Only half the adult rats fed a high energy (HE) diet develop diet-induced obesity (DIO); the rest are diet-resistant (DR), gaining no more weight or fat than chow-fed rats can, however, be separated prospectively by their plasma norepinephrine (NE response to a glucose load thus allowing the study of factors underlying the expression of the DIO/DR phenotypes before HE diet exposure. This proposal will examine brain mechanisms responsible for the differing patterns of weight gain, glucose and lipid metabolism seen in these rats. Emphasis will be placed on brain NE metabolism responsible for the differing patterns of weight gain, glucose and lipid metabolism seen in these rats. Emphasis will be placed on brian NE metabolism and alpha-adrenoreceptor (alpha-AR) binding because these parameters modulate systems important in body weight regulation and because they differ in DIO and DR rats. The diurnal variability of these parameters and in food intake and motor activity will be studied in Sprague-Dawley DIO/DR rats before and after 1mo of HE diet intake to identify early concomitants of the DIO/DR states. Comparison will be made to Fisher F-344 rats, all of which develop an attenuated degree of DIO on HE diet. Acute and chronic intracranial infusions of alpha-AR ligands will test the functional status of DIO versus DR brain alpha-AR's with regard to weight gain, food intake, motor and sympathoadrenal activity, glucose and lipid metabolism, before and after HE diet exposure. Differential sensitivity of brain alpha-AR binding in DIO versus DR rats to altered plasma glucose and food intake levels will also be tested. Finally, transfer of the DR/DIO traits will be attempted by transplanting fetal rat hypothalamus from DIO- to DR-prone rat strains and vice versa, again with emphasis on the role of brain NE metabolism and alpha-AR binding.
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