Leukemia inhibitory factor increases glucose uptake in mouse skeletal muscle

Area of Science:

• Molecular Biology
• Metabolic Signaling
• Skeletal Muscle Physiology

Background:

• Interleukin-6 (IL-6) family members like IL-6 and ciliary neurotrophic factor (CNTF) promote glucose uptake and fatty acid oxidation in skeletal muscle.
• The metabolic role of leukemia inhibitory factor (LIF), another IL-6 family member, in skeletal muscle remains largely uncharacterized.

Purpose of the Study:

• To investigate the effects of LIF on glucose uptake, palmitate oxidation, and associated signaling pathways in mouse skeletal muscle.
• To determine the involvement of specific signaling pathways, including JAK, PI 3-kinase, and mTOR complexes, in LIF-mediated effects.
• To examine LIF's metabolic impact in models of insulin resistance and in the absence of specific signaling proteins (AMPKα2, SOCS3).

Main Methods:

• Ex vivo incubation of mouse soleus and EDL muscles from wild-type, AMPKα2 kinase-dead, SOCS3 knockout, and high-fat-fed mice.
• Dose- and time-course analysis of LIF-stimulated glucose uptake and palmitate oxidation.
• Pharmacological inhibition of specific signaling pathways (JAK, PI 3-kinase, mTORC1/2) and assessment of downstream effectors (Akt, STAT3).

Main Results:

• LIF significantly increased glucose uptake in a dose- and time-dependent manner, with maximal effect at 30 minutes.
• LIF stimulated Akt phosphorylation (Ser473) but not AMPK phosphorylation (Thr172).
• LIF-induced glucose uptake required JAK, PI 3-kinase, and mTORC2 signaling, but not mTORC1. Palmitate oxidation was unaffected by LIF.
• LIF-stimulated glucose uptake was maintained in EDL from obese, insulin-resistant mice, while soleus exhibited LIF resistance.
• Absence of SOCS3 or AMPKα2 did not alter LIF-stimulated glucose uptake.

Conclusions:

• LIF acutely enhances skeletal muscle glucose uptake through the PI 3-kinase/mTORC2/Akt signaling axis.
• LIF-mediated glucose uptake is preserved in EDL muscles of obese, insulin-resistant mice, suggesting potential therapeutic relevance.
• LIF does not influence palmitate oxidation and its effects are independent of AMPKα2 and SOCS3 in this model.