Siah2 modulates sex-dependent metabolic and inflammatory responses in adipose tissue to a high-fat diet challenge

The obesity-related risk of developing metabolic syndrome is higher in males than in females of reproductive age, likely due to estrogen-mediated reduced adipose tissue inflammation and fibrosis with hypertrophied adipocytes. Depletion of the ubiquitin ligase Siah2 reduced white adipose tissue inflammation and improved glucose metabolism in obese male mice. Siah2 is a transcriptional target of estrogen, but data is lacking about the effect of Siah2 on adipose tissue of females. We therefore evaluated the impact of Siah2 deficiency on white and brown adipose tissue in females of reproductive age.

Body composition, adipose tissue morphology, brown adipose tissue gene, and protein expression and adipocyte sizing were evaluated in wild-type and Siah2KO female and male mice fed a low-fat or high-fat diet. Glucose and insulin tolerance, fasting glucose, insulin, fatty acids and triglycerides, and gene expression of inflammation markers in perigonadal fat were evaluated in wild-type and Siah2KO female mice. Microarray analysis of brown fat gene expression was carried out in both sexes. Statistical analysis was assessed by unpaired two-tailed t test and repeated measures ANOVA.

Siah2 deficiency improves glucose and insulin tolerance in the presence of hypertrophied white adipocytes in high-fat-fed female mice with percent fat comparable to male mice. While previous studies showed Siah2KO reduces the white adipose tissue inflammatory response in male mice, the response in females is biased toward the upregulation of M2-like markers in white adipose tissue. In contrast, loss of Siah2 leads to increased whitening of brown fat in males, but not in females. This corresponded to increased expression of markers of inflammation (F4/80, Ccl2) and thermogenic genes (Pgc1alpha, Dio2, Ucp-1) and proteins (PGC-1α, UCP-1) in females. Contrary to expectations, increased expression of thermogenic markers in females was coupled with a downregulation of ERalpha and ERRgamma protein levels.

The most striking sex-related effect of Siah2 deficiency is reduced whitening of brown fat in high-fat-fed females. Protection from accumulating unilocular adipocytes in the brown fat corresponds to increased expression of thermogenic genes and proteins in female, but not in male mice. These results raise the possibility that Siah2 contributes to the estrogen-related effects on brown fat function in males and females.