Adipocyte ZAG Improves Obesity-Triggered Insulin Resistance by Reshaping Macrophages Populations in Adipose Tissue

Adipose tissues macrophages (ATMs) serve as critical effectors in the mediating occurrence of metabolic inflammation to impact whole-body insulin sensitivity in obesity. Discovering the key adipokines mediating crosstalk of adipocyte-macrophage and understanding the molecular mechanism of ATMs polarization and function have become hot topic issues in the immunometabolism fields. Zinc-α2-glycoprotein (ZAG) as an anti-inflammatory adipokines plays important roles in obesity-related metabolic diseases. We attempt to explore the precise role of adipose ZAG in metabolic inflammation and obesity-associated insulin resistance. Here we showed that Omental ZAG was positively associated with insulin sensitivity and M2 macrophages markers. ZAG-specific ablation in adipocyte aggravated insulin resistance and adipose tissues inflammation as evidenced by enhanced M1 macrophages proportion and inhibited AKT signaling pathway in mice fed with a high-fat diet. ZAG overexpression attenuated insulin resistance and accumulation of pro-inflammatory macrophages. Exogenous ZAG inhibits PA-induced M1 macrophage polarization via β3-AR/PKA/STAT3 signaling in RAW264.7 macrophages. These findings suggest that adipocyte ZAG maintains insulin sensitivity via the cross talk with adipose-resident macrophages. Keywords: ZAG; inflammation; insulin resistance; obesity; adipose tissue macrophages Disclosure X. Xiao: None. Z. Liao: None. Y. Wang: None. X. Qi: None. Funding National Natural Science Foundation of China (82070873, 82000813) , Natural Science Foundation of Hunan province (2020JJ8097, 2021JJ40496) and Major special projects of Hunan provincial health and family planning commission (A2017011)