The Effects Of Metformin And Rosiglitazone On The Expression And Secretion Of PEDF In Fat And Liver

Objective: Pigment epithelium-derived factor (PEDF) as an adipokinehas been shown to induce insulin resistance (IR). The anti-diabetic drug,metformin, can improve IR, although its mechanism is unclear. This studyaimed to investigate the effect of metformin on the expression and secretionof PEDF in liver and fat during IR improvement.Methods: SD rats were fed normal diet (normal control group, NCgroup) or high-fat diet for15weeks, then to be gavaged saline (high fatgroup, HF group) or metformin400mg/kg/d (MET group) for4weeks.Hyperinsulinemic euglycemic clamp test was performed to evaluate insulinsensitivity which was expressed as glucose infusion rate. IR models of3T3-L1and HepG2cell were established by50nM insulin treatment for24hand validated by glucose (2-NBDG) uptake;0.1mM metformin in combination with or without40uM compound C (an AMPK inhibitor) wereused for the intervention.Results: Compared with the NC group, the HF group showeddecreased glucose infusion rate, accompanied with increased serum PEDFlevels which negatively correlated with glucose infusion rate. The METgroup revealed significantly improved IR, concomitant with downregulatedPEDF and upregulated p-AMPK protein levels in liver, white adipose tissue,brown adipose tissue and muscle. Treated with50nM insulin for24h,3T3-L1adipocytes and HepG2cells showed decreased2-NBDG uptake,accompanied with increased PEDF secretion, as well as upregulated PEDF.Whereas metformin increased2-NBDG uptake, accompanied with loweredPEDF secretion in two IR cell models, as well as downregulated PEDF andupregulated p-AMPK protein levels. With compound C treatment, theinhibitive effect of metformin on PEDF secretion and protein expression hadbeen attenuated in both IR cell models.Conclusions: Metformin inhibits expression and secretion of PEDF inliver and fat through promoting AMPK phosphorylation, which is closelyassociated with insulin resistance improvement. Objective: Rosiglitazone is used to improve insulin resistance (IR) intype2diabetes and other IR related diseases. Pigment epithelium-derivedfactor (PEDF), an adipokine discovered in recent years, plays an importantrole in obesity-induced IR. This study aimed to investigate the effect ofrosiglitazone on the expression and secretion of PEDF in liver and fat duringIR improvement.Methods: SD rats were fed normal diet (normal control group, NCgroup) or high-fat diet for15weeks, then to be gavaged saline (high fatgroup, HF group) or rosiglitazone4mg/kg/d (RSG group) for4weeks.Hyperinsulinemic euglycemic clamp test was performed to evaluate insulinsensitivity which was expressed as glucose infusion rate. IR models of3T3-L1and HepG2cell were established by50nM insulin treatment for24hand validated by glucose (2-NBDG) uptake;1uM rosiglitazone,1uMrosiglitazone plus10uM GW9662(a PPARγ inhibitor),1uM rosiglitazoneplus40uM compound C (an AMPK inhibitor) were used for the interventionof IR cell models.Results: Compared with the NC group, the HF group showed decreased glucose infusion rate, accompanied with increased serum PEDFlevels which negatively correlated with glucose infusion rate. The RSGgroup revealed significantly improved IR, concomitant with downregulatedPEDF and upregulated p-AMPK protein levels in liver, white adipose tissue,brown adipose tissue and muscle. Treated with50nM insulin for24h,3T3-L1adipocytes and HepG2cells showed decreased2-NBDG uptake,accompanied with increased PEDF secretion, as well as upregulated PEDF.Whereas rosiglitazone increased2-NBDG uptake, accompanied withlowered PEDF secretion in two IR cell models, as well as downregulatedPEDF and upregulated p-AMPK protein levels. Compared with the RSGgroup, PEDF secretion and expression did not change significantly in theGW9662group. However, with compound C treatment, the inhibitive effectof rosiglitazone on PEDF secretion and expression had been attenuated inboth IR cell models.Conclusions: Rosiglitazone inhibits expression and secretion of PEDFin liver and fat, mediated by activating AMPK phosphorylation, which isindependent of PPARγ pathway, and the change of PEDF is closelyassociated with improvement of insulin resistance.