LKB1 regulates lipid oxidation during exercise independently of AMPK

Jacob Fuglsbjerg Jeppesen; Stine Just Maarbjerg; Andreas Børsting Jordy; Andreas Mæchel Fritzen; Christian Pehmøller; Lykke Sylow; Annette Karen Lundbeck Serup; Niels Jessen; Kasper Thorsen; Clara Prats Gavalda; Klaus Qvortrup; Jason R B Dyck; Roger W Hunter; Kei Sakamoto; David M Thomson; Peter Schjerling; Jørgen Wojtaszewski; Erik Richter; Bente Kiens

doi:10.2337/db12-1160

LKB1 regulates lipid oxidation during exercise independently of AMPK

Jacob Fuglsbjerg Jeppesen, Stine Just Maarbjerg, Andreas Børsting Jordy, Andreas Mæchel Fritzen, Christian Pehmøller, Lykke Sylow, Annette Karen Lundbeck Serup, Niels Jessen, Kasper Thorsen, Clara Prats Gavalda, Klaus Qvortrup, Jason R B Dyck, Roger W Hunter, Kei Sakamoto, David M Thomson, Peter Schjerling, Jørgen Wojtaszewski, Erik Richter, Bente Kiens

54 Citations (Scopus)

Abstract

Lipid metabolism is important for health and insulin action, yet the fundamental process of regulating lipid metabolism during muscle contraction is incompletely understood. Here, we show that liver kinase B1 (LKB1) muscle-speci fic knockout (LKB1 MKO) mice display decreased fatty acid (FA) oxidation during treadmill exercise. LKB1 MKO mice also show decreased muscle SIK3 activity, increased histone deacetylase 4 expression, decreased NAD⁺ concentration and SIRT1 activity, and decreased expression of genes involved in FA oxidation. In AMP-activated protein kinase (AMPK)α2 KO mice, substrate use was similar to that in WT mice, which excluded that decreased FA oxidation in LKB1 MKO mice was due to decreased AMPKα2 activity. Additionally, LKB1 MKO muscle demonstrated decreased FA oxidation in vitro. A markedly decreased phosphorylation of TBC1D1, a proposed regulator of FA transport, and a low CoA content could contribute to the low FA oxidation in LKB1 MKO. LKB1 deficiency did not reduce muscle glucose uptake or oxidation during exercise in vivo, excluding a general impairment of substrate use during exercise in LKB1 MKO mice. Our findings demonstrate that LKB1 is a novel molecular regulator of major importance for FA oxidation but not glucose uptake in muscle during exercise.

Original language	English
Journal	Diabetes
Volume	62
Issue number	5
Pages (from-to)	1490-1499
Number of pages	10
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db12-1160
Publication status	Published - May 2013

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Jeppesen, J. F., Maarbjerg, S. J., Jordy, A. B., Fritzen, A. M., Pehmøller, C., Sylow, L., Serup, A. K. L., Jessen, N., Thorsen, K., Prats Gavalda, C., Qvortrup, K., Dyck, J. R. B., Hunter, R. W., Sakamoto, K., Thomson, D. M., Schjerling, P., Wojtaszewski, J., Richter, E., & Kiens, B. (2013). LKB1 regulates lipid oxidation during exercise independently of AMPK. Diabetes, 62(5), 1490-1499. https://doi.org/10.2337/db12-1160

Jeppesen, JF, Maarbjerg, SJ, Jordy, AB, Fritzen, AM, Pehmøller, C, Sylow, L, Serup, AKL, Jessen, N, Thorsen, K, Prats Gavalda, C , Qvortrup, K, Dyck, JRB, Hunter, RW, Sakamoto, K, Thomson, DM, Schjerling, P , Wojtaszewski, J , Richter, E & Kiens, B 2013, 'LKB1 regulates lipid oxidation during exercise independently of AMPK', Diabetes, vol. 62, no. 5, pp. 1490-1499. https://doi.org/10.2337/db12-1160

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title = "LKB1 regulates lipid oxidation during exercise independently of AMPK",

abstract = "Lipid metabolism is important for health and insulin action, yet the fundamental process of regulating lipid metabolism during muscle contraction is incompletely understood. Here, we show that liver kinase B1 (LKB1) muscle-speci fic knockout (LKB1 MKO) mice display decreased fatty acid (FA) oxidation during treadmill exercise. LKB1 MKO mice also show decreased muscle SIK3 activity, increased histone deacetylase 4 expression, decreased NAD+ concentration and SIRT1 activity, and decreased expression of genes involved in FA oxidation. In AMP-activated protein kinase (AMPK)α2 KO mice, substrate use was similar to that in WT mice, which excluded that decreased FA oxidation in LKB1 MKO mice was due to decreased AMPKα2 activity. Additionally, LKB1 MKO muscle demonstrated decreased FA oxidation in vitro. A markedly decreased phosphorylation of TBC1D1, a proposed regulator of FA transport, and a low CoA content could contribute to the low FA oxidation in LKB1 MKO. LKB1 deficiency did not reduce muscle glucose uptake or oxidation during exercise in vivo, excluding a general impairment of substrate use during exercise in LKB1 MKO mice. Our findings demonstrate that LKB1 is a novel molecular regulator of major importance for FA oxidation but not glucose uptake in muscle during exercise.",

author = "Jeppesen, {Jacob Fuglsbjerg} and Maarbjerg, {Stine Just} and Jordy, {Andreas B{\o}rsting} and Fritzen, {Andreas M{\ae}chel} and Christian Pehm{\o}ller and Lykke Sylow and Serup, {Annette Karen Lundbeck} and Niels Jessen and Kasper Thorsen and {Prats Gavalda}, Clara and Klaus Qvortrup and Dyck, {Jason R B} and Hunter, {Roger W} and Kei Sakamoto and Thomson, {David M} and Peter Schjerling and J{\o}rgen Wojtaszewski and Erik Richter and Bente Kiens",

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T1 - LKB1 regulates lipid oxidation during exercise independently of AMPK

AU - Jeppesen, Jacob Fuglsbjerg

AU - Maarbjerg, Stine Just

AU - Jordy, Andreas Børsting

AU - Fritzen, Andreas Mæchel

AU - Pehmøller, Christian

AU - Sylow, Lykke

AU - Serup, Annette Karen Lundbeck

AU - Jessen, Niels

AU - Thorsen, Kasper

AU - Prats Gavalda, Clara

AU - Qvortrup, Klaus

AU - Dyck, Jason R B

AU - Hunter, Roger W

AU - Sakamoto, Kei

AU - Thomson, David M

AU - Schjerling, Peter

AU - Wojtaszewski, Jørgen

AU - Richter, Erik

AU - Kiens, Bente

N1 - CURIS 2013 NEXS 026

PY - 2013/5

Y1 - 2013/5

N2 - Lipid metabolism is important for health and insulin action, yet the fundamental process of regulating lipid metabolism during muscle contraction is incompletely understood. Here, we show that liver kinase B1 (LKB1) muscle-speci fic knockout (LKB1 MKO) mice display decreased fatty acid (FA) oxidation during treadmill exercise. LKB1 MKO mice also show decreased muscle SIK3 activity, increased histone deacetylase 4 expression, decreased NAD+ concentration and SIRT1 activity, and decreased expression of genes involved in FA oxidation. In AMP-activated protein kinase (AMPK)α2 KO mice, substrate use was similar to that in WT mice, which excluded that decreased FA oxidation in LKB1 MKO mice was due to decreased AMPKα2 activity. Additionally, LKB1 MKO muscle demonstrated decreased FA oxidation in vitro. A markedly decreased phosphorylation of TBC1D1, a proposed regulator of FA transport, and a low CoA content could contribute to the low FA oxidation in LKB1 MKO. LKB1 deficiency did not reduce muscle glucose uptake or oxidation during exercise in vivo, excluding a general impairment of substrate use during exercise in LKB1 MKO mice. Our findings demonstrate that LKB1 is a novel molecular regulator of major importance for FA oxidation but not glucose uptake in muscle during exercise.

AB - Lipid metabolism is important for health and insulin action, yet the fundamental process of regulating lipid metabolism during muscle contraction is incompletely understood. Here, we show that liver kinase B1 (LKB1) muscle-speci fic knockout (LKB1 MKO) mice display decreased fatty acid (FA) oxidation during treadmill exercise. LKB1 MKO mice also show decreased muscle SIK3 activity, increased histone deacetylase 4 expression, decreased NAD+ concentration and SIRT1 activity, and decreased expression of genes involved in FA oxidation. In AMP-activated protein kinase (AMPK)α2 KO mice, substrate use was similar to that in WT mice, which excluded that decreased FA oxidation in LKB1 MKO mice was due to decreased AMPKα2 activity. Additionally, LKB1 MKO muscle demonstrated decreased FA oxidation in vitro. A markedly decreased phosphorylation of TBC1D1, a proposed regulator of FA transport, and a low CoA content could contribute to the low FA oxidation in LKB1 MKO. LKB1 deficiency did not reduce muscle glucose uptake or oxidation during exercise in vivo, excluding a general impairment of substrate use during exercise in LKB1 MKO mice. Our findings demonstrate that LKB1 is a novel molecular regulator of major importance for FA oxidation but not glucose uptake in muscle during exercise.

U2 - 10.2337/db12-1160

DO - 10.2337/db12-1160

M3 - Journal article

C2 - 23349504

SN - 0012-1797

VL - 62

SP - 1490

EP - 1499

JO - Diabetes

JF - Diabetes

IS - 5

ER -

LKB1 regulates lipid oxidation during exercise independently of AMPK

Abstract

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