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

J Hepatol. 2020 Aug;73(2):383-393. doi: 10.1016/j.jhep.2020.02.026. Epub 2020 Mar 6.

Abstract

Background & aims: Circulating peptides and G protein-coupled receptors (GPCRs) have gained much attention because of their biofunctions in metabolic disorders including obesity and non-alcoholic fatty liver disease (NAFLD). Herein, we aimed to characterize the role and therapeutic potential of a newly identified peptide hormone in NAFLD.

Methods: Using bioinformatics, we identified a murine circulating pentadecapeptide flanked by potential convertase cleavage sites of osteocalcin (OCN), which we named 'metabolitin (MTL)'. We used ligand-receptor binding, receptor internalization, bioluminescence resonance energy transfer and Nano isothermal titration calorimetry 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 in NAFLD.

Results: We confirmed that MTL binds to GPRC6A and OCN interacts with GPRC6A using in vitro biological studies. Both intraperitoneal and oral administration of MTL greatly improved NAFLD and insulin resistance in a mouse model. Interacting with GPRC6A expressed in intestines, MTL can significantly inhibit intestinal neurotensin secretion, which in turn inhibits triglyceride but not cholesterol gut absorption, mediated by the 5'AMP-activated protein kinase pathway. In addition, glucagon like peptide-1 secretion was induced by MTL treatment.

Conclusions: Oral or intraperitoneal MTL significantly improves the symptoms of NAFLD by inhibiting lipid absorption and insulin resistance. MTL could be a potential therapeutic candidate for the treatment of NAFLD.

Lay summary: A novel murine peptide hormone, herein named 'metabolitin', inhibits fatty acid absorption and improves systemic insulin resistance in a murine model of obesity and non-alcoholic fatty liver disease. Thus, metabolitin has therapeutic potential for the treatment of patients with non-alcoholic fatty liver disease.

Keywords: Diabetes; Hormone; Insulin; Metabolism; NAFLD; Obesity; Oral peptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dietary Fats / metabolism
  • Disease Models, Animal
  • Glucagon-Like Peptide 1 / metabolism*
  • Hypolipidemic Agents / metabolism
  • Hypolipidemic Agents / pharmacology
  • Insulin Resistance
  • Intestinal Absorption / drug effects*
  • Mice
  • Non-alcoholic Fatty Liver Disease* / drug therapy
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Obesity / metabolism
  • Osteocalcin / metabolism
  • Peptide Hormones* / metabolism
  • Peptide Hormones* / pharmacology
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Treatment Outcome
  • Triglycerides / metabolism*

Substances

  • Dietary Fats
  • GPRC6A protein, mouse
  • Hypolipidemic Agents
  • Peptide Hormones
  • Receptors, G-Protein-Coupled
  • Triglycerides
  • Osteocalcin
  • Glucagon-Like Peptide 1