American society is experiencing an epidemic of obesity. Because of the key role of the hypothalamus in controlling body weight, the long-term objective of this research has been to examine arcuate nucleus hypothalamic genes involved in energy homeostasis. The proposed studies focus upon the hypothalamic melanocortinergic system which has become a focal point for basic research and drug development. That system contains alpha melanocyte-stimulating hormone (?-MSH) and melanocortin receptor (MCR) subtypes MC3R and MC4R. ?-MSH is a potent satiety-inducing factor that mediates its effects by binding and activating MC3R and MC4R. A continuing analysis of hypothalamic gene expression changes has identified ankyrin repeat and SOCS box containing protein 4 (Asb-4) as a very promising investigative target. Asb-4 is an important intracellular regulatory protein in CNS energy homeostatic circuits that is highly regulated in hypothalamic neurons. The proposed research is contained in four specific aims: 1) To examine alternative melanocortin signaling pathways. We hypothesize that MC3R and MC4R activate mitogen-activated protein kinase signaling pathways in addition to well- recognized cyclic AMP-dependent processes in hypothalamic neurons. 2) To determine the role of melanocortin signaling in regulation of c-Jun NH2-terminal kinase (JNK). We hypothesize that MC3R and MC4R, via Asb-4, regulate arcuate nucleus JNK activity. 3) To elucidate transcriptional regulation of Asb-4. We hypothesize that Asb-4 expression in the hypothalamus is regulated by the melanocortinergic peptide, ?-MSH. 4) To determine the role Asb-4 in feeding behavior. We hypothesize that ankyrin repeat and SOCS box containing protein 4 is a crucial intracellular protein in hypothalamic neurons. We hypothesize that directed overexpression of Asb-4 in hypothalamic proopiomelanocortin neurons will decrease food intake, increase energy expenditure and confer resistance to high fat diet-induced obesity.

Public Health Relevance

American Society is experiencing an epidemic of obesity. The hypothalamis, an area in the brain that is essential in control of appetite and food intake, is the focus of these investigations. The proposal examines carefully the hypothalamic melanocortin signaling system, an important energy regulatory system that has postulated to effect appetite, energy expenditure, and glucose metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054032-14
Application #
8292182
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Hyde, James F
Project Start
1998-08-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
14
Fiscal Year
2012
Total Cost
$335,104
Indirect Cost
$117,032
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Li, Ji-Yao; Chai, Biaoxin; Zhang, Weizhen et al. (2014) LGR4 and its ligands, R-spondin 1 and R-spondin 3, regulate food intake in the hypothalamus of male rats. Endocrinology 155:429-40
Fritze, Danielle; Zhang, Weizhen; Li, Ji-Yao et al. (2014) TNFα causes thrombin-dependent vagal neuron apoptosis in inflammatory bowel disease. J Gastrointest Surg 18:1632-41
Zhang, Weizhen; Zhang, Chao; Fritze, Danielle et al. (2013) Modulation of food intake by mTOR signalling in the dorsal motor nucleus of the vagus in male rats: focus on ghrelin and nesfatin-1. Exp Physiol 98:1696-704
Chai, B; Li, J-Y; Fritze, D et al. (2013) A novel transcript is up-regulated by fasting in the hypothalamus and enhances insulin signalling. J Neuroendocrinol 25:292-301
Li, Ziru; Xu, Geyang; Li, Yin et al. (2012) mTOR-dependent modulation of gastric nesfatin-1/NUCB2. Cell Physiol Biochem 29:493-500
Xia, Ze-Feng; Fritze, Danielle M; Li, Ji-Yao et al. (2012) Nesfatin-1 inhibits gastric acid secretion via a central vagal mechanism in rats. Am J Physiol Gastrointest Liver Physiol 303:G570-7
Xu, G; Wang, Z; Li, Y et al. (2012) Ghrelin contributes to derangements of glucose metabolism induced by rapamycin in mice. Diabetologia 55:1813-23
Li, Ji-Yao; Chai, Biaoxin; Zhang, Weizhen et al. (2011) Ankyrin repeat and SOCS box containing protein 4 (Asb-4) colocalizes with insulin receptor substrate 4 (IRS4) in the hypothalamic neurons and mediates IRS4 degradation. BMC Neurosci 12:95
Wu, X; Zhang, W; Li, J-Y et al. (2011) Induction of apoptosis by thrombin in the cultured neurons of dorsal motor nucleus of the vagus. Neurogastroenterol Motil 23:279-85, e123-4
An, Wenjiao; Li, Yin; Xu, Geyang et al. (2010) Modulation of ghrelin O-acyltransferase expression in pancreatic islets. Cell Physiol Biochem 26:707-16

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