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Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120

Nature Medicine volume 11, pages 90–94 (2005)Cite this article

Abstract

Diabetes, a disease in which the body does not produce or use insulin properly, is a serious global health problem1,2,3. Gut polypeptides secreted in response to food intake, such as glucagon-like peptide-1 (GLP-1), are potent incretin hormones that enhance the glucose-dependent secretion of insulin from pancreatic beta cells4,5,6. Free fatty acids (FFAs) provide an important energy source and also act as signaling molecules in various cellular processes, including the secretion of gut incretin peptides7,8. Here we show that a G-protein-coupled receptor, GPR120, which is abundantly expressed in intestine, functions as a receptor for unsaturated long-chain FFAs. Furthermore, we show that the stimulation of GPR120 by FFAs promotes the secretion of GLP-1 in vitro and in vivo, and increases circulating insulin. Because GLP-1 is the most potent insulinotropic incretin9,10, our results indicate that GPR120-mediated GLP-1 secretion induced by dietary FFAs is important in the treatment of diabetes.

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Figure 1: Tissue distribution and signal transduction of Gpr120.
Figure 2: Long FFA–induced GLP-1 secretion and ERK activation in STC-1 cells.
Figure 3: Gpr120, but not Gpr40, mediates FFA-induced [Ca2+]i response and GLP-1 secretion.
Figure 4: Colocalization of GPR120 mRNA and GLP-1 in human colonic cells, and FFA-induced GLP-1 and insulin secretion in mice.

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Gene Expression Omnibus

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Acknowledgements

We thank S. Mine, T. Tanaka, Y. Kitagawa and S. Suzuki for their technical assistance. This study was performed through Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology, the Japanese Government (G.T.). S.K. and T.A. are supported by the 21st Century Center of Excellence Program “Knowledge Information Infrastructure for Genome Science.”

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Authors and Affiliations

  1. Department of Molecular, Cell Pharmacology, National Research Institute for Child Health and Development, 3-35-31, Taishi-do, Setagaya-ku, Tokyo, 154-8567, Japan

    Akira Hirasawa, Keiko Tsumaya & Masateru Yamada

  2. Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Akira Hirasawa & Gozoh Tsujimoto

  3. Shinanomachi Research Park 7S7, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Akira Hirasawa & Gozoh Tsujimoto

  4. Department of Physiology, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan

    Takeo Awaji & Shunichi Miyazaki

  5. Bioinformatics Center, Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan

    Susumu Katsuma & Tetsuya Adachi

  6. Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan

    Yukihiko Sugimoto

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  1. Akira Hirasawa
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Correspondence to Gozoh Tsujimoto.

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Supplementary information

Supplementary Table 1

pEC50s of fatty acids tested on HEK 293 cells stably expressing Gpr120-Gα16 (PDF 19 kb)

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Hirasawa, A., Tsumaya, K., Awaji, T. et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med 11, 90–94 (2005). https://doi.org/10.1038/nm1168

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