Targeting COL6A3-C5 with nigericin suppresses endotrophin formation and enhances insulin sensitivity in obesity

Endotrophin, a cleavage product of collagen VIα3 (COL6A3), contributes to fibroinflammation in adipose tissue and exacerbates systemic insulin resistance in obesity. Previously, we demonstrated that various hypoxia-induced matrix metalloproteinases (MMPs) are directly involved in the cleavage of COL6A3 to generate endotrophin in obese adipose tissue; thus, inhibition of endotrophin generation by blocking MMP access could be beneficial for treating obesity-related metabolic disease. Here we identified nigericin as an inhibitor of endotrophin generation, which improves fibroinflammation and insulin sensitivity in both hypoxic adipocytes in vitro and diet-induced obese mice in vivo. Mechanistically, nigericin directly binds to the COL6A3-C5 domain, competing with MMPs and thereby disrupting the interactions between the COL6A3-C5 domain and MMPs. This interference prevents the cleavage of endotrophin from the COL6A3 by MMPs, ultimately inhibiting its generation. Taken together, these results strongly suggest that pharmacological blockade of endotrophin cleavage, by using nigericin, effectively decreases endotrophin levels and improves endotrophin-mediated fibroinflammation and insulin resistance in obesity. Furthermore, this new therapeutic strategy could be applied to various metabolic diseases and solid tumors where endotrophin levels are pathologically elevated.