Feature Article: Transplantation of neuregulin 4-overexpressingadipose-derived mesenchymal stem cells ameliorates insulin resistance byattenuating hepatic steatosis

摘要

The aim of this study is to assess whether overexpressing neuregulin 4 (Nrg4), agrowth factor known to attenuate hepatic lipogenesis, in mesenchymal stem cells(MSCs) could enhance their ability to ameliorate insulin resistance (IR) andimprove lipid metabolism in high-fat diet (HFD)-fed mice. Six-week-old C57BL/6mice were fed a HFD for 12 weeks and then were given intravenous transplantationof adipose tissue-derived MSCs (ADSCs) or ADSCs overexpressing Nrg4(Nrg4-ADSCs). Assessment of body weight and blood glucose and insulin levels aswell as glucose tolerance test and insulin tolerance test was performed four andeight weeks after cell injection. Triglyceride (TG) and total cholesterol (TC)levels in the plasma and liver were also measured. The mRNA levels of glucosetransporter 4 (GLUT4), interleukin-6 (IL-6), and tumor necrosis factor-alpha(TNF-α) in muscle and adipose tissues were assessed by Real-time PolymeraseChain Reaction (RT-PCR) analysis. Expression of genes related to lipidmetabolism, including sterol regulatory element binding protein-1c (SREBP-1c)and fatty acid synthase, was evaluated at the mRNA and protein levels by RT-PCRand western blotting, respectively. The HFD-fed mice receiving ADSCs orNrg4-ADSCs showed reduced blood glucose levels and enhanced insulin sensitivity,with the Nrg4-ADSC group exhibiting increased improvement in these aspects.HFD-induced changes in the expression of GLUT4 and IL-6 and TNF-α in skeletalmuscle and adipose tissues were partially reversed by ADSC or Nrg4-ADSCinfusion; however, no difference was observed between these two groups.Nrg4-ADSC-treated mice showed less fat cell deposition and lower TG and TClevels in the serum and liver with decreased expression of SREBP-1c and fattyacid synthase compared with the ADSC group. ADSC transplantation can reduceblood glucose level and ameliorate IR induced by HFD. The protective effects ofADSC can be attributed to suppression of inflammation and augmentation ofglucose uptake in skeletal muscle and adipose tissues. More importantly, Nrg4overexpression in ADSCs could strengthen this efficacy by attenuating hepaticlipogenesis.