Overweight and obesity are important surgical problems. As major contributing factors to the pathogenesis of many disease processes treated by the surgeon, overweight and obesity have a profound impact on present day surgical practice. The broad, long-term objective of our research has been to study the molecular basis of overweight and obesity. Because of the key role of the hypothalamus in the control of body weight we have approached our study of overweight and obesity by examining hypothalamic genes involved in energy homeostasis. In this competing renewal we outline a plan to continue this avenue of research. We propose to continue our study of the hypothalamic melanocortinergic system, an important energy homeostatic system that consists of the melanocortin receptor (MCR) subtypes MC3R and MC4R, the opposing neuropeptides alpha melanocyte-stimulating hormone (alpha-MSH) and agouti-related protein (AgRP), and syndecan-3. We also propose to continue our analysis of hypothalamic gene expression changes that accompany states of energy imbalance. To continue research that was initiated in the original RO1 this proposal has four specific aims.
Specific Aim 1 is to identify MC4R ligand binding pockets. This will involve three-dimensional computer modeling of the MC4R and receptor mutagenesis.
Specific Aim 2 is to identify the functional regions of AgRP. This will involve the synthesis of modified AgRP proteins. The intent of Specific Aims 1 and 2 is to examine at a molecular level the interactions that occur between components of the melanocortinergic system.
Specific Aim 3 is to identify hypothalamic genes that are differentially expressed in the food-deprived rat and the obese Ay mouse, a mouse that has a defect in the melanocortinergic system. This will involve the use of differential gene expression technologies.
Specific Aim 4 is to study the role of minoxidil sulfotransferase, serum glucocorticoid-inducible kinase, and EST AA818585, genes identified by our microarray studies, in energy homeostasis. This will involve the use of neuroanatomical techniques and in vivo physiological experiments. The intent of Specific Aims 3 and 4 is to expand understanding of the complex process of energy homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054032-08
Application #
6875048
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Sato, Sheryl M
Project Start
1998-08-01
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
8
Fiscal Year
2005
Total Cost
$358,848
Indirect Cost
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) 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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