Dataset Information

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-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)?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?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.

SUBMITTER: Jeppesen J

PROVIDER: S-EPMC3636614 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

LKB1 regulates lipid oxidation during exercise independently of AMPK.

Jeppesen Jacob J Maarbjerg Stine J SJ Jordy Andreas B AB Fritzen Andreas M AM Pehmøller Christian C Sylow Lykke L Serup Annette Karen AK Jessen Niels N Thorsen Kasper K Prats Clara C Qvortrup Klaus K Dyck Jason R B JR Hunter Roger W RW Sakamoto Kei K Thomson David M DM Schjerling Peter P Wojtaszewski Jørgen F P JF Richter Erik A EA Kiens Bente B

Diabetes 20130124 5

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 expressio ...[more]

PMID: 23349504

Similar Datasets

Project description:Background: Substantial interindividual variability exists in the maximal rate of fat oxidation (MFO) during exercise with potential implications for metabolic health. Although the diet can affect the metabolic response to exercise, the contribution of a self-selected diet to the interindividual variability in the MFO requires further clarification.Objective: We sought to identify whether recent, self-selected dietary intake independently predicts the MFO in healthy men and women.Design: The MFO and maximal oxygen uptake ([Formula: see text]O2 max) were determined with the use of indirect calorimetry in 305 healthy volunteers [150 men and 155 women; mean ± SD age: 25 ± 6 y; body mass index (BMI; in kg/m2): 23 ± 2]. Dual-energy X-ray absorptiometry was used to assess body composition with the self-reported physical activity level (SRPAL) and dietary intake determined in the 4 d before exercise testing. To minimize potential confounding with typically observed sex-related differences (e.g., body composition), predictor variables were mean-centered by sex. In the analyses, hierarchical multiple linear regressions were used to quantify each variable's influence on the MFO.Results: The mean absolute MFO was 0.55 ± 0.19 g/min (range: 0.19-1.13 g/min). A total of 44.4% of the interindividual variability in the MFO was explained by the [Formula: see text]O2 max, sex, and SRPAL with dietary carbohydrate (carbohydrate; negative association with the MFO) and fat intake (positive association) associated with an additional 3.2% of the variance. When expressed relative to fat-free mass (FFM), the MFO was 10.8 ± 3.2 mg · kg FFM-1 · min-1 (range: 3.5-20.7 mg · kg FFM-1 · min-1) with 16.6% of the variability explained by the [Formula: see text]O2 max, sex, and SRPAL; dietary carbohydrate and fat intakes together explained an additional 2.6% of the variability. Biological sex was an independent determinant of the MFO with women showing a higher MFO [men: 10.3 ± 3.1 mg · kg FFM-1 · min-1 (3.5-19.9 mg · kg FFM-1 · min-1); women: 11.2 ± 3.3 mg · kg FFM-1 · min-1 (4.6-20.7 mg · kg FFM-1 · min-1); P < 0.05].Conclusion: Considered alongside other robust determinants, dietary carbohydrate and fat intake make modest but independent contributions to the interindividual variability in the capacity to oxidize fat during exercise. This trial was registered at clinicaltrials.gov as NCT02070055.

Project description:Recent work indicates that the LKB1 tumour suppressor protein kinase, which is mutated in Peutz-Jeghers cancer syndrome, phosphorylates and activates a group of protein kinases that are related to AMPK (AMP-activated protein kinase). Ten of the 14 AMPK-related protein kinases activated by LKB1, including SIK (salt-induced kinase), MARK (microtubule-affinity-regulating kinase) and BRSK (brain-specific kinase) isoforms, possess a ubiquitin-associated (UBA) domain immediately C-terminal to the kinase catalytic domain. These are the only protein kinases in the human genome known to possess a UBA domain, but their roles in regulating AMPK-related kinases are unknown. We have investigated the roles that the UBA domain may play in regulating these enzymes. Limited proteolysis of MARK2 revealed that the kinase and UBA domains were contained within a fragment that was resistant to trypsin proteolysis. SAXS (small-angle X-ray scattering) analysis of inactive and active LKB1-phosphorylated MARK2 revealed that activation of MARK2 is accompanied by a significant conformational change that alters the orientation of the UBA domain with respect to the catalytic domain. Our results indicate that none of the UBA domains found in AMPK-related kinases interact with polyubiquitin or other ubiquitin-like molecules. Instead, the UBA domains appear to play an essential conformational role and are required for the LKB1-mediated phosphorylation and activation of AMPK-related kinases. This is based on the findings that mutation or removal of the UBA domains of several AMPK-related kinases, including isoforms of MARK, SIK and BRSK, markedly impaired the catalytic activity and LKB1-mediated phosphorylation of these enzymes. We also provide evidence that the UBA domains do not function as LKB1-STRAD (STE20-related adaptor)-MO25 (mouse protein 25) docking/interacting sites and that mutations in the UBA domain of SIK suppressed the ability of SIK to localize within punctate regions of the nucleus. Taken together, these findings suggest that the UBA domains of AMPK-related kinases play an important role in regulating the conformation, activation and localization of these enzymes.

Dataset Information

LKB1 regulates lipid oxidation during exercise independently of AMPK.

Publications

LKB1 regulates lipid oxidation during exercise independently of AMPK.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets