TARGETED ABLATION OF GIP-PRODUCING CELLS IN TRANSGENIC MICE REDUCES OBESITY AND INSULIN RESISTANCE INDUCED BY A HIGH FAT DIET Matthew C. Althage 1 , Eric L. Ford 1 , Songyan Wang 1 , Patrick Tso 2 , Kenneth S. Polonsky 1 , and Burton M. Wice 1 From 1 Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Saint Louis, Missouri 63110 and 2 Department of Pathology, University of Cincinnati School of Medicine, Cincinnati, Ohio Running head: GIP regulates obesity and insulin resistance Address correspondence to: Burton M. Wice, Ph.D. Washington University School of Medicine, Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Campus Box 8127, 660 South Euclid Avenue, Saint Louis, Missouri 63110 Phone: 314-747-0423, Fax: 314-362-8284, Email: bwice@im.wustl.edu SUMMARY The K cell is a specific sub-type of enteroendocrine cell located in the proximal small intestine that produces glucose-dependent insulinotropic polypeptide (GIP), xenin, and potentially other unknown hormones. Since GIP promotes weight gain and insulin resistance, reducing hormone release from K cells could lead to weight loss and increased insulin sensitivity. However, the consequences of coordinately reducing circulating levels of all K cell-derived hormones are unknown. To reduce the number of functioning K cells, regulatory elements from the rat GIP promoter/gene were used to express an attenuated Diphtheria Toxin A chain in transgenic mice. K cell number, GIP transcripts, and plasma GIP levels were profoundly reduced in the GIP/DT transgenic mice. Other enteroendocrine cell types were not ablated. Food intake, body weight, and blood glucose levels in response to insulin or intraperitoneal glucose were similar in control and GIP/DT mice fed standard chow. In contrast to single or double incretin receptor knockout mice, the incretin response was absent in GIP/DT animals suggesting K cells produce GIP plus an additional incretin hormone. Following high fat feeding for 21-35 weeks, the incretin response was partially restored in GIP/DT mice. Transgenic versus wild type mice demonstrated significantly reduced body weight (25%), plasma leptin levels (77%) and daily food intake (16%) plus enhanced energy expenditure (10%) and insulin sensitivity. Regardless of diet, long- term glucose homeostasis was not grossly perturbed in the transgenic animals. In conclusion, studies using GIP/DT mice demonstrate an important role for K cells in the regulation of body weight and insulin sensitivity. INTRODUCTION Enteroendocrine (EE) cells are a complex population of rare, diffusely distributed hormone producing intestinal epithelial cells (1-3). Peptides and hormones secreted by EE cells play important roles in many aspects of gastrointestinal and whole animal physiology (4-6). There are at least 16 different sub-types of EE cells based upon the major product(s) synthesized and secreted by individual cells (1). Several EE cell products including GIP, glucagon-like peptide 1 (GLP-1), ghrelin, cholecystokinin (CCK), and peptide tyrosine tyrosine regulate food intake and/or degree of adiposity (7-11). GIP is produced almost exclusively by K cells located in the proximal small intestine and is secreted immediately after ingestion of a meal (4,5,12,13). GIP release is regulated by nutrients in the intestinal lumen, but not by those in the blood (4,6,13,14). Glucose (12,15,16), protein hydrolysates (17), specific amino acids (18), and fat (19) are major GIP secretagogues. Long-term administration of a high fat diet increases http://www.jbc.org/cgi/doi/10.1074/jbc.M710466200 The latest version is at JBC Papers in Press. Published on April 17, 2008 as Manuscript M710466200 Copyright 2008 by The American Society for Biochemistry and Molecular Biology, Inc. by guest on April 11, 2016 http://www.jbc.org/ Downloaded from