MicroRNA-29 Ameliorates Fibro-Inflammation and Insulin Resistance in HIF1α-Deficient Obese Adipose Tissue by Inhibiting Endotrophin Generation

Abstract

Dysregulation of extracellular matrix proteins in obese adipose tissue (AT) induces systemic insulin resistance. The metabolic roles of type VI collagen and its cleavage peptide endotrophin in obese AT are well established. However, the mechanisms regulating endotrophin generation remain elusive. Herein, we identified that several endotrophin-containing peptides (pre-endotrophins) were generated from the COL6A3 chain in a stepwise manner for the efficient production of mature endotrophin, partly through the action of hypoxia-induced matrix metalloproteinases (MMPs), including MMP2, MMP9, and MMP16. Hypoxia is an upstream regulator of COL6A3 expression and the proteolytic processing that regulates endotrophin generation. Hypoxia-inducible factor 1α (HIF1α) and the hypoxia-associated suppression of microRNA (miR)-29 cooperatively control the levels of COL6A3 and MMPs, which are responsible for endotrophin generation in hypoxic ATs. Adipocyte-specific Hif1a knock-out (APN-HIF1αKO) mice fed a chronic high-fat diet exhibited the significant amelioration of both local fibro-inflammation in AT and systemic insulin resistance compared to the control littermates, partly through the inhibition of endotrophin generation. Strikingly, adenovirus-mediated miR-29 overexpression in the ATs of APN-HIF1αKO mice in obesity significantly decreased endotrophin levels, suggesting that miR-29, combined with HIF1α inhibition in AT, could be a promising therapeutic strategy for treating obesity and related metabolic diseases.

Collagen remodeling leads to inflammation-free expansion of periprostatic adipose tissue and promotes prostate cancer progression

“…We found elevated levels specifically of MMP9 mRNA, MMP9 protein and activity in abundant PPAT. This is consistent with a report that in vitro MMP9 activity, along with MMP2 and MMP16, is key to produce active endotrophin (Jo et al, 2022), which might explain the high levels of this matrikine in abundant PPAT.…”

“…We found elevated levels specifically of MMP9 mRNA, MMP9 protein and activity in abundant PPAT. This is consistent with a report that in vitro MMP9 activity, along with MMP2 and MMP16, is key to produce active endotrophin (Jo et al, 2022), which might explain the high levels of this matrikine in abundant PPAT. At first sight, our findings appear to contradict those of a study that used inducible adipocyte-specific endotrophin overexpression, which found that endotrophin amplifies AT dysfunction in obesity by enhancing fibrosis and inflammation leading, ultimately, to increased insulin resistance (Sun et al, 2014).…”

Cross-platform proteomics signatures of extreme old age

“…Interestingly, endostatin inhibits MMP2 activity [60], suggesting that intact COL18A1 is a marker of healthy aging. Alternatively, in addition to the IGF/IGFBP/IGFALS ternary complex, MMP2 can cleave COL6A3 to generate endotrophin [61], which is associated with onset of obesity-related metabolic disorders [62]. However, MMP2 is more likely to capture intact COL6A3, and cannot characterize its cleavage activity.…”

The Mechanism for Adipose Endotrophin Production

“… Mechanism for how adipose endotrophins are made in obese adipose tissue. The latest findings by Jo et al ( 11 ) are highlighted in red. …”

“…In this issue of Diabetes , Jo et al ( 11 ) provide new insights that fill the gaps in our understanding of how adipose tissue endotrophin production is increased in obesity. They find that matrix metalloproteinase 2 (MMP2), MMP9, and MMP16 mediate stepwise cleavage of COL6A3 to efficiently produce endotrophin ( Fig.…”