Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle

Ho Jin Koh; Taro Toyoda; Michelle M. Didesch; Min Young Lee; Mark W. Sleeman; Rohit N. Kulkarni; Nicolas Musi; Michael F. Hirshman; Laurie J. Goodyear

doi:10.1038/ncomms2851

Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle

Ho Jin Koh, Taro Toyoda, Michelle M. Didesch, Min Young Lee, Mark W. Sleeman, Rohit N. Kulkarni, Nicolas Musi, Michael F. Hirshman, Laurie J. Goodyear

Research output: Contribution to journal › Article › peer-review

93 Scopus citations

Abstract

Endoplasmic reticulum stress has been linked to insulin resistance in multiple tissues but the role of endoplasmic reticulum stress in skeletal muscle has not been explored. Endoplasmic reticulum stress has been reported to increase tribbles 3 expression in multiple cell lines. Here, we report that high-fat feeding in mice, and obesity and type 2 diabetes in humans significantly increases tribbles 3 and endoplasmic reticulum stress markers in skeletal muscle. Overexpression of tribbles 3 in C2C12 myotubes and mouse tibialis anterior muscles significantly impairs insulin signalling. Incubation of C2C12 cells and mouse skeletal muscle with endoplasmic reticulum stressors thapsigargin and tunicamycin increases tribbles 3 and impairs insulin signalling and glucose uptake, effects reversed in cells overexpressing RNAi for tribbles 3 and in muscles from tribbles 3 knockout mice. Furthermore, tribbles 3 knockout mice are protected from high-fat diet-induced insulin resistance in skeletal muscle. These data demonstrate that tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle.

Original language	English (US)
Article number	1871
Journal	Nature communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms2851
State	Published - 2013
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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title = "Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle",

abstract = "Endoplasmic reticulum stress has been linked to insulin resistance in multiple tissues but the role of endoplasmic reticulum stress in skeletal muscle has not been explored. Endoplasmic reticulum stress has been reported to increase tribbles 3 expression in multiple cell lines. Here, we report that high-fat feeding in mice, and obesity and type 2 diabetes in humans significantly increases tribbles 3 and endoplasmic reticulum stress markers in skeletal muscle. Overexpression of tribbles 3 in C2C12 myotubes and mouse tibialis anterior muscles significantly impairs insulin signalling. Incubation of C2C12 cells and mouse skeletal muscle with endoplasmic reticulum stressors thapsigargin and tunicamycin increases tribbles 3 and impairs insulin signalling and glucose uptake, effects reversed in cells overexpressing RNAi for tribbles 3 and in muscles from tribbles 3 knockout mice. Furthermore, tribbles 3 knockout mice are protected from high-fat diet-induced insulin resistance in skeletal muscle. These data demonstrate that tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle.",

author = "Koh, {Ho Jin} and Taro Toyoda and Didesch, {Michelle M.} and Lee, {Min Young} and Sleeman, {Mark W.} and Kulkarni, {Rohit N.} and Nicolas Musi and Hirshman, {Michael F.} and Goodyear, {Laurie J.}",

note = "Funding Information: We thank M. Montminy (Salk Institute) for providing TRB3 antibody and adenoviruses for TRB3 and RNAi for TRB3, E.A. Caniano (Joslin Diabetes Center) for editorial contributions, and all other members of the Goodyear lab for critical discussions. This work was supported by NIH grants to H.-J.K. (5P30DK036836 and P30DK040561), to L.J.G. (R01AR045670), to R.N.K. (5R01DK067536) and to the Joslin DERC (P30DK036836). T.T. and M.-Y.L. were supported by ADA mentor-based fellowships (to L.J.G.).",

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doi = "10.1038/ncomms2851",

language = "English (US)",

volume = "4",

journal = "Nature communications",

issn = "2041-1723",

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T1 - Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle

AU - Koh, Ho Jin

AU - Toyoda, Taro

AU - Didesch, Michelle M.

AU - Lee, Min Young

AU - Sleeman, Mark W.

AU - Kulkarni, Rohit N.

AU - Musi, Nicolas

AU - Hirshman, Michael F.

AU - Goodyear, Laurie J.

N1 - Funding Information: We thank M. Montminy (Salk Institute) for providing TRB3 antibody and adenoviruses for TRB3 and RNAi for TRB3, E.A. Caniano (Joslin Diabetes Center) for editorial contributions, and all other members of the Goodyear lab for critical discussions. This work was supported by NIH grants to H.-J.K. (5P30DK036836 and P30DK040561), to L.J.G. (R01AR045670), to R.N.K. (5R01DK067536) and to the Joslin DERC (P30DK036836). T.T. and M.-Y.L. were supported by ADA mentor-based fellowships (to L.J.G.).

PY - 2013

Y1 - 2013

N2 - Endoplasmic reticulum stress has been linked to insulin resistance in multiple tissues but the role of endoplasmic reticulum stress in skeletal muscle has not been explored. Endoplasmic reticulum stress has been reported to increase tribbles 3 expression in multiple cell lines. Here, we report that high-fat feeding in mice, and obesity and type 2 diabetes in humans significantly increases tribbles 3 and endoplasmic reticulum stress markers in skeletal muscle. Overexpression of tribbles 3 in C2C12 myotubes and mouse tibialis anterior muscles significantly impairs insulin signalling. Incubation of C2C12 cells and mouse skeletal muscle with endoplasmic reticulum stressors thapsigargin and tunicamycin increases tribbles 3 and impairs insulin signalling and glucose uptake, effects reversed in cells overexpressing RNAi for tribbles 3 and in muscles from tribbles 3 knockout mice. Furthermore, tribbles 3 knockout mice are protected from high-fat diet-induced insulin resistance in skeletal muscle. These data demonstrate that tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle.

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Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle

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