Research Project
3230570
Dietary obesity will develop in most, but not all, animals which consume a high fat diet composed of triglycerides with long chain fatty acids. The failure of animals to adapt to a calorically dense diet may involve mechanisms for either regulating energy intake or energy expenditure. The long term objective of this research grant is to develop a mechanism for the role of fat in the development of dietary obesity. A high fat diet is associated with the development of obesity in experimental animals, and in all liklihood plays a role in the epidemic of obesity seen in affluent western nations. To approach this problem we have selected for study two strains of rats which differ markedly in their susceptibility to obesity when eating a high fat diet. The failure of one strain of rats to adapt to a calorically dense diet must involve the absence of decompensation of mechanisms for reducing food (energy) intake or for increasing energy expenditure when faced with the high fat diet. The proposed studies will investigate the physiological mechanisms which underlie the development of obesity in one sensitive strain (the Osborne-Mendel rat), but which allow another strain (the S 5B/Pl rat) to avoid obesity when eating the same high fat diet. The first hypothesis is that this difference is associated with changes in the way the gut of the two strains senses food intake. This will be tested by examining the effect on food intake of introducing fat or carbohydrates into various portions of the gastrointestinal tract of sensitive and resistant rats eating either high or low fat diets. The corollary to this hypothesis is that a metabolic signal, either ketones or cholecystokinin is generated more readily in the rats resistant to dietary obesity. This will be tested by experimentally manipulating the peripheral ketone level and by direct intraventricular injection of ketones in these two strains of rats. The dose-response to exogeneous cholecystokinin will also be determined. The finding that ventromedial hypothalamic lesions convert resistant rats into sensitive ones suggests the hypothesis that integration of signals in the brain of the rats resistant to dietary obesity is more responsive to diet than in the rats which become obese. This will be tested by examining central neurotransmitters in both strains as a function of diet. The final hypothesis is that the two strains differ in efferent thermogenic mechanisms as manifested by differences in metabolic response to exogenous norepinephrine, or in the activity of the parasympathetic or sympathetic limbs of the autonomic nervous system.
