Effect of Glucose on Human Adipogenesis and its Regulation by Macrophages

Abstract

Adipose tissue expands via differentiation of preadipocytes into adipocytes (adipogenesis) and/or hypertrophy of existing adipocytes. A low adipogenic capacity promotes adipocyte hypertrophy, causing inflammatory macrophage accumulation and insulin resistance. Macrophage-conditioned medium (MacCM) inhibits adipogenesis and promotes adipocyte inflammation, but it is unknown if these effects are altered by high glucose (HG) versus normal glucose (NG) concentrations. The effect of HG on adipogenesis was assessed. Human subcutaneous abdominal preadipocytes were induced to differentiate in HG or NG conditions. HG did not affect adipogenesis. HG increased ChREBP-β mRNA and protein levels, and increased GLUT4 mRNA, in differentiated adipocytes. It did not change mRNA levels of ACC, SCD, and FAS. The increase in ChREBP-β mRNA was positively correlated with HG-induced increase in GLUT4 mRNA. The effect of HG-MacCM versus NG-MacCM on human adipogenesis and adipocyte inflammation was compared. Human monocyte-derived macrophages (MDM) were placed in NG or HG glucose for 24 hours to generate MacCM. HG-MacCM, but not NG-MacCM inhibited triacylglycerol accumulation and protein expression of PPARγ during human adipogenesis. Preadipocytes differentiated in HG-MacCM displayed a more pro-inflammatory phenotype, as assessed by increased MCP-1 and IL-6 and reduced adiponectin mRNA expression. HG increased phosphorylation of IKK-β and decreased protein expression of IκBα in MDMs. In addition, HG reduced protein expression of PPARγ in MDMs. The pro-inflammatory effect of HG-MacCM on MCP-1 expression in adipocytes was partially inhibited when MDMs were treated with sc-514 (IKKβ inhibitor). My data demonstrate that HG-induced expression of ChREBP-β in adipocytes may be associated with increased GLUT4 mRNA. The anti-adipogenic and pro-inflammatory effects of HG-MacCM are more potent than NG-MacCM. This suggests the possibility that adipose tissue cellular remodeling in vivo may be altered with hyperglycemia.