Bilobetin ameliorates insulin resistance by PKA-mediated phosphorylation of PPARα in rats fed a high-fat diet

Authors


  • X-H Kou and M-F Zhu contributed equally to this article.

Xin-Hui Kou, 299 Qingyang Road, Wuxi, Jiangsu 214023, China. E-mail: xinhuikou1980@yahoo.com

Abstract

BACKGROUND AND PURPOSE The amelioration of insulin resistance by bilobetin is closely related to its hypolipidaemic effect. The aim of the present study was to determine the insulin-sensitizing mechanism of bilobetin by elucidating its effect on lipid metabolism.

EXPERIMENTAL APPROACH Rats fed a high-fat diet were treated with bilobetin for either 4 or 14 days before applying a hyperinsulinaemic–euglycaemic clamp. Triglyceride and fatty acids labelled with radioactive isotopes were used to track the transportation and the fate of lipids in tissues. The activity of lipid metabolism-related enzymes and β-oxidation rate were measured. Western blot was used to investigate the phosphorylation, translocation and expression of PPARα in several tissues and cultured cells. The location of amino acid residues subjected to phosphorylation in PPARα was also studied.

KEY RESULTS Bilobetin ameliorated insulin resistance, increased the hepatic uptake and oxidation of lipids, reduced very-low-density lipoprotein triglyceride secretion and blood triglyceride levels, enhanced the expression and activity of enzymes involved in β-oxidation and attenuated the accumulation of triglycerides and their metabolites in tissues. Bilobetin also increased the phosphorylation, nuclear translocation and activity of PPARα accompanied by elevated cAMP level and PKA activity. Threonine-129–alanine and/or serine-163–alanine mutations on the PPARα genes and PKA inhibitors prevented the effects of bilobetin on PPARα. However, cells overexpressing PKA appeared to stimulate the phosphorylation, nuclear translocation and activity of PPARα.

CONCLUSIONS AND IMPLICATIONS Bilobetin treatment ameliorates hyperlipidaemia, lipotoxicity and insulin resistance in rats by stimulating PPARα-mediated lipid catabolism. PKA activation is crucial for this process.

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