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

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 ?-oxidation rate were measured. Western blot was used to investigate the phosphorylation, translocation and expression of PPAR? in several tissues and cultured cells. The location of amino acid residues subjected to phosphorylation in PPAR? 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 ?-oxidation and attenuated the accumulation of triglycerides and their metabolites in tissues. Bilobetin also increased the phosphorylation, nuclear translocation and activity of PPAR? accompanied by elevated cAMP level and PKA activity. Threonine-129-alanine and/or serine-163-alanine mutations on the PPAR? genes and PKA inhibitors prevented the effects of bilobetin on PPAR?. However, cells overexpressing PKA appeared to stimulate the phosphorylation, nuclear translocation and activity of PPAR?.

Conclusions and implications

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

SUBMITTER: Kou XH 

PROVIDER: S-EPMC3423259 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature