? The overall objective of this proposal is to examine the neuroendocrine regulation of appetite and body weight using a clinical model of disordered appetite and obesity. My colleagues and I discovered that children with Prader-Willi Syndrome (PWS), a genetic disorder accompanied by severe obesity and voracious appetite, have high fasting and post-prandial levels of ghrelin, an orexigenic peptide produced in the stomach. In contrast, ghrelin levels are suppressed in children and adults with """"""""exogenous"""""""" obesity or with obesity caused by mutations in leptin or the melanocortin-4 receptor. The high circulating concentrations of ghrelin may be critical for the pathogenesis of weight gain in PWS because ghrelin stimulates appetite and weight gain in rodents and human adults. ? ? We hypothesize that: (a) increases in fasting and post-prandial plasma ghrelin concentrations precede or coincide with the emergence of disordered appetite and weight gain in children with PWS; (b) the macronutrient regulation of plasma ghrelin in PWS differs from that in """"""""exogenous obesity"""""""" and (c) long-term suppression of plasma ghrelin in children with PWS will reduce food intake, body weight and fat mass. ? ? To test these hypotheses, we will compare the pattern of change in fasting ghrelin concentrations in children with PWS throughout infancy and early childhood with the pattern of change in otherwise normal (nonobese and obese) infants and children. We will then compare the suppressive effects of dietary carbohydrate and fat on ghrelin concentrations in children with PWS with those in age-, gender- and BMI-matched normal controls. Finally, we will determine if long-term suppression of ghrelin by octreotide reduces food intake, body weight and fat mass and increases energy expenditure in children with PWS. ? ? Our studies should provide novel insights into the role of ghrelin and other hormones and adipocytokines in the regulation of body weight in both children with Prader-willi syndrome and normal children. ? ?

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
1K23RR021979-01
Application #
6965033
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Wilde, David B
Project Start
2005-09-01
Project End
2010-06-30
Budget Start
2005-09-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$147,976
Indirect Cost
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Irizarry, Krystal A; Miller, Mark; Freemark, Michael et al. (2016) Prader Willi Syndrome: Genetics, Metabolomics, Hormonal Function, and New Approaches to Therapy. Adv Pediatr 63:47-77
Gumus Balikcioglu, Pinar; Balikcioglu, Metin; Muehlbauer, Michael J et al. (2015) Macronutrient Regulation of Ghrelin and Peptide YY in Pediatric Obesity and Prader-Willi Syndrome. J Clin Endocrinol Metab 100:3822-31
Haqq, Andrea M; Muehlbauer, Michael J; Newgard, Christopher B et al. (2011) The metabolic phenotype of Prader-Willi syndrome (PWS) in childhood: heightened insulin sensitivity relative to body mass index. J Clin Endocrinol Metab 96:E225-32
Han, Joan C; Muehlbauer, Michael J; Cui, Huaxia N et al. (2010) Lower brain-derived neurotrophic factor in patients with prader-willi syndrome compared to obese and lean control subjects. J Clin Endocrinol Metab 95:3532-6
Newgard, Christopher B; An, Jie; Bain, James R et al. (2009) A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 9:311-26
Lien, Lillian F; Haqq, Andrea M; Arlotto, Michelle et al. (2009) The STEDMAN project: biophysical, biochemical and metabolic effects of a behavioral weight loss intervention during weight loss, maintenance, and regain. OMICS 13:21-35
Tantibhedhyangkul, Julierut; Copland, Susannah D; Haqq, Andrea M et al. (2008) A case of female epispadias. Fertil Steril 90:2017.e1-3
Rubin, Daniela A; McMurray, Robert G; Harrell, Joanne S et al. (2008) The association between insulin resistance and cytokines in adolescents: the role of weight status and exercise. Metabolism 57:683-90
Rubin, Daniela A; McMurray, Robert G; Harrell, Joanne S et al. (2008) Do surrogate markers for adiposity relate to cytokines in adolescents? J Investig Med 56:786-92
Haqq, Andrea M; Grambow, Steven C; Muehlbauer, Michael et al. (2008) Ghrelin concentrations in Prader-Willi syndrome (PWS) infants and children: changes during development. Clin Endocrinol (Oxf) 69:911-20

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