MicroRNA-29 Ameliorates Fibro-Inflammation and Insulin Resistance in HIF1a-Deficient Obese Adipose Tissue by Inhibiting Endotrophin Generation

Abstract

The metabolic roles of type VI collagen and its cleavage peptide endotrophin in obese adipose tissue (AT) are well established. However, the mechanisms regulating endotrophin generation remain elusive. Herein, we identified that several endotrophin containing peptides were generated from the COL6A3 chain through the action of hypoxia-induced matrix metalloproteinases. Hypoxia is an upstream regulator of COL6A3 expression and the proteolytic processing that regulates endotrophin generation. Hypoxia-inducible factor 1a and the hypoxia-associated suppression of microRNA-29 cooperatively control the levels of COL6A3 and MMPs, responsible for endotrophin generation in hypoxic ATs. Adipocyte-specific Hif1a knock-out (APN-HIF1aKO) mice fed a chronic high-fat diet exhibited the significant amelioration of both local fibro-inflammation in AT and systemic insulin resistance compared with their control littermates, partly through the inhibition of endotrophin generation. Strikingly, adenovirus-mediated miR-29 overexpression in the ATs of APN-HIF1aKO mice in obesity significantly decreased endotrophin levels.