Metformin Alleviates Hyperuricemia-Induced Serum Free Fatty Acid Elevation and Insulin Resistance by Improving Adipose Tissue Function

Background: Hyperuricemia (HUA) significantly increases risk of metabolic syndrome, and is strongly associated with the increased prevalence of high serum free fatty acids (FFA) and insulin resistance. However, the detailed mechanism remains unclear. Adipose tissue plays a crucial role in FFA metabolism. In this study, we aimed to explore the effects and underlying mechanism of uric acid (UA) on the metabolic function of adipocytes. Further, we investigated whether the administration of metformin could alleviate HUA-related metabolic disorders Methods: We performed H&E and immunohistochemistry to analyze adipose tissues of normal and HUA patients. Then mRNA microarray analysis was used to compare mRNA expression profiles of 3T3-L1 cells with and without UA. HUA mice were treated with UA lowering agent (benzbromarone) and metformin, respectively, and then epididymal white adipose tissue (eWAT) were isolated for in vitro experiment. Fundings: UA induced adipocyte hypertrophy, inhibited hyperplasia and reduced its beige-like characteristics. The mRNA microarray data indicated that UA significantly decreased the expression of leptin, which was closely related to FFA metabolism and 5-AMP-activated protein kinase (AMPK) signaling pathway according to KEGG pathway analysis. Moreover, benzbromarone and metformin induced activation of AMPK expression significantly attenuated UA-induced FFA metabolism impairment and adipose beiging depression, which subsequently alleviated serum FFA elevation and insulin resistance in HUA mice. Interpretation: UA is involved in the etiology of serum FFA elevation and insulin resistance by impairing adipose tissue function, which is mediated by leptin-AMPK pathway. AMPK activation by metformin represents a novel potential treatment strategy for HUA-related metabolic disorders. Funding Statement: This project was supported by grants from National Nature Scientific Foundation of China (No.81830012, No.81670297). Doctoral Fund of Ministry of Education of Heilongjiang Province (LBH-Z17180) and Harbin Medical University Science Innovation Foundation (YJSKYCX2018-91HYD) also provided additional support. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Clinical sampling was approved by the Ethical Committee of First Affiliated Hospital of Harbin Medical University. The Animal Care and Use Committee of the First Affiliated Hospital of Harbin Medical University approved all protocols.