Poster only 3rd Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity 2022

Does the intestinal melanocortin-4 receptor (MC4R) play a role in regulating metabolic outcomes? (#53)

Rifa Haque 1 , Ryan Keenan 1 , Jesse Dicello 1 , Angel Zi Shan Wee 1 , Vanessa Haynes 2 , Tomris Mustafa 1 , Stephanie Simonds 1 , Michael Cowley 1
  1. Physiology, Monash University, Melbourne, Victoria, Australia
  2. Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia

Introduction

The central melanocortin-4-receptor (MC4R) has a crucial role in the regulation of energy homeostasis. Notably, MC4R has been identified on enteroendocrine cells of the intestine and its activation on these cells increases secretion of glucagon-like peptide 1 and peptide YY (1). However, the metabolic role of the receptor in the gut remains poorly understood. We assessed the involvement of MC4R in the intestine in regulating metabolic outcomes in an in vivo mouse model. This may highlight its potential as an obesity therapeutic target within the gut.

Methodology and results

Conditional MC4R knockout mice were generated using Cre-Lox technology. Re-expression of the Mc4r gene was achieved exclusively in the intestinal cells of Mc4r loxTB; Vil1-CreERT2 (ΔMc4rIntestine) mice with five daily intraperitoneal injections of tamoxifen (100mg/kg). Mc4r loxTB mice (Mc4r-KOGlobal) controls were also treated with tamoxifen. Upon re-expression of MC4R on intestinal cells, male mice lost significantly more body weight than Mc4r-KOGlobal mice (mean ± SEM: -7.56±1.12% vs. -2.95±0.69%). Changes in body composition were analysed using EchoMRI scans and showed that the weight loss was associated with a reduction in fat mass but no changes in lean mass. During the period of peak weight loss, daily food intake was significantly less in ΔMc4rIntestine compared to Mc4r-KOGlobal mice (2.29±0.43g vs. 4.83±0.41g). Assessment of faecal energy content using bomb calorimetry revealed that re-expressing MC4R in the gut increased faecal calorie excretion. Glucose homeostasis was studied using glucose tolerance tests. The ΔMc4rIntestine mice demonstrated significantly lower fasting blood glucose levels and improved glucose tolerance.

Conclusion

This research suggests that intestinal MC4R may play a crucial role in mediating the actions of melanocortin agonists in the periphery, as indicated by its effects on body weight, food intake, energy excretion and glucose homeostasis. We are continuing to explore the mechanism underpinning these metabolic effects.

  1. Panaro et al. Cell Metab 2014; 20, 1018-1029