title: Leukemia inhibitory factor increases glucose uptake in mouse skeletal muscle.
abstract: Members of the IL-6 family, IL-6 and ciliary neurotrophic factor (CNTF), have been shown to increase glucose uptake and fatty acid oxidation in skeletal muscle. However, the metabolic effects of another family member, leukemia inhibitory factor (LIF), are not well characterized. Effects of LIF on skeletal muscle glucose uptake and palmitate oxidation and signaling were investigated in ex vivo incubated mouse soleus and EDL muscles from muscle-specific AMPKα2 kinase-dead, muscle-specific SOCS3 knockout, and lean and high-fat-fed mice. Inhibitors were used to investigate involvement of specific signaling pathways. LIF increased muscle glucose uptake in dose (50-5,000 pM/l) and time-dependent manners with maximal effects at the 30-min time point. LIF increased Akt Ser(473) phosphorylation (P) in soleus and EDL, whereas AMPK Thr(172) P was unaffected. Incubation with parthenolide abolished LIF-induced glucose uptake and STAT3 Tyr(705) P, whereas incubation with LY-294002 and wortmannin suppressed both basal and LIF-induced glucose uptake and Akt Ser(473) P, indicating that JAK and PI 3-kinase signaling is required for LIF-stimulated glucose uptake. Incubation with rapamycin and AZD8055 indicated that mammalian target of rapamycin complex (mTORC)2, but not mTORC1, also is required for LIF-stimulated glucose uptake. In contrast to CNTF, LIF stimulation did not alter palmitate oxidation. LIF-stimulated glucose uptake was maintained in EDL from obese insulin-resistant mice, whereas soleus developed LIF resistance. Lack of SOCS3 and AMPKα2 did not affect LIF-stimulated glucose uptake. In conclusion, LIF acutely increased muscle glucose uptake by a mechanism potentially involving the PI 3-kinase/mTORC2/Akt pathway and is not impaired in EDL muscle from obese insulin-resistant mice.
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Nina
authors.initials: N
authors.lastname: Brandt
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada;
authors.forename: Hayley M
authors.initials: HM
authors.lastname: O'Neill
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kleinert
authors.affiliation: Institute of Sports Medicine, Department of Orthopedic Surgery M, Bispebjerg Hospital and Center for Healthy Aging, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Schjerling
authors.affiliation: Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark.
authors.forename: Erik
authors.initials: E
authors.lastname: Vernet
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada;
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.affiliation: Molecular Physiology Group, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Erik A
authors.initials: EA
authors.lastname: Richter
authors.affiliation: Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark sbbj@novonordisk.com.
authors.forename: Sebastian B
authors.initials: SB
authors.lastname: Jørgensen
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D011994:Recombinant Proteins; D005947:Glucose
keywords: AMPK; glucose homeostasis; leukemia inhibitory factor; skeletal muscle