STRATEGIES FOR THE MOLECULAR-GENETIC ANALYSIS OF OBESITY IN HUMANS

Studies of twins, adopted children, and some human populations indicat e that body composition is significantly influenced by genetic factors . However, in no specific instance in either man or animals is the pre cise etiology of obesity known at the molecular level. Attempts to ide ntify the molecular basis of obesity in humans have been hampered by d ifficulties in measuring food intake and energy expenditure with suffi cient accuracy, as well as the apparent polygenic control of body comp osition in man. These constraints have stimulated interest in inbred a nimal strains, particularly mice, that have a genetic predisposition t o obesity. Using the techniques of positional cloning, molecular marke rs flanking two autosomal recessive mouse obesity mutants (ob and db), which demonstrate a metabolic/behavioral phenotype similar to that ob served in obese humans, have been identified. These markers are being used: (1) as starting points for chromosome walks to identify these ge nes, (2) as an aid in identifying genetically obese rodents prior to t he development of the experimentally confounding obese phenotype, and (3) to investigate the possible contribution of the ob and db gene pro ducts to obesity in families segregating an obese phenotype. Additiona lly, genetic crosses segregating these obesity mutations are being use d to identify ''polygenes'' that influence the severity of obesity and type II diabetes. Such studies may ultimately lead to the characteriz ation of genes that influence the development and severity of obesity and non-insulin-dependent diabetes (NIDDM) in humans.