Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle

Jonas Thue Treebak; Christian Frøsig; Christian Pehmøller; Shuai Chen; Stine Just Maarbjerg; Nina Brandt; C. Mackintosh; J. R. Zierath; D. G. Hardie; Bente Kiens; Erik Richter; Henriette Pilegaard; Jørgen Wojtaszewski

doi:10.1007/s00125-009-1294-y

Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle

Jonas Thue Treebak, Christian Frøsig, Christian Pehmøller, Shuai Chen, Stine Just Maarbjerg, Nina Brandt, C. Mackintosh, J. R. Zierath, D. G. Hardie, Bente Kiens, Erik Richter, Henriette Pilegaard, Jørgen Wojtaszewski

Molecular Integrative Physiology

86 Citations (Scopus)

Abstract

AIMS/HYPOTHESIS: TBC1 domain family, member 4 (TBC1D4; also known as AS160) is a cellular signalling intermediate to glucose transport regulated by insulin-dependent and -independent mechanisms. Skeletal muscle insulin sensitivity is increased after acute exercise by an unknown mechanism that does not involve modulation at proximal insulin signalling intermediates. We hypothesised that signalling through TBC1D4 is involved in this effect of exercise as it is a common signalling element for insulin and exercise. METHODS: Insulin-regulated glucose metabolism was evaluated in 12 healthy moderately trained young men 4 h after one-legged exercise at basal and during a euglycaemic-hyperinsulinaemic clamp. Vastus lateralis biopsies were taken before and immediately after the clamp. RESULTS: Insulin stimulation increased glucose uptake in both legs, with greater effects (~80%, p < 0.01) in the previously exercised leg. TBC1D4 phosphorylation, assessed using the phospho-AKT (protein kinase B)substrate antibody and phospho- and site-specific antibodies targeting six phosphorylation sites on TBC1D4, increased at similar degrees to insulin stimulation in the previously exercised and rested legs (p < 0.01). However, TBC1D4 phosphorylation on Ser-318, Ser-341, Ser-588 and Ser-751 was higher in the previously exercised leg, both in the absence and in the presence of insulin (p < 0.01; Ser-588, p = 0.09; observed power = 0.39). 14-3-3 binding capacity for TBC1D4 increased equally (p < 0.01) in both legs during insulin stimulation. CONCLUSION/INTERPRETATION: We provide evidence for site-specific phosphorylation of TBC1D4 in human skeletal muscle in response to physiological hyperinsulinaemia. The data support the idea that TBC1D4 is a nexus for insulin- and exercise-responsive signals that may mediate increased insulin action after exercise.

Original language	English
Journal	Diabetologia
Volume	52
Issue number	5
Pages (from-to)	891-900
Number of pages	10
ISSN	0012-186X
DOIs	https://doi.org/10.1007/s00125-009-1294-y
Publication status	Published - 2009

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title = "Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle",

abstract = "AIMS/HYPOTHESIS: TBC1 domain family, member 4 (TBC1D4; also known as AS160) is a cellular signalling intermediate to glucose transport regulated by insulin-dependent and -independent mechanisms. Skeletal muscle insulin sensitivity is increased after acute exercise by an unknown mechanism that does not involve modulation at proximal insulin signalling intermediates. We hypothesised that signalling through TBC1D4 is involved in this effect of exercise as it is a common signalling element for insulin and exercise. METHODS: Insulin-regulated glucose metabolism was evaluated in 12 healthy moderately trained young men 4 h after one-legged exercise at basal and during a euglycaemic-hyperinsulinaemic clamp. Vastus lateralis biopsies were taken before and immediately after the clamp. RESULTS: Insulin stimulation increased glucose uptake in both legs, with greater effects (~80%, p < 0.01) in the previously exercised leg. TBC1D4 phosphorylation, assessed using the phospho-AKT (protein kinase B)substrate antibody and phospho- and site-specific antibodies targeting six phosphorylation sites on TBC1D4, increased at similar degrees to insulin stimulation in the previously exercised and rested legs (p < 0.01). However, TBC1D4 phosphorylation on Ser-318, Ser-341, Ser-588 and Ser-751 was higher in the previously exercised leg, both in the absence and in the presence of insulin (p < 0.01; Ser-588, p = 0.09; observed power = 0.39). 14-3-3 binding capacity for TBC1D4 increased equally (p < 0.01) in both legs during insulin stimulation. CONCLUSION/INTERPRETATION: We provide evidence for site-specific phosphorylation of TBC1D4 in human skeletal muscle in response to physiological hyperinsulinaemia. The data support the idea that TBC1D4 is a nexus for insulin- and exercise-responsive signals that may mediate increased insulin action after exercise.",

author = "Treebak, {Jonas Thue} and Christian Fr{\o}sig and Christian Pehm{\o}ller and Shuai Chen and Maarbjerg, {Stine Just} and Nina Brandt and C. Mackintosh and Zierath, {J. R.} and Hardie, {D. G.} and Bente Kiens and Erik Richter and Henriette Pilegaard and J{\o}rgen Wojtaszewski",

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year = "2009",

doi = "10.1007/s00125-009-1294-y",

language = "English",

volume = "52",

pages = "891--900",

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T1 - Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle

AU - Treebak, Jonas Thue

AU - Frøsig, Christian

AU - Pehmøller, Christian

AU - Chen, Shuai

AU - Maarbjerg, Stine Just

AU - Brandt, Nina

AU - Mackintosh, C.

AU - Zierath, J. R.

AU - Hardie, D. G.

AU - Kiens, Bente

AU - Richter, Erik

AU - Pilegaard, Henriette

AU - Wojtaszewski, Jørgen

N1 - CURIS 2009 5200 011

PY - 2009

Y1 - 2009

N2 - AIMS/HYPOTHESIS: TBC1 domain family, member 4 (TBC1D4; also known as AS160) is a cellular signalling intermediate to glucose transport regulated by insulin-dependent and -independent mechanisms. Skeletal muscle insulin sensitivity is increased after acute exercise by an unknown mechanism that does not involve modulation at proximal insulin signalling intermediates. We hypothesised that signalling through TBC1D4 is involved in this effect of exercise as it is a common signalling element for insulin and exercise. METHODS: Insulin-regulated glucose metabolism was evaluated in 12 healthy moderately trained young men 4 h after one-legged exercise at basal and during a euglycaemic-hyperinsulinaemic clamp. Vastus lateralis biopsies were taken before and immediately after the clamp. RESULTS: Insulin stimulation increased glucose uptake in both legs, with greater effects (~80%, p < 0.01) in the previously exercised leg. TBC1D4 phosphorylation, assessed using the phospho-AKT (protein kinase B)substrate antibody and phospho- and site-specific antibodies targeting six phosphorylation sites on TBC1D4, increased at similar degrees to insulin stimulation in the previously exercised and rested legs (p < 0.01). However, TBC1D4 phosphorylation on Ser-318, Ser-341, Ser-588 and Ser-751 was higher in the previously exercised leg, both in the absence and in the presence of insulin (p < 0.01; Ser-588, p = 0.09; observed power = 0.39). 14-3-3 binding capacity for TBC1D4 increased equally (p < 0.01) in both legs during insulin stimulation. CONCLUSION/INTERPRETATION: We provide evidence for site-specific phosphorylation of TBC1D4 in human skeletal muscle in response to physiological hyperinsulinaemia. The data support the idea that TBC1D4 is a nexus for insulin- and exercise-responsive signals that may mediate increased insulin action after exercise.

AB - AIMS/HYPOTHESIS: TBC1 domain family, member 4 (TBC1D4; also known as AS160) is a cellular signalling intermediate to glucose transport regulated by insulin-dependent and -independent mechanisms. Skeletal muscle insulin sensitivity is increased after acute exercise by an unknown mechanism that does not involve modulation at proximal insulin signalling intermediates. We hypothesised that signalling through TBC1D4 is involved in this effect of exercise as it is a common signalling element for insulin and exercise. METHODS: Insulin-regulated glucose metabolism was evaluated in 12 healthy moderately trained young men 4 h after one-legged exercise at basal and during a euglycaemic-hyperinsulinaemic clamp. Vastus lateralis biopsies were taken before and immediately after the clamp. RESULTS: Insulin stimulation increased glucose uptake in both legs, with greater effects (~80%, p < 0.01) in the previously exercised leg. TBC1D4 phosphorylation, assessed using the phospho-AKT (protein kinase B)substrate antibody and phospho- and site-specific antibodies targeting six phosphorylation sites on TBC1D4, increased at similar degrees to insulin stimulation in the previously exercised and rested legs (p < 0.01). However, TBC1D4 phosphorylation on Ser-318, Ser-341, Ser-588 and Ser-751 was higher in the previously exercised leg, both in the absence and in the presence of insulin (p < 0.01; Ser-588, p = 0.09; observed power = 0.39). 14-3-3 binding capacity for TBC1D4 increased equally (p < 0.01) in both legs during insulin stimulation. CONCLUSION/INTERPRETATION: We provide evidence for site-specific phosphorylation of TBC1D4 in human skeletal muscle in response to physiological hyperinsulinaemia. The data support the idea that TBC1D4 is a nexus for insulin- and exercise-responsive signals that may mediate increased insulin action after exercise.

U2 - 10.1007/s00125-009-1294-y

DO - 10.1007/s00125-009-1294-y

M3 - Journal article

C2 - 19252894

SN - 0012-186X

VL - 52

SP - 891

EP - 900

JO - Diabetologia

JF - Diabetologia

IS - 5

ER -

Potential role of TBC1D4 in enhanced post-exercise insulin action in human skeletal muscle

Abstract

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