HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 26, 18365-18376, June 27, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/26/18365    most recent M710466200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Althage, M. C. Articles by Wice, B. M. Search for Related Content PubMed PubMed Citation Articles by Althage, M. C. Articles by Wice, B. M. Social Bookmarking                      What's this?

Targeted Ablation of Glucose-dependent Insulinotropic Polypeptide-producing Cells in Transgenic Mice Reduces Obesity and Insulin Resistance Induced by a High Fat Diet^*

Matthew C. Althage, Eric L. Ford, Songyan Wang, Patrick Tso, Kenneth S. Polonsky, and Burton M. Wice¹

From the Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Saint Louis, Missouri 63110 and the Department of Pathology, University of Cincinnati School of Medicine, Cincinnati, Ohio 45267

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. Because 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 knock-out 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.

Received for publication, December 22, 2007 , and in revised form, April 16, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK31842 (to K. S. P.). This work was also supported by funds from a Career Development Award from the American Diabetes Association (to B. M. W.); a research grant from the Juvenile Diabetes Research Foundation (to B. M. W.); a pilot and feasibility grant from the Washington University Clinical Nutrition Research Center (Grant P30 DK056341) (to B. M. W.); the Washington University Digestive Diseases Research Core Center Morphology and Transgenic Mouse Cores (Grant 5P30 DK052574); the Washington University Diabetes Research and Training Center Transgenic Core and Mouse Phenotyping Core (Grant P60 DK020579); The University of Cincinnati Mouse Metabolic Phenotyping Center (Grant DK59630); and the Blum Kovler Foundation (to K. S. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: 314-747-0423; Fax: 314-362-8284; E-mail: bwice{at}im.wustl.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. R. Kelly, L. M. Brooks, T. P. J. Solomon, S. R. Kashyap, V. B. O'Leary, and J. P. Kirwan The glucose-dependent insulinotropic polypeptide and glucose-stimulated insulin response to exercise training and diet in obesity Am J Physiol Endocrinol Metab, June 1, 2009; 296(6): E1269 - E1274. [Abstract] [Full Text] [PDF]

				A. Shimotoyodome, D. Fukuoka, J. Suzuki, Y. Fujii, T. Mizuno, S. Meguro, I. Tokimitsu, and T. Hase Coingestion of Acylglycerols Differentially Affects Glucose-Induced Insulin Secretion via Glucose-Dependent Insulinotropic Polypeptide in C57BL/6J Mice Endocrinology, May 1, 2009; 150(5): 2118 - 2126. [Abstract] [Full Text] [PDF]