Search

Obesity is a global health epidemic, closely associated with cardiovascular diseases (CVD), hypertension, type 2 diabetes, and atherosclerosis. Obese adipose tissue is a site and source for inflammation that is strongly associated with these metabolic diseases. In obese mice models, males exhibit profound adipose tissue macrophage (ATM) accumulation in gonadal white adipose tissue (GWAT) linked to insulin resistance, while females are protected even with enhanced adiposity. This dampened inflammation may directly explain reduced metabolic and cardiovascular disease in young women. However, it is not clear what metabolic and inflammatory responses occur in post-menopausal models. We hypothesized an increased inflammatory response would occur in obese older females. We challenged male and female C57Bl6/j mice to 16-24 weeks of 60% high fat diet (HFD) starting at 6 weeks of age (young) or 10 month of age (old). Animal body weights and metabolic depot (adipose and liver) weights were measured at the completion of diet challenge. Flow cytometry was used to determine ATM populations in visceral (GWAT) compared to subcutaneous inguinal WAT (IWAT). Lipolysis was stimulated with a beta3 adrenergic receptor (ADRB3) agonist CL-316, 243 and free fatty acids (FFA), glycerol, and triglyceride (TG) levels assessed in serum and liver. Obesity in young mice led to fat accumulation in GWAT and IWAT of both males and females. In old male animals, fat pads did not expand, and liver weights were as a result larger than in females. Both young and old females had reduced adipose inflammation compared to males. ADRB3 activation had no effect on adipose tissue weights but significantly increased liver weights in obese young females. Obese CL treated young and old female mice showed elevated FFA compared to levels induced in males. Lipolysis promoted appearance of crown like structures (CLS) in both obese young and old males and females, due to CD11c- ATM accumulation. Obesity during aging continues to lead to enhanced inflammation in males along with steatosis but females continue to be protected with appropriate storage of fatty acids with very little induced inflammation. Sex differences in inflammation that persist in aging demonstrate that differences in meta-inflammation may explain sex differences in metabolic and cardiovascular diseases regardless of age and need to be further explored for targeted treatment strategies.

Males are known to have profound adipose tissue macrophage (ATM) accumulation in gonadal white adipose tissue (GWAT) during obesity, whereas females are protected from such an inflammatory response even with increased adiposity. The inflammatory tone in males is linked to insulin resistance and might be the underlying cause for sex differences in metabolic disease. Factors regulating the meta-inflammatory response remain unclear but enhanced lipid storage in females may explain the reduced inflammatory response to high-fat diets. In this study, we evaluated lean and obese females with stimulated lipolysis to understand whether a stress release of free fatty acids (FFAs) could induce female ATMs. We demonstrate that in both lean and obese females, GWAT CD11c(−) resident ATMs accumulate with β-3 adrenergic receptor–stimulated lipolysis. Lipolysis elevated serum FFA, triglyceride, and IL-6 levels in females that corresponded to significant phosphorylated hormone-sensitive lipase and adipose triglyceride lipase protein expression in obese female GWAT compared with males. Increased lipolytic response in obese females was associated with crown-like structures and induced Il6, Mcp1, Arg1, and Mgl1 expression in obese female GWAT, suggesting an environment of lipid clearance and adipose remodeling. With this finding we next investigated whether lipid storage and lipolytic mediators differed by sex. Diacylglycerol, ceramides, phospholipids, and certain fatty acid species associated with inflammation were elevated in male GWAT compared with obese female GWAT. Overall, our data demonstrate a role for GWAT lipid storage and lipolytic metabolites to induce inflammation in males and induce remodeling in females that might explain sex differences in overall metabolic health.