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J. Biol. Chem., Vol. 280, Issue 41, 34764-34775, October 14, 2005

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Targeted Intestinal Overexpression of the Immediate Early Gene tis7 in Transgenic Mice Increases Triglyceride Absorption and Adiposity^*

Yuan Wang1, Hristo Iordanov1, Elzbieta A. Swietlicki, Lihua Wang, Christine Fritsch2, Trey Coleman, Clay F. Semenkovich, Marc S. Levin¶, and Deborah C. Rubin||3

From the Departments of Medicine, ^||Molecular Biology and Pharmacology, and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110 and ^¶Specialty Care Service Line, St. Louis Veterans Affairs Medical Center, St. Louis, Missouri 63106

Following loss of functional small bowel surface area due to surgical resection, the remnant gut undergoes an adaptive response characterized by increased crypt cell proliferation and enhanced villus height and crypt depth, resulting in augmented intestinal nutrient absorptive capacity. Previous studies showed that expression of the immediate early gene tis7 is markedly up-regulated in intestinal enterocytes during the adaptive response. To study its role in the enterocyte, transgenic mice were generated that specifically overexpress TIS7 in the gut. Nucleotides -596 to +21 of the rat liver fatty acid-binding protein promoter were used to direct abundant overexpression of TIS7 into small intestinal upper crypt and villus enterocytes. TIS7 transgenic mice had increased total body adiposity and decreased lean muscle mass compared with normal littermates. Oxygen consumption levels, body weight, surface area, and small bowel weight were decreased. On a high fat diet, transgenic mice exhibited a more rapid and proportionately greater gain in body weight with persistently elevated total body adiposity and increased hepatic fat accumulation. Bolus fat feeding resulted in a greater increase in serum triglyceride levels and an accelerated appearance of enterocytic, lamina propria, and hepatic fat. Changes in fat homeostasis were linked to increased expression of genes involved in enterocytic triglyceride metabolism and changes in growth with decreased insulin-like growth factor-1 expression. Thus, TIS7 overexpression in the intestine altered growth, metabolic rate, adiposity, and intestinal triglyceride absorption. These results suggest that TIS7 is a unique mediator of nutrient absorptive and metabolic adaptation following gut resection.

Received for publication, June 28, 2005 , and in revised form, August 1, 2005.

^* This work was supported by National Institutes of Health Grants DK46122 and DK61216 (to D. C. R.), DK50466 (to M. S. L.), AG20091 (to C. F. S.) and by the Morphology, Murine Models, and Functional Genomics Cores of the Digestive Diseases Research Core Centers (National Institutes of Health Grant DK52574) and the Clinical Nutrition Research Unit (National Institutes of Health Grant DK56341). 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 Both authors contributed equally to this work.

² Present address: Novartis Ophthalmics, 4056 Basel, Switzerland.

³ To whom correspondence should be addressed: Division of Gastroenterology, Washington University School of Medicine, 660 South Euclid Ave., Box 8124, St. Louis, MO 63110. Tel.: 314-362-8935; Fax: 314-362-8959; E-mail: drubin{at}wustl.edu.

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