ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways

Hye Jeong Lee, Jiyoung Moon, In Hyeok Chung, Ji Hyung Chung, Chan Park, Jung Ok Lee, Jeong Ah Han, Min Ju Kang, Eun Hye Yoo, So Young Kwak, Garam Jo, Wonil Park, Jonghoon Park, Kyoung Min Kim, Soo Lim, Kevin R.W. Ngoei, Naomi X.Y. Ling, Jonathan S. Oakhill, Sandra Galic, Lisa Murray-SegalBruce E. Kemp, Christos S. Mantzoros, Ronald M. Krauss, Min Jeong Shin, Hyeon Soo Kim

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

ATPase inhibitory factor 1 (IF1) is an ATP synthase-interacting protein that suppresses the hydrolysis activity of ATP synthase. In this study, we observed that the expression of IF1 was up-regulated in response to electrical pulse stimulation of skeletal muscle cells and in exercized mice and healthy men. IF1 stimulates glucose uptake via AMPK in skeletal muscle cells and primary cultured myoblasts. Reactive oxygen species and Rac family small GTPase 1 (Rac1) function in the upstream and downstream of AMPK, respectively, in IF1-mediated glucose uptake. In diabetic animal models, the administration of recombinant IF1 improved glucose tolerance and down-regulated blood glucose level. In addition, IF1 inhibits ATP hydrolysis by β-F1-ATPase in plasma membrane, thereby increasing extracellular ATP and activating the protein kinase B (Akt) pathway, ultimately leading to glucose uptake. Thus, we suggest that IF1 is a novel myokine and propose a mechanism by which AMPK and Akt contribute independently to IF1-mediated improvement of glucose tolerance impairment. These results demonstrate the importance of IF1 as a potential antidiabetic agent.-Lee, H. J., Moon, J., Chung, I., Chung, J. H., Park, C., Lee, J. O., Han, J. A., Kang, M. J., Yoo, E. H., Kwak, S.-Y., Jo, G., Park, W., Park, J., Kim, K. M., Lim, S., Ngoei, K. R. W., Ling, N. X. Y., Oakhill, J. S., Galic, S., Murray-Segal, L., Kemp, B. E., Mantzoros, C. S., Krauss, R. M., Shin, M.-J., Kim, H. S. ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways.

Original languageEnglish
Pages (from-to)14825-14840
Number of pages16
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number12
DOIs
Publication statusPublished - 2019 Dec 1

Keywords

  • diabetes
  • glucose uptake

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Lee, H. J., Moon, J., Chung, I. H., Chung, J. H., Park, C., Lee, J. O., Han, J. A., Kang, M. J., Yoo, E. H., Kwak, S. Y., Jo, G., Park, W., Park, J., Kim, K. M., Lim, S., Ngoei, K. R. W., Ling, N. X. Y., Oakhill, J. S., Galic, S., ... Kim, H. S. (2019). ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33(12), 14825-14840. https://doi.org/10.1096/fj.201901440RR