LKB1 regulates lipid oxidation during exercise independently of AMPK
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LKB1 regulates lipid oxidation during exercise independently of AMPK. / Jeppesen, Jacob Fuglsbjerg; Maarbjerg, Stine Just; Jordy, Andreas Børsting; Fritzen, Andreas Mæchel; Pehmøller, Christian; Sylow, Lykke; Serup, Annette Karen Lundbeck; Jessen, Niels; Thorsen, Kasper; Prats Gavalda, Clara; Qvortrup, Klaus; Dyck, Jason R B; Hunter, Roger W; Sakamoto, Kei; Thomson, David M; Schjerling, Peter; Wojtaszewski, Jørgen; Richter, Erik A.; Kiens, Bente.
In: Diabetes, Vol. 62, No. 5, 2013, p. 1490-1499.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
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 A.
AU - Kiens, Bente
N1 - CURIS 2013 NEXS 026
PY - 2013
Y1 - 2013
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 LKB1 muscle-specific 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 AMPKa2 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 AMPKa2 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 LKB1 muscle-specific 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 AMPKa2 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 AMPKa2 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
VL - 62
SP - 1490
EP - 1499
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 5
ER -
ID: 44035967