Inactivation of MAPK in epididymal fat and amelioration of triglyceride secretion by injection of GRK2 siRNA in ob/ob mice.

Abnormal G protein-coupled receptor kinase 2 (GRK2) accumulation has a crucial role in the development of insulin resistance and diabetes. Although GRK2 siRNA transfection in the liver improves insulin resistance-related vascular complications, the effects of GRK2 siRNA in lipid metabolism and obesity remain unknown. To investigate how GRK2 siRNA affects obesity, ob/ob mice were transfected with GRK2 siRNA, mainly in the liver, by using a hydrodynamic-based procedure. Epididymal fat, glucose, triglyceride, non-esterified fatty acid (NEFA), and alanine transaminase activity were higher in the control siRNA-transfected ob/ob mice than in the control siRNA-transfected Lean mice, but these parameters were reduced by GRK2 siRNA transfection into the ob/ob mice. GRK2 expression in epididymal fat was not altered among the 3 groups, although hepatic GRK2 expression was higher in the control siRNA-transfected ob/ob mice than in the control siRNA-transfected Lean mice. Additionally, we found that Akt interacted with GRK2 in the liver. Furthermore, phosphorylation levels of ERK1/2 and JNK were higher in the epididymal fats from the control siRNA-transfected ob/ob mice than in those from the control siRNA-transfected Lean mice, but they were lowered by transfection with GRK2 siRNA. The study results showed that GRK2 siRNA improved blood triglyceride levels and abnormal or excessive activity of mitogen-activated protein kinases in epididymal fat. This effect may be promoted by inhibition of the NEFA production pathway in the liver. Therefore, the interaction of organs (hepatic GRK2-epididymal fat) may help improve insulin resistance and diabetes-associated pathophysiology.