BAIBA attenuates insulin resistance and inflammation induced by palmitate or a high fat diet via an AMPK-PPARδ-dependent pathway in mice

Aims/hypothesis We explored the effects of beta-aminoisobutyric acid (BAIBA) on hyperlipidaemic-condition-induced insulin resistance and inflammation as mediated through a signalling pathway involving AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor delta (PPAR delta). Methods Mouse skeletal muscle C2C12 cells and C57BL/6J mice were treated with palmitate or a high-fat diet (HFD) and BAIBA. Inflammation and the expression of genes associated with insulin signalling were determined by western blot and quantitative real-time PCR. Selected genes from candidate pathways were evaluated by small interfering (si)RNA knock-down and specific inhibitors. Results BAIBA treatment ameliorated impairment of insulin receptor substrate (IRS)-1/Akt-mediated insulin signalling in palmitate-treated C2C12 myocytes and in skeletal muscle of HFD-fed mice. In addition, BAIBA treatment reversed HFD-induced increases in body weight and improved impaired glucose tolerance in mice. In vitro and in vivo, inhibitory kappa B alpha (I kappa B alpha) phosphorylation, nuclear factor kappa B (NF kappa B) nuclear translocation and downstream inflammatory cytokines were significantly suppressed by BAIBA. Furthermore, BAIBA treatment significantly induced AMPK phosphorylation and expression of PPAR delta in C2C12 myocytes and in skeletal muscle of mice. Both compound C, an AMPK inhibitor, and Ppar delta (also known as Ppard) siRNA abrogated the inhibitory effects of BAIBA on palmitate-induced inflammation and insulin resistance. BAIBA significantly induced the expression of genes associated with fatty acid oxidation, such as carnitine palmitoyltransferase 1 (Cpt1), acyl-CoA oxidase (Aco; also known as Acox1) and fatty acid binding protein 3 (Fabp3); this effect of BAIBA was significantly reduced by compound C and Ppar delta siRNA. Conclusions/interpretation These results are the first to demonstrate that BAIBA attenuates insulin resistance, suppresses inflammation and induces fatty acid oxidation via the AMPK-PPAR delta pathway in skeletal muscle.