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

Jun 25, 2015Diabetologia

BAIBA reduces insulin resistance and inflammation caused by fatty acids or high-fat diet in mice through an energy-regulating pathway

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Abstract

BAIBA treatment significantly improved impaired glucose tolerance and reversed HFD-induced increases in body weight in mice.

BAIBA treatment ameliorated insulin signalling impairments in muscle cells and in HFD-fed mice.
In vitro and in vivo, BAIBA significantly suppressed markers of inflammation, including IκBα phosphorylation and NFκB nuclear translocation.
BAIBA induced AMPK phosphorylation and increased PPARδ expression in muscle cells.
Inhibition of AMPK or PPARδ blocked BAIBA's beneficial effects on inflammation and insulin resistance.
BAIBA enhanced the expression of genes linked to fatty acid oxidation, which was reduced by AMPK inhibition and PPARδ knockdown.

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AIMS/HYPOTHESIS: We explored the effects of β-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 δ (PPARδ).

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 knockdown 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 κBα (IκBα) phosphorylation, nuclear factor κB (NFκB) nuclear translocation and downstream inflammatory cytokines were significantly suppressed by BAIBA. Furthermore, BAIBA treatment significantly induced AMPK phosphorylation and expression of PPARδ in C2C12 myocytes and in skeletal muscle of mice. Both compound C, an AMPK inhibitor, and Pparδ (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 Pparδ 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-PPARδ pathway in skeletal muscle.

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

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