Newly identified peptide hormone inhibits intestinal fat absorption and improves NAFLD through its receptor GPRC6A.

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Obesity and its related comorbidities, especially non-alcoholic fatty liver disease (NAFLD), are leading medical challenges worldwide due to various obesogenic factors in modern societies. Circulating peptides and G protein-coupled receptors (GPCRs) have gained much attention because of their biofunctions on these metabolic disorders.In this study, based on the bioinformatics, we have identified a murine circulating pentadecapeptide flanked by potential convertase cleavage sites of osteocalcin (OCN), which we here name 'metabolitin (MTL)'. We use ligand-receptor binding, receptor internalization, BRET and Nano ITC assays to study the binding relationship between MTL and GPRC6A. For in vivo biological studies, wild-type mice kept on a high-fat diet (HFD) were injected or gavaged with MTL to study its function on NAFLD.We have confirmed that the binding between MTL and GPRC6A, along with the interaction of GPRC6A and OCN by those in vitro biological studies. From the functional studies, both intraperitonial (i.p.) and oral administration of MTL improved NAFLD and insulin resistance (IR) potently in a mice model. Interacting with GPRC6A expressed in intestines, gavaged or i.p. injected MTL can significantly inhibit intestinal neurotensin (NT) secretion, which in turn inhibits triglyceride but not cholesterol gut absorption, mediated by AMPK pathway. In addition, GLP-1 secretion was induced by MTL treatment.Overall, gavaged or i.p. injected MTL can significantly improves NAFLD symptoms through inhibiting lipid absorption and IR via reducing NT and stimulating GLP-1 secretion. MTL could be a potential therapeutic candidate for the treatment of NAFLD.



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