Abstract
Secretion of gastric inhibitory polypeptide (GIP), a duodenal hormone, is primarily induced by absorption of ingested fat. Here we describe a novel pathway of obesity promotion via GIP. Wild-type mice fed a high-fat diet exhibited both hypersecretion of GIP and extreme visceral and subcutaneous fat deposition with insulin resistance. In contrast, mice lacking the GIP receptor (Gipr−/−) fed a high-fat diet were clearly protected from both the obesity and the insulin resistance. Moreover, double-homozygous mice (Gipr−/−, Lepob/Lepob) generated by crossbreeding Gipr−/− and obese ob/ob (Lepob/Lepob) mice gained less weight and had lower adiposity than Lepob/Lepob mice. The Gipr−/− mice had a lower respiratory quotient and used fat as the preferred energy substrate, and were thus resistant to obesity. Therefore, GIP directly links overnutrition to obesity and it is a potential target for anti-obesity drugs.
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Acknowledgements
We thank S. Seino for critically reading the manuscript and for helpful discussions; H. Yano, H. Niwa and J. Miyazaki for help in generating the knockout mice; and H. Kohda for technical assistance in morphological examinations. This study was supported in part by Grants-in-Aid for Creative Scientific Research (10NP0201) and for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and by a grant from 'Research for the Future' Program of the Japan Society for the Promotion of Science (JSPS-RFTF97I00201) and by Health Sciences Research Grants for Research on Human Genome, Tissue Engineering and Food Biotechnology from the Ministry of Health, Labor and Welfare.
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Miyawaki, K., Yamada, Y., Ban, N. et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 8, 738–742 (2002). https://doi.org/10.1038/nm727
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DOI: https://doi.org/10.1038/nm727
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