Nigericin protects obesity-induced insulin resistance by reducing endotrophin generation via MMP activatio

Abstract

Endotrophin, a cleavage product of collagen VIα3 (COL6A3), is a major contributor of adipose fibro-inflammation and exacerbates metabolic derangements such as insulin resistance. Previously we demonstrated that endotrophin was generated from the COL6A3 through the action of hypoxia-induced matrix metalloproteinases (MMPs) in obese adipose tissue. We reasoned that inhibition of MMPs activity may ameliorate the vicious phenotypes of obese adipose environment. In this study, we identified nigericin as an inhibitor of MMPs to suppress the endotrophin generation. The metabolic effects of nigericin were validated with HFD-fed obese mice compared to those in lean controls. Nigericen markedly improved metabolic parameters such as glucose intolerance and insulin responsiveness in CoCl2-stimulated adipocytes and in the obese mice. Also, nigericin-treated obese mice have reduced fibrosis and inflammation in adipose tissues. This was accompanied by decreased levels of endotrophin and its MMPs’ cleavage activities in adipose tissue. In vitro studies have revealed that nigericin effectively suppresses MMPs activation (MMP9 and MMP16) in HEK293T cells, and the action of nigericin was partly mediated by the disruption of endotrophin/MMP9 interaction. Our findings strongly suggest that nigericin protects local fibro-inflammation in adipose tissues and systemic insulin resistance in HFD-fed obese mice, and that is mediated by inhibition of endotrophin cleavage activities via blocking interactions between MMP9 and endotrophin, at least in part. Therefore, Nigericin could be a potential drug candidate to treat for the obesity-related complications.