Obesity and diabetic conditions are complex multifactorial syndromes that develop from an interaction between genetic and environmental factors. The GI tract and, in particular, GI regulatory peptides represent an ideal starting point for investigating nutrition-related disorders since the former represents the route by which all nutrients are processed and absorbed. In addition to its effects on islet beta-cell insulin release, we have recently identified receptors to glucose-dependent insulinotropic polypeptide (GIP) on human adipocytes. We have also found that a GIP-specific receptor antagonist developed in our laboratory inhibits binding of this peptide to fat cells. Moreover, we have observed that GIP inhibits isoproterenol-induced lipolysis in rat adipocytes, consistent with the hypothesis that GIP is functioning physiologically to enhance lipid deposition. Thus, it appears plausible that by antagonizing the adipocyte GIP receptor, the storage of lipid, and thereby obesity, might be prevented. However, neither the precise effects of GIP on adipocyte function nor the role of GIP in the pathogenesis of obesity have been determined.
Specific aims of this project are to: 1. Characterize the GIP receptor, including regulation of receptor expression, intracellular signaling in adipocytes, and the relationship of GIP to insulin in fat cells; 2. Ascertain the effects of a GIP antagonist on the development of obesity using rodent models; and 3. Determine GIP expression in normal, obese, and diabetic states, employing a novel, sensitive bioassay to measure GIP concentrations in different rodent models. The studies outlined in this proposal will help clarify the precise role of GIP in the pathogenesis of these common multifactorial disorders and its physiological role in regulating fat cell function. Moreover, owing to the critical functional relationship between GIP and insulin, a detailed analysis of the intracellular pathways mediating the biological properties of GIP will facilitate the determination of the precise relationship between these two peptide hormones, as well as the physiological and pathological significance of GIP and its importance in the regulation of fat and glucose homeostasis. Finally, these studies will enable us to ascertain whether an antagonist to the GIP receptor on the adipocyte, as well as possibly in other organs, might be useful for the prevention of lipid deposition and in the treatment of obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK053158-06S1
Application #
6915963
Study Section
Nutrition Study Section (NTN)
Program Officer
May, Michael K
Project Start
1997-02-15
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$94,818
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
Musson, Michelle C; Jepeal, Lisa I; Finnerty, John R et al. (2011) Evolutionary expression of glucose-dependent-insulinotropic polypeptide (GIP). Regul Pept 171:26-34
Musson, Michelle C; Jepeal, Lisa I; Sharifnia, Torfay et al. (2010) Evolutionary conservation of glucose-dependent insulinotropic polypeptide (GIP) gene regulation and the enteroinsular axis. Regul Pept 164:97-104
Prabakaran, Daniel; Wang, Baogui; Feuerstein, Joseph D et al. (2010) Glucose-dependent insulinotropic polypeptide stimulates the proliferation of colorectal cancer cells. Regul Pept 163:74-80
Musson, Michelle C; Jepeal, Lisa I; Mabray, Patrick D et al. (2009) Expression of glucose-dependent insulinotropic polypeptide in the zebrafish. Am J Physiol Regul Integr Comp Physiol 297:R1803-12
Jepeal, Lisa I; Boylan, Michael O; Michael Wolfe, M (2008) GATA-4 upregulates glucose-dependent insulinotropic polypeptide expression in cells of pancreatic and intestinal lineage. Mol Cell Endocrinol 287:20-9
Singh, Satish K; Bartoo, Aaron C; Krishnan, Selvi et al. (2008) Glucose-dependent insulinotropic polypeptide (GIP) stimulates transepithelial glucose transport. Obesity (Silver Spring) 16:2412-6
Song, Diane H; Getty-Kaushik, Lisa; Tseng, Eva et al. (2007) Glucose-dependent insulinotropic polypeptide enhances adipocyte development and glucose uptake in part through Akt activation. Gastroenterology 133:1796-805
Wolfe, M Michael (2007) Gastrointestinal regulatory peptides: an overview. Curr Opin Endocrinol Diabetes Obes 14:41-5
Song, Diane H; Wolfe, M Michael (2007) Glucose-dependent insulinotropic polypeptide and its role in obesity. Curr Opin Endocrinol Diabetes Obes 14:46-51
Boylan, Michael O; Jepeal, Lisa I; Wolfe, M Michael (2006) Sp1/Sp3 binding is associated with cell-specific expression of the glucose-dependent insulinotropic polypeptide receptor gene. Am J Physiol Endocrinol Metab 290:E1287-95

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