Physical activity has many beneficial effects on metabolic disorders, such as obesity, insulin resistance, and diabetes. Meteorin-like protein (METRNL), a novel secreted protein homologous to the neurotrophin Metrn, is induced after exercise in the skeletal muscle. Herein, we investigated the effects of METRNL on lipid-mediated inflammation and insulin resistance in skeletal muscle via AMP-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor ¥ä (PPAR¥ä). Treatment with METRNL suppressed inflammatory markers, such as nuclear factor ¥êB (NF¥êB) nuclear translocation, inhibitory ¥êB¥á (I¥êB¥á) phosphorylation, interleukin-6 (IL-6) expression, and pro-inflammatory cytokines (such as TNF¥á and MCP-1). METRNL treatment also attenuated the impaired insulin response both in palmitate-treated differentiated C2C12 cells and the skeletal muscle of high-fat diet (HFD)-fed mice. Furthermore, METRNL administration rescued glucose intolerance and reduced HFD-induced body weight gain in mice; however, METRNL did not affect calorie intake. METRNL treatment increased AMPK phosphorylation and PPAR¥ä expression both in differentiated C2C12 cells and mouse skeletal muscle. siRNA-mediated suppression of AMPK and PPAR¥ä abrogated the suppressive effects of METRNL on palmitate-induced inflammation and insulin resistance. Moreover, METRNL augmented the mRNA expression of fatty acid oxidation-associated genes, such as carnitine palmitoyltransferase 1 (CPT1), acyl-CoA oxidase (ACO), and fatty acid binding protein 3 (FABP3). siRNAs for AMPK and PPAR¥ä reversed these changes. In the current study, we report for the first time that METRNL alleviates inflammation and insulin resistance and induces fatty acid oxidation through AMPK or PPAR¥ä-dependent signaling in skeletal muscle.
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