title: AMPK and insulin action--responses to ageing and high fat diet.
abstract: The 5'-AMP-activated protein kinase (AMPK) is considered "a metabolic master-switch" in skeletal muscle reducing ATP- consuming processes whilst stimulating ATP regeneration. Within recent years, AMPK has also been proposed as a potential target to attenuate insulin resistance, although the exact role of AMPK is not well understood. Here we hypothesized that mice lacking α2AMPK activity in muscle would be more susceptible to develop insulin resistance associated with ageing alone or in combination with high fat diet. Young (∼4 month) or old (∼18 month) wild type and muscle specific α2AMPK kinase-dead mice on chow diet as well as old mice on 17 weeks of high fat diet were studied for whole body glucose homeostasis (OGTT, ITT and HOMA-IR), insulin signaling and insulin-stimulated glucose uptake in muscle. We demonstrate that high fat diet in old mice results in impaired glucose homeostasis and insulin stimulated glucose uptake in both the soleus and extensor digitorum longus muscle, coinciding with reduced insulin signaling at the level of Akt (pSer473 and pThr308), TBC1D1 (pThr590) and TBC1D4 (pThr642). In contrast to our hypothesis, the impact of ageing and high fat diet on insulin action was not worsened in mice lacking functional α2AMPK in muscle. It is concluded that α2AMPK deficiency in mouse skeletal muscle does not cause muscle insulin resistance in young and old mice and does not exacerbate obesity-induced insulin resistance in old mice suggesting that decreased α2AMPK activity does not increase susceptibility for insulin resistance in skeletal muscle.
authors.affiliation: Section of Molecular Physiology, The August Krogh Centre, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark. cfrosig@ifi.ku.dk
authors.forename: Christian
authors.initials: C
authors.lastname: Frøsig
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Jensen
authors.forename: Jacob
authors.initials: J
authors.lastname: Jeppesen
authors.forename: Christian
authors.initials: C
authors.lastname: Pehmøller
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Treebak
authors.forename: Stine J
authors.initials: SJ
authors.lastname: Maarbjerg
authors.forename: Jonas M
authors.initials: JM
authors.lastname: Kristensen
authors.forename: Lykke
authors.initials: L
authors.lastname: Sylow
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Alsted
authors.forename: Peter
authors.initials: P
authors.lastname: Schjerling
authors.forename: Bente
authors.initials: B
authors.lastname: Kiens
authors.forename: Jørgen F P
authors.initials: JF
authors.lastname: Wojtaszewski
authors.forename: Erik A
authors.initials: EA
authors.lastname: Richter
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose; D001823:Body Composition; D059305:Diet, High-Fat / Q000009:adverse effects*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D009124:Muscle Proteins; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse; D006593:Hexokinase; C534978:Prkaa2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases