Leukemia inhibitory factor increases glucose uptake in mouse skeletal muscle

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Introduction: Members of the interleukin-6 (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.

Methods: Effects of LIF on skeletal muscle glucose uptake, 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.

Results: LIF increased muscle glucose uptake in dose (50-5000 pM/L) and time-dependent manners with maximal effects at the 30 min time-point. LIF increased Akt Ser473-P in soleus and EDL, whereas AMPK Thr172-P was unaffected. Incubation with Parthenolide abolished LIF-induced glucose uptake and STAT3 Tyr705-P, whereas, incubation with LY-294002 and Wortmannin suppressed both basal and LIF-induced glucose uptake and Akt Ser473-P, indicating that JAK- and PI3-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 α2AMPK did not affect LIF-stimulated glucose uptake.

Conclusion: LIF acutely increased muscle glucose uptake by a mechanism potentially involving the PI3-kinase/mTORC2/Akt pathway and is not impaired in EDL muscle from obese insulin resistant mice.

Original languageEnglish
JournalAmerican Journal of Physiology: Endocrinology and Metabolism
Issue number2
Pages (from-to)E142-E153
Number of pages12
Publication statusPublished - 2015

ID: 137682459