LKB1 regulates lipid oxidation during exercise independently of AMPK.
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-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 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.
August Krogh Centre and Molecular Physiology Group, Department of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark.
Jacob
J
Jeppesen
Stine J
SJ
Maarbjerg
Andreas B
AB
Jordy
Andreas M
AM
Fritzen
Christian
C
Pehmøller
Lykke
L
Sylow
Annette Karen
AK
Serup
Niels
N
Jessen
Kasper
K
Thorsen
Clara
C
Prats
Klaus
K
Qvortrup
Jason R B
JR
Dyck
Roger W
RW
Hunter
Kei
K
Sakamoto
David M
DM
Thomson
Peter
P
Schjerling
Jørgen F P
JF
Wojtaszewski
Erik A
EA
Richter
Bente
B
Kiens
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D003065:Coenzyme A / Q000378:metabolism; D015536:Down-Regulation; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D009243:NAD / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation
D005230:Fatty Acids, Nonesterified; D020690:GTPase-Activating Proteins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; C095906:Tbc1d1 protein, mouse; D009243:NAD; C534978:Prkaa2 protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D003065:Coenzyme A