Adipose miR-34a in obesity-induced metabolic inflammation and insulin resistance

Abstract

Adipose tissue macrophages (ATMs) are central to local and systemic inflammation. Upon obesity, ATMs are more prone to polarize to the pro-inflammatory M1 subtype, whereas the anti-inflammatory M2 profile is suppressed. These two events collectively lead to adipose tissue inflammation. However, the underlying mechanisms explaining macrophage polarization are not fully explored. Furthermore, a clinical study has detected altered expression of microRNA (miR)-34a in obese subcutaneous adipose tissue, but whether adipose-originated miR-34a modulates obesity-associated adipose tissue remodeling and whole body metabolism remains elusive. Therefore, this study aims to investigate: 1) whether adipose miR-34a mediates adipose tissue inflammatory response and systemic insulin insensitivity via affecting macrophage polarization; 2) the potential mechanisms linking adipose miR-34a and macrophage polarization; 3) how adipocytes and macrophages crosstalk with each other under obese condition. Our results show that high fat diet (HFD) and inflammatory cues cause a strong elevation of miR-34a in adipose tissues. Adipose tissue-specific depletion of miR-34a protects mice from high fat diet-induced glucose intolerance, insulin insensitivity and other metabolic abnormalities. Macrophage depletion experiment demonstrated that the metabolic benefits in adipose-restricted miR-34a knockout mice are mainly attributed to its modulation on adipose macrophages. Indeed, miR-34a deficiency in adipose tissue leads to reduced number of crown-like structures, and increased macrophage polarization toward the anti-inflammatory M2 subtypes. Luciferase assay determined that miR-34a directly targets 3’-UTR of Kruppel-like factor 4 (Klf4). Lentivirus-mediated knocking-down of Klf4 in miR-34a knockout mice leads to exacerbated macrophage infiltration, pro-inflammatory phenotypes of macrophages in vivo, while overexpression of Klf4 improves diet-induced adipose inflammation. More importantly, adipocyte miR-34a modulates macrophage polarization in a paracrine manner via transportation of exosome. Furthermore, a strong and positive association is revealed between visceral adipose tissue miR-34a and inflammation in overweight/obese human individuals. Generally, our findings demonstrate adipose miR-34a polarizes macrophages to M1 profile and induces insulin resistance. Furthermore, the miR-34a/KLF4 axis, exhibiting as the crosstalk between adipocytes and macrophages, constitutes a critical branch in the regulation of ATM and systemic metabolic homeostasis.