This is a revised competitive renewal application of our grant entitled """"""""Ghrelin in Hypothalamic Regulation of Metabolism"""""""" (R01 DK-060711-04A1). The original application was planned for 5 years, but was cut to 2 years, 11 months, and the funds requested for each year were then further decreased due to budgetary constraints of NIDDK. Nevertheless, even with these funding and time constraints, we have made progress in the past two and a half years to better understand ghrelin's action within the brain. Of the newly acquired information, there are 2 critical findings which provide the basis for the request for continuation: 1) ghrelin induces synaptic remodeling of the melanocortin system while inducing positive energy balance;2) peripheral ghrelin administration activates ventral tegmental dopamine neurons elevating dopamine release in the nucleus accumbens, and, ghrelin administration selectively to the ventral tegmental area induces acute food intake. We make 2 inferences from these findings: 1) The action of ghrelin on the output of neuronal circuitry associated with metabolism regulation involves and partially relies on synaptic plasticity, and 2) ghrelin's effect on food intake is greatly augmented by direct activation of the basal forebrain reward circuitry. We propose the following Specific Aims to follow up on these premises:
Specific Aim 1) To reveal a) whether circulating ghrelin affects synaptic plasticity in the arcuate nucleus in a dose-dependent manner, b) the time course of synaptic changes to emerge and to diminish after acute ghrelin administration, c) if the circadian fluctuation of the synaptic input organization of POMC neurons is ghrelin dependent, d) the interaction between ghrelin and leptin orcorticosterone (CORT) in the acute regulation of synaptic plasticity and feeding, and e) whether ghrelin-induced synaptic plasticity in the arcuate nucleus is impaired in mice with mutations in ghrelin signaling Specific Aim 2) To determine a) if ghrelin-induced synaptic plasticity also occurs in the major neuronal populations within the ventral tegmental area (VTA). In b) We will examine the role of GHS-R 1a in mediating synaptic changes in VTA neurons.
Specific Aim 3) To determine that ghrelin targets the VTA to enhance motivational aspects of feeding and to promote the consumption of calorie rich diets, if the resistance of ghrelin knockout animals to diet-induced obesity is due to ghrelin's inaction upon reward circuitry. . The proposed studies will deliver new insights to metabolism regulation, likely revealing novel targets for obesity drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060711-07
Application #
7742193
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2001-12-01
Project End
2010-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
7
Fiscal Year
2010
Total Cost
$313,108
Indirect Cost
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
043207562
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
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
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

Showing the most recent 10 out of 40 publications