LKB1 Regulates Lipid Oxidation During Exercise Independently of AMPK

作者：Jeppesen Jacob; Maarbjerg Stine J; Jordy Andreas B; Fritzen Andreas M; Pehmoller Christian; Sylow Lykke; Serup Annette Karen; Jessen Niels; Thorsen Kasper; Prats Clara; Qvortrup Klaus; Dyck Jason R B; Hunter Roger W; Sakamoto Kei; Thomson David M; Schjerling Peter; Wojtaszewski Jorgen F P; Richter Erik A^*; Kiens Bente

来源：Diabetes, 2013, 62(5): 1490-1499.

DOI：10.2337/db12-1160

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)alpha 2 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 AMPK alpha 2 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. Diabetes 62:1490-1499, 2013

• 出版日期2013-5