A role for cyclooxygenase2-prostaglandin E2 (COX2-PGE2) pathway in fatty acid-induced insulin resistance and mitochondrial dysfunction in L6 rat myotubes

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    Abstract

    Aims: The mechanisms by which free fatty acids such as palmitate (PA) induce insulin resistance (IR) remain elusive, but we have recently shown that activation of proinflammatory NFκB signalling contributes to IR and mitochondrial dysfunction in rat L6 myotubes. Here, we have explored the role of the COX2-PGE2 pathway, which lies downstream of NFκB in PA-induced IR and mitochondrial dysfunction.

    Methods: Rat L6 skeletal myotubes were used for Seahorse XF24 mitochondrial function analysis, qPCR and western blotting, 2-deoxyglucose uptake and confocal microscopy.

    Results: Our data show that PA reduced insulin-stimulated PKB-S473 phosphorylation, glucose uptake, and reduced ATP-linked respiration by ˜50%, whereas mitochondrial superoxide and H2O2 production were increased by two-fold and 30%, respectively. PA also increased expression of COX2. These metabolic perturbations were mitigated using a COX2 inhibitor, celecoxib, which reduced PA-driven IR, inflammation and excessive superoxide generation, but only partially recovered mitochondrial function. Prostaglandin E2, which is synthesised by the COX2 pathway, targets prostanoid (EP) receptors. EP4 is abundantly expressed in L6 myotubes and, significantly, inhibiting EP4 using an EP4 antagonist ONO-AE3-208 partially protected myotubes against PA-induced IR and reduced inflammatory signalling. In contrast, stimulating EP4 using an EP4 agonist TCS 2510 induced IR in myotubes which was attenuated by ONO-AE3-208, without inducing any changes in mitochondrial function.

    Summary: The COX2-PGE2 pathway contributes to PA-induced IR. PGE2 synthesised by the COX2 pathway may act in an autocrine manner to activate EP4 and contribute to PA-induced IR without affecting mitochondrial function.
    Original languageEnglish
    Article numberP44
    Pages (from-to)41-42
    Number of pages2
    JournalDiabetic Medicine
    Volume37
    Issue numberS1
    DOIs
    Publication statusPublished - Sept 2022

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