Obesity is now considered a worldwide health concern, being a major contributor to the increased incidences of coronary heart disease and type II diabetes. By 1998, 18% of the adults in the United states were defined as being obese, with greater than twice that number categorized as overweight. Furthermore, the number of obese adults in the United States is increasing at a rate of 0.7% per year. Even more disturbing is the dramatic increase in obesity and type II diabetes among children. The central hypothesis of this proposal is that body weight management during adulthood is directly determined by the hypothalamic feeding circuits established during a """"""""critical period"""""""" postnatal development. Furthermore, if exposure to perturbations in energy balance occurs during this """"""""critical period"""""""" of neural plasticity, permanent alterations in body weight management may occur and lead to abnormal body weight phenotypes during adulthood. One of the most potent modulators of appetite and energy expenditure in the hypothalamus is neuropeptide Y (NPY). There are dynamic changes in the hypothalamic NPY system during postnatal development that implicate this system as being pivotal for the proper maturation of hypothalamic feeding circuitry. This proposal will study the postnatal period to 1) Determine the functional importance of the development of ARH projections. 2) Determine if NPY plays a role in the regulation of body weight management during early postnatal development. 3) Determine if changes in the endogenous NPY system are responsible for the obese phenotype induced by chronic overfeeding during the postnatal period. The main goal of this proposal is to use a multidisciplinary approach to determine if modification of the endogenous NPY system during postnatal development leads to abnormal body weight management during adulthood. To identify the role of the endogenous NPY system in the regulation of food intake and energy expenditure during the postnatal period we will use a combination of in vivo (changes in food intake and adiposity in whole animals) and in vitro (peptide release and electrophysiology in hypothalamic explants) physiological and pharmacological experiments, coupled with neuroanatomical measures (immunocytochemistry and in situ hybridization). The changes in the hypothalamic NPY system in these models will be correlated with changes in peripheral markers of energy expenditure and body weight status, using RIA and real-time PCR. These studies will provide important insight into the consequences of manipulation of the NPY feeding circuits, during the postnatal period on metabolic rate and body weight during childhood. Understanding of the normal and abnormal development of this circuitry is critical to determining the physiological mechanisms that underlie adult obesity and identify a critical period for possible intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060685-02
Application #
6744741
Study Section
Endocrinology Study Section (END)
Program Officer
Sato, Sheryl M
Project Start
2003-05-05
Project End
2008-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$225,601
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
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Cox, James; Williams, Sarah; Grove, Kevin et al. (2009) A maternal high-fat diet is accompanied by alterations in the fetal primate metabolome. Am J Obstet Gynecol 201:281.e1-9
Xu, Jing; Kirigiti, Melissa A; Cowley, Michael A et al. (2009) Suppression of basal spontaneous gonadotropin-releasing hormone neuronal activity during lactation: role of inhibitory effects of neuropeptide Y. Endocrinology 150:333-40
Sinnayah, Puspha; Jobst, Erin E; Rathner, Joseph A et al. (2008) Feeding induced by cannabinoids is mediated independently of the melanocortin system. PLoS One 3:e2202

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