Obesity has a high morbidity, is extremely difficult to treat and has a major financial impact on health care costs and productivity. Mounting evidence implicates neural systems regulating -energy balance in the development and maintenance of obesity. To study these systems, we will use a model of diet-induced obesity (DIO) in which half the adult male Sprague-Dawley rats fed a diet high in energy, fat and sucrose (HE diet) become obese and insulin resistant. The rest are diet-resistant (DR), gaining the same weight as chow-fed controls. Our prior work showed that chowfed rats predisposed to develop DIO (DIO-prone) and HE-diet fed rats with fully developed DIO had major deficits in brain catecholamine (CA) metabolism. Many of the metabolic abnormalities seen with the development and persistence of DIO can be mimicked by central administration of neuropeptide Y (NPY), an endogenous neuropeptide which stimulates food intake, insulin secretion and fat deposition. Central NPY expression is altered by energy intake, CA and insulin. We postulate that the development and persistence of DIO results from aberrant interactions among central NPY and CA metabolism with peripheral insulin, glucose and sympathetic nervous system (SNS) function. These interactions will be studied here in the DIO model with intracerebral and intravascular infusions of glucose, insulin and CA agents, together with fasting and refeeding, to assess central NPY expression (in situ hybridization and radioimmunoassay), neuronal activation (cFOS immunocytochemistry) and CA turnover. Peripheral measures of SNS activity (organ norepinephrine turnover and 24h urine levels), plasma CA, insulin, glucose and glycerol levels, white adipose lipoprotein lipase activity, oxygen consumption and respiratory quotient, food intake and carcass composition will also be made. Substrains of rats are being inbred for the DIO and DR traits. Once stable substrains of DIO and DR rats are established, studies of the relative contributions of genotype vs maternal milieu on the subsequent weight gain phenotype of their offspring will be carried out by manipulating maternal diet, adiposity and insulin levels during gestation and weaning. Taken together, these studies will provide a comprehensive neurochemical, physiologic and behavioral picture of the role of central NPY, genotype and environment in the development and persistence of DIO.
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