Obesity is a major contributing risk factor to leading causes Of death in the United States including cardiovascular disease, diabetes, and certain cancers (breast, colorectal, and genitourinary). These obesity associated diseases have an enormous impact on many surgical specialties. Indeed, operative treatment of these ailments or their sequelae has very substantially shaped the present day practice Of surgery. Recent advances in the scientific understanding of weight homeostasis have generated considerable hope that additional approaches can be developed to regulate body weight and help diminish the threat of obesity to the health of many Americans. In the past year exciting discoveries have demonstrated that the pro- opiomelanocortin (POMC) derived melanocortin peptides and the melanocortin-4 receptor (MC4R) play a key role in the hypothalamic control of body weight. These findings suggest that the melanocortins act as important hormonal messengers that signal satiety. Recently, additional complexity surrounding the function Of the melanocortins in weight homeostasis has been uncovered with the isolation of a novel antagonist of these peptides named agouti gene-related protein (AGRP). This proposal is directed towards the study of the role of melanocortins and the MC4R in the hypothalamic control of body weight. We propose to use in situ hybridization and immunohistochemistry to delineate the hypothalamic circuitry of the MC4R, POMC prohormone and three elements which we hypothesize antagonize the anorexic action of melanocortins, AGRP, neuropeptide Y, and the neuropeptide Y Y5 receptor. In order to gain insight into these interactions, normal rodents, fasted rodents, and several rodent models of obesity (fatty Zucker rat and obese and tubby mice) will be examined. Secondly, we propose to aid the development of drugs designed to control body weight by performing three dimensional receptor modeling and site-directed mutagenesis of the human MC4R. Thirdly, we propose to examine the sequence of the coding region of the human MC4R gene of obese patients to determine if receptor variants underlie some human obesity. Finally, we propose to examine the mechanisms through which AGRP antagonizes the melanocortins by characterizing the action of recombinant AGRP.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054032-03
Application #
6177623
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Smith, Philip F
Project Start
1998-08-01
Project End
2003-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
3
Fiscal Year
2000
Total Cost
$334,358
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
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) TNF? 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
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, Ziru; Xu, Geyang; Li, Yin et al. (2012) mTOR-dependent modulation of gastric nesfatin-1/NUCB2. Cell Physiol Biochem 29:493-500
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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