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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Metabolism Study Section (MET)
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Yanovski, Susan Z
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University of Medicine & Dentistry of NJ
Schools of Medicine
United States
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Le Foll, Christelle; Johnson, Miranda D; Dunn-Meynell, Ambrose A et al. (2015) Amylin-induced central IL-6 production enhances ventromedial hypothalamic leptin signaling. Diabetes 64:1621-31
Cottone, P; Sabino, V; Nagy, T R et al. (2013) Centrally administered urocortin 2 decreases gorging on high-fat diet in both diet-induced obesity-prone and -resistant rats. Int J Obes (Lond) 37:1515-23
Levin, Barry E (2010) Interaction of perinatal and pre-pubertal factors with genetic predisposition in the development of neural pathways involved in the regulation of energy homeostasis. Brain Res 1350:10-7
Irani, Boman G; Le Foll, Christelle; Dunn-Meynell, Ambrose A et al. (2009) Ventromedial nucleus neurons are less sensitive to leptin excitation in rats bred to develop diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 296:R521-7
Patterson, Christa M; Bouret, Sebastien G; Dunn-Meynell, Ambrose A et al. (2009) Three weeks of postweaning exercise in DIO rats produces prolonged increases in central leptin sensitivity and signaling. Am J Physiol Regul Integr Comp Physiol 296:R537-48
Labelle, Denise R; Cox, Julia M; Dunn-Meynell, Ambrose A et al. (2009) Genetic and dietary effects on dendrites in the rat hypothalamic ventromedial nucleus. Physiol Behav 98:511-6
Patterson, Christa M; Dunn-Meynell, Ambrose A; Levin, Barry E (2008) Three weeks of early-onset exercise prolongs obesity resistance in DIO rats after exercise cessation. Am J Physiol Regul Integr Comp Physiol 294:R290-301
Gorski, Judith N; Dunn-Meynell, Ambrose A; Levin, Barry E (2007) Maternal obesity increases hypothalamic leptin receptor expression and sensitivity in juvenile obesity-prone rats. Am J Physiol Regul Integr Comp Physiol 292:R1782-91
Irani, Boman G; Dunn-Meynell, Ambrose A; Levin, Barry E (2007) Altered hypothalamic leptin, insulin, and melanocortin binding associated with moderate-fat diet and predisposition to obesity. Endocrinology 148:310-6
Gorski, Judith N; Dunn-Meynell, Ambrose A; Hartman, Thomas G et al. (2006) Postnatal environment overrides genetic and prenatal factors influencing offspring obesity and insulin resistance. Am J Physiol Regul Integr Comp Physiol 291:R768-78

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