo in the Zucker fafa, faFa and FaFA rat. (3) We will determine whether or not the putative adipocyte protease, adipsin, is lacking in obese rats, and if so, will explore the implications of its absence to the presence of the fa gene and to its potential role in regulation of LPL activity, and a (4) Using SV cultures derived from week old Zucker obese and lean rat pups, we will investigate the relationship between differentiation of adipoblasts to adipocytes and the rate of synthesis of LPL to determine if these correlate with presence or dosage of the fa gene. We will also detail the expression of other genetic markers during the differentiation program in primary SV cultures.
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