Siah2 is a lipid-mediated metabolic sensor in adipose tissue macrophage

Adipose tissue macrophage (ATM) lipid accumulation is associated with developing obesity-related insulin resistance, yet the underlying mechanisms influencing excess lipid accumulation in ATM are not well understood. Global deletion of the ubiquitin ligase seven in absentia homolog 2 (SIAH2) improves glucose tolerance and insulin sensitivity while reducing adipose tissue inflammation with obesity. While Siah2 mRNA is expressed in preadipocytes and adipocytes, recent small nuclear RNA-sequencing data show that Siah2 is broadly expressed in adipose tissue immune cells, including macrophages. Here, we generated a macrophage-specific SIAH2 deletion mouse model to assess the role of macrophage SIAH2 in the relationship between adipose tissue expansion and insulin resistance with a high-fat dietary challenge. Loss of SIAH2 in macrophages robustly increased glucose intolerance and insulin resistance without relative increases in body weight, serum lipids, or lipid accumulation in skeletal muscle or liver in male mice compared with WT male mice fed a high-fat diet but not a low-fat diet. The physiological changes in the male mice were associated with increased adipose tissue inflammation and increased lipid accumulation in the ATM. Macrophage Siah2 depletion also increased the expression of Cd36, Trem2, Tyrobp, and Hilpda1 in adipose tissue. Using the M1-like, M2-like paradigm of proinflammatory and anti-inflammatory macrophages, we found that Siah2 mRNA is stimulated by a proinflammatory lipid and suppresses expression of selected PPARγ target genes involved in lipid metabolism and inflammation. These findings place SIAH2 as a lipid-stimulated stress response protein that functions to regulate lipid accumulation in ATM and the associated obesity-induced systemic insulin resistance.