Ghrelin is produced by the stomach and hypothalamic neurons and it is an endogenous ligand for the growth hormone secretagogue receptor. Recently, ghrelin has also been found to regulate food intake and energy expenditure through an apparent hypothalamic mode of action. We discovered that ghrelin is present in a subset of hypothalamic neurons. Our preliminary studies also showed direct connectivity between the hypothalamic ghrelin network and arcuate nucleus neuropeptide Y (NPY)- and agouti related peptide (AGRP)-containing cells and POMC neurons and parvocellular thyrotropin releasing hormone (TRH)- and corticotropin releasing hormone (CRF)-producing neurons. We also revealed a direct presynaptic association between ghrelin and GABA axon terminals using electron microscopy and electrophysiology. Our observations, together with other available data on ghrelin's hypothalamic effects raised the intriguing possibility that ghrelin is a neuromodulator regulating the signaling flow in the hypothalamus to underlie normal daily energy homeostasis. In testing this hypothesis, the following specific aims will be addressed in mice: 1) Determine the interaction of ghrelin with key hypothalamic peptidergic systems that are involved in energy homeostasis. 2) Reveal ghrelin's effect on food intake, energy expenditure, electrophysiological properties and neuropeptide expression patterns of hypothalamic neurons in mice strains with altered metabolic functions. 3) Assess the effects of metabolic alterations on the expression levels of ghrelin and its receptor in the hypothalamus, stomach and blood. The execution of these studies using a multidisciplinary approach will shed light on a novel hypothalamic mechanism that may prove to be critical for the control of obesity and related disorders, including diabetes mellitus

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK060711-01A1
Application #
6544678
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Sato, Sheryl M
Project Start
2002-07-15
Project End
2005-06-30
Budget Start
2002-07-15
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$392,400
Indirect Cost
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Simon-Areces, Julia; Dietrich, Marcelo O; Hermes, Gretchen et al. (2012) UCP2 induced by natural birth regulates neuronal differentiation of the hippocampus and related adult behavior. PLoS One 7:e42911
Abizaid, A; Mineur, Y S; Roth, R H et al. (2011) Reduced locomotor responses to cocaine in ghrelin-deficient mice. Neuroscience 192:500-6
Gyengesi, Erika; Liu, Zhong-Wu; D'Agostino, Giuseppe et al. (2010) Corticosterone regulates synaptic input organization of POMC and NPY/AgRP neurons in adult mice. Endocrinology 151:5395-402
Korosi, Aniko; Shanabrough, Marya; McClelland, Shawn et al. (2010) Early-life experience reduces excitation to stress-responsive hypothalamic neurons and reprograms the expression of corticotropin-releasing hormone. J Neurosci 30:703-13
Andrews, Zane B; Erion, Derek M; Beiler, Rudolph et al. (2010) Uncoupling protein-2 decreases the lipogenic actions of ghrelin. Endocrinology 151:2078-86
Sotonyi, Peter; Gao, Qian; Bechmann, Ingo et al. (2010) Estrogen promotes parvalbumin expression in arcuate nucleus POMC neurons. Reprod Sci 17:1077-80
Horvath, Tamas L; Sarman, Beatrix; Garcia-Caceres, Cristina et al. (2010) Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc Natl Acad Sci U S A 107:14875-80
Dietrich, Marcelo O; Horvath, Tamas L (2010) The role of mitochondrial uncoupling proteins in lifespan. Pflugers Arch 459:269-75
Sotonyi, Peter; Mezei, Gabor; Racz, Bence et al. (2010) Gonadotropin-releasing hormone fibers contact POMC neurons in the hypothalamic arcuate nucleus. Reprod Sci 17:1024-8
Dietrich, Marcelo O; Antunes, Catiele; Geliang, Gan et al. (2010) Agrp neurons mediate Sirt1's action on the melanocortin system and energy balance: roles for Sirt1 in neuronal firing and synaptic plasticity. J Neurosci 30:11815-25

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