miR-34a Aggravates Obesity-Induced Adipose Inflammation and Metabolic Dysfunction via Blocking Polarization of Anti-inflammatory M2 Macrophage

Adipose tissue-resident macrophages are an important contributor to systemic chronic inflammation and cardiometabolic abnormalities associated with obesity. However, the etiological factors that alter the number and polarization of adipose-resident macrophages remain poorly characterized. As our previous clinical study has identified microRNA (miR)-34a as one of the most significantly elevated genes in visceral fat of obese patients, we investigated the roles of miR-34a in obesity-related adipose tissue inflammation and metabolic disorders by generated adipose tissue-specific miR-34a knockout (KO) mice. After feeding with high fat diet (HFD), adipose miR-34a KO mice exhibited significant attenuation of HFD-induced glucose intolerance, insulin resistance, hyperlipidemia, steatohepatitis and systemic inflammation compared to HFD-fed wild type (WT) controls. These benefits of miR-34a deficiency were mainly attributed to the reduced number of total macrophages and polarization of adipose macrophages towards the pro-inflammatory M1 phenotype. Mechanistically, we found that miR-34a directly repressed the expression of the transcription factor Klf4, thereby enhancing macrophage polarization to the M1 phenotype. Silencing of Klf4 in the adipose-specific miR-34a KO mice suppressed M2 macrophage polarization. In visceral fat from obese patients, the expression of Klf4 was significantly decreased and negatively correlated with miR-34a level. These data demonstrated that increased miR-34a in adipose tissues exacerbates obesity-induced adipose tissue inflammation by suppressing the expression of Klf4, thereby leading to increased accumulation of pro-inflammatory M1 macrophages.