Oral Presentation ANZOS-OSSANZ-AOCO Joint Annual Scientific Meeting 2017

The Melanocortin-4 Receptor regulates the secretion of PYY and GLP-1 from human gut epithelia (#170)

Emily W Sun 1 , Amanda Lumsden 1 , Alice P Liou 2 , Dayan de Fontgalland 3 4 , Steven L Due 3 4 , Paul Hollington 3 4 , Philippa Rabbitt 3 4 , David A Wattchow 3 4 , Margaret V Jackson 2 , Richard L Young 5 6 , Damien J Keating 1 6
  1. Department of Human Physiology, Flinders University, Bedford Park, SA, Australia
  2. Pfizer Worldwide Research and development, Cardiovascular and Metabolic diseases Research Unit, Boston, MA, USA
  3. Department of Surgery, Flinders Medical Centre, Bedford Park, SA, Australia
  4. Department of Surgery, Flinders University, Bedford Park, SA, Australia
  5. School of Medicine, Adelaide University, Adelaide, SA, Australia
  6. Nutrition and Metabolism Theme, South Australia Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia

Background:

he central melanocortin system is a key regulator of energy homeostasis. Loss-of-function mutations of the melanocortin-4 receptor (MC4R) represents one of the most common monogenic obesity disorders[1]. A recent rodent study showed that MC4R is expressed by enteroendocrine L cells in the gut and intraperitoneal administration of MC4R peptide agonists caused significant release of the anorectic peptides, PYY and GLP-1, in vivo[2]. However, it remains unclear if this pathway exists in human.

Method:

Immunochemistry was performed on human duodenal biopsies and colon sections to characterize the MC4R system in the gut epithelia. An ex vivo preparation of human mucosa for secretion assays was developed from endoscopic duodenal biopsies and surgically resected human ileum and sections. 15 minute static incubations of the preparations different MC4R agonists and antagonists were performed and the secretion supernatants were assayed for PYY and GLP-1 content.

Results:

Immunohistochemistry showed gut epithelial cells express proopiomelanocortin (POMC, precursor for endogenous MC4R ligands) and a small portion also expresses GLP-1. 15 minute incubation with the endogenous MC4R agonist, α-Melanocyte stimulating hormone (MSH), and its more potent analogue, [Nle4,D-Phe7]-α-MSH (NDP-α-MSH), significantly triggered PYY and GLP-1 secretion from ileal and colonic mucosae. The stimulatory effect of NDP-α-MSH was attenuated by the endogenous MC4R antagonist, Agouti-related peptide (AgRP).

Conclusion:

This is the first study to confirm human L cells express MC4R and it is also the first to report that cells in the human gut epithelia express POMC. We demonstrated activation of MC4R by α-MSH and NDP-α-MSH caused significant PYY and GLP-1 secretion and this effect was blocked by the MC4R antagonist, AgRP. Together, this work suggests a local enteric MC4R system may exist in the gut to complement the central actions of the hypothalamic MC4R system.

  1. 1. Farooqi , I. S., Keogh , J. M., Yeo , G. S. H., Lank , E. J., Cheetham , T. & O'Rahilly , S. (2003) Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene, New Engl J Med. 348, 1085-1095.
  2. 2. Panaro, B. L., Tough, I. R., Engelstoft, M. S., Matthews, R. T., Digby, G. J., Moller, C. L., Svendsen, B., Gribble, F., Reimann, F., Holst, J. J., Holst, B., Schwartz, T. W., Cox, H. M. & Cone, R. D. (2014) The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo, Cell Metab. 20, 1018-29.