As one of the largest endocrine organs in the body, adipose tissue secrets a number of bioactive hormones, called adipokines. The expression and secretion of adipokines are tightly controlled and coordinated by physiological and pathophysiological conditions. In multiple physiological conditions, such as obesity, cold adaptation, exercise training, expression and secretion of adipokines are altered accordingly, which in turn modulate the metabolism of the whole body in endocrine, paracrine and autocrine manners. The varied changes in adipose tissues are pivotal mediators that aid the body to adapt to various physiological and pathological conditions, whereas almost all obesity-associated diseases are attributable to dysregulation of adipokines.

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. Disclosure Y. Pan: None. H. Hui: None. R. Hoo: None. T. Feng: None. K.S. Lam: None. A. Xu: None.