Siah2 in Adipocytes Promotes M2-Like Macrophage Activation in Adipose Tissue

Obesity is associated with chronic, low-grade adipose tissue inflammation that is linked to glucose intolerance and insulin resistance. Although enzymes of the ubiquitin-proteasome system are known to regulate signaling in classical inflammation, involvement of the ubiquitin-proteasome system in obesity-induced metabolic inflammation is relatively unexplored. We previously found that the ubiquitin ligase mammalian homolog of seven-in-absentia (Siah2) alters peroxisome proliferator-activated receptor γ (PPARγ) protein levels and selectively regulates PPARγ activity. Using a mouse model of global Siah2 deletion (Siah2KO), we observed that Siah2KO mice become obese on a high fat diet (HFD), but remain glucose tolerant and insulin sensitive. This corresponds to reduced expression of pro-inflammatory markers, substantially fewer crown-like structures and less fibrosis in adipose tissue although the adipocytes are enlarged. To determine if Siah2 expression in adipocytes accounts for the Siah2KO phenotype, we created an adipocyte-specific Siah2KO model (Siah2AdKO). Although HFD-induced obesity is attenuated in Siah2AdKO mice, the mice become glucose intolerant and insulin resistant. The visceral adipose tissue is infiltrated by M1-like macrophages, corresponding to increased crown-like structures and fibrosis while M2-like macrophages are reduced. PPARγ activity is selectively regulated, but PPARγ protein levels are unchanged in the Siah2AdKO mice. The levels of pro-inflammatory markers such as IL-6 are increased, but as in the global Siah2KO model, TNFα, SAA3 and PAI-1 expression is decreased. Thus, our data indicates Siah2 in adipocytes influences polarization of macrophages in adipose tissue independent of regulating PPARγ protein levels. Moreover, Siah2 in adipocytes mediates expression of a subset of pro-inflammatory adipokines, but surprisingly, these factors do not appear to drive adipose tissue inflammation in this model of obesity.