Phosphatidylinositol 3,4,5-Trisphosphate Phosphatase SKIP Links Endoplasmic Reticulum Stress in Skeletal Muscle to Insulin Resistance

Takeshi Ijuin; Tetsuya Hosooka; Tadaomi Takenawa

doi:10.1128/MCB.00921-15

Phosphatidylinositol 3,4,5-Trisphosphate Phosphatase SKIP Links Endoplasmic Reticulum Stress in Skeletal Muscle to Insulin Resistance

Mol Cell Biol. 2015 Oct 19;36(1):108-18. doi: 10.1128/MCB.00921-15. Print 2016 Jan 1.

Authors

Takeshi Ijuin¹, Tetsuya Hosooka², Tadaomi Takenawa³

Affiliations

¹ Division of Biochemistry, Kobe University Graduate School of Medicine, Kobe, Japan tijuin@med.kobe-u.ac.jp.
² Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
³ Division of Membrane Biology, Biosignal Research Center, Kobe University, Kobe, Japan.

Abstract

Insulin resistance is critical in the pathogenesis of type 2 diabetes. Endoplasmic reticulum (ER) stress in liver and adipose tissues plays an important role in the development of insulin resistance. Although skeletal muscle is a primary site for insulin-dependent glucose disposal, it is unclear if ER stress in those tissues contributes to insulin resistance. In this study, we show that skeletal muscle kidney-enriched inositol polyphosphate phosphatase (SKIP), a PIP3 (phosphatidylinositol-3,4,5-trisphosphate) phosphatase, links ER stress to insulin resistance in skeletal muscle. SKIP expression was increased due to ER stress and was higher in the skeletal muscle isolated from high-fat-diet-fed mice and db/db mice than in that from wild-type mice. Mechanistically, ER stress promotes activating transcription factor 6 (ATF6) and X-box binding protein 1 (XBP1)-dependent expression of SKIP. These findings underscore the specific and prominent role of SKIP in the development of insulin resistance in skeletal muscle.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue
Animals
Diabetes Mellitus, Type 2 / enzymology
Diet, High-Fat / adverse effects
Endoplasmic Reticulum Stress / physiology*
Insulin / metabolism
Insulin Resistance / physiology*
Mice
Mice, Transgenic
Muscle, Skeletal / enzymology*
Phosphatidylinositol Phosphates / metabolism
Phosphoric Monoester Hydrolases / genetics
Phosphoric Monoester Hydrolases / metabolism*

Substances

Insulin
Phosphatidylinositol Phosphates
phosphatidylinositol 3,4,5-triphosphate
Pps protein, mouse
Phosphoric Monoester Hydrolases

Grants and funding

This work was supported in part by grants to T.I. from the Japan Society for the Promotion of Science (JSPS; Kakenhi grant number 25460365), the Japan Diabetes Foundation, Novo Nordisk Pharma Ltd., and the Hyogo Science and Technology Association and by a grant-in-aid for scientific research (S) to T.T. by the Ministry of Education, Culture, Sports, Science and Technology, Japan (Kakenhi grant number Scientific Research 23227005). The funders had no role in study design, data collection and analysis, decision to publish, or presentation of the manuscript.