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Inhibition of gastric inhibitory polypeptide signaling prevents obesity

Nature Medicine volume 8, pages 738–742 (2002)Cite this article

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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Figure 1: Inhibition of GIP signal prevents high fat-induced obesity.
Figure 2: Inhibition of GIP signal prevents hyperphagia-induced obesity.
Figure 3: Energy homeostasis.
Figure 4: Effects of GIP on adipocytes.
Figure 5: GIP links excessive fat intake to obesity.

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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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Author notes

  1. Kazumasa Miyawaki and Yuichiro Yamada: K.M. and Y.Y. contributed equally to this study.

Authors and Affiliations

  1. Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kazumasa Miyawaki, Yuichiro Yamada, Nobuhiro Ban, Yu Ihara, Katsushi Tsukiyama, Heying Zhou, Shimpei Fujimoto, Akira Oku, Kinsuke Tsuda & Yutaka Seino

  2. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Shinya Toyokuni & Hiroshi Hiai

  3. Division of Food Sciences and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan

    Wataru Mizunoya & Tohru Fushiki

  4. Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark

    Jens Juul Holst

  5. Sanwa Kagaku Kenkyusho Co. Ltd., Inabe, Mie, Japan

    Mitsuhiro Makino, Akira Tashita, Yukari Kobara, Yoshiharu Tsubamoto, Takayoshi Jinnouchi & Takahito Jomori

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Correspondence to Yutaka Seino.

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The authors declare no competing financial interests.

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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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