1α,25-VitD₃, TLR2 Agonist And Fermentative Polysacchrides CFX Improve Insulin Sensitivity In MSG Obese Rats By Regulating Immune Responses

Modern lifestyle, with abundant nutrient supply and reduced physical activity,has resulted in dramatic increase in the rates of obesity-associated diseasesconditions, including hyperglycemia, hyperinsulin, dyslipidiaemia and type 2diabetes, which is named after metabolic syndrome (MS). The underlyingcause of metabolic syndrome is a chronic inflammatory response characterizedby enhancement of Th1 immune response that may be responsible forpathogenesis of insulin resistance. Pattern recognition receptors the Toll-likereceptors (TLRs) link the innate immunity and adaptive immunity, TLRs areprimary sensors of both innate and adaptive immune systems and play a pivotalrole in response against structurally conserved components of pathogens. Wewonder if shift of Th1/Th2 balance toward to regulatory T (Treg) cells or Th2responses improves insulin sensitivity in MSG obese rats. The insulinsensitivity was determined by body weight, the insulin sensitivity index, oralglucose tolerance test, insulin tolerance test, and hyperinsulinemic-euglycemicclamp. The expression and activity of TLRs and their signal pathways wereconfirmed by PCR or western blot. We found that 1α, 25-VitD3 (VitD3), animmunomodulator, significantly blocked the maturation induced by highconcentration of glucose or TLR4 agonist and promoted the macrophagestimulated by palmitate to M2 polarization in vitro. We also found theincidence of insulin resistance decreased by pretreatment with VitD3. VitD3improved the insulin sensitivity by activating insulin signaling and attenuatingthe inflammation status in system and local immune microenvironments.Furthermore, a TLR2 agonist peptidoglycan (PGN), markedly improved theinsulin sensitivity because PGN stimulated TLR2 leading to a Th2 immuneresponse. We also found VitD3 and PGN increased the Treg cell number inspleen, lymph node and insulin target tissue-adipose tissue, liver and muscle tissue, leading to polarization of T cell development toward Treg direction viaupregulating the TLR2 in spleen. VitD3 and PGN stimulated immunesuppression responses via phosphorylation of STAT3, upregulation of TGFβand reduced the activation of NF-κB. VitD3 and PGN ameliorated thedyslipidiaemia via upregulation of PPARα, improved the function of pancreaseβcells via upregulating GLUT2 and reducing macrophage infiltration. Inaddition, we reported that the mixture of polysaccharides CFX stimulatesimmaturation of dendritic cells (DCs) and the immaturated DCs promote Tregcell development in DC-based functional screening system. We found theaccident of insulin resistance decreased by pretreatment with CFX, CFXobservably improved the dyslipidiaemia and the insulin sensitivity byactivating the STAT3 in liver and elevating of Treg in adipose tissue. Takentogether, we conclude that the insulin sensitivity can be improved byimmunomodulator through regulation in immune microenviroment.