Oral Presentation 4th Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity Meeting 2024

Intestinal melanocortin-4 receptor mediated peptide YY secretion decreases food intake and body weight in mice (#31)

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

The gut is an emerging target for obesity therapeutics, as it is the source of numerous satiety-inducing and incretin hormones. Notably, enteroendocrine cells of the intestine express melanocortin-4 receptor (MC4R) and activation of the receptor increases glucagon-like peptide-1 and peptide YY (PYY) secretion1-2. Although the function of hypothalamic MC4R in energy homeostasis is well established, the metabolic role of the intestinally expressed receptor remains poorly understood. We aimed to study the physiological effects of intestinal MC4R expression, independent of centrally mediated actions.

Cre/lox technology was used to generate conditional MC4R knockout mice. Re-expression of the Mc4r gene was achieved exclusively in intestinal cells of Mc4r Lox-Transcription Blocker; Villin1Cre-Estrogen ReceptorT2(Mc4rΔIntestine) mice using tamoxifen (100mg/kg). Mc4r Lox-Transcription Blocker mice (Mc4r-KOGlobal) were used as controls. Daily body weight, food intake (BIODAQ cages) and body composition (EchoMRI) were assessed. Metabolic cages (TSE PhenoMaster) were used to investigate energy expenditure. We assessed levels of GLP-1, total PYY and insulin in plasma using multiplex immunoassays.

After re-expression of MC4R on intestinal cells, mice lost ~10% more body weight than Mc4r-KOGlobal control mice. This weight loss was associated with a reduction in fat mass. During the period of peak weight loss, daily food intake was reduced in Mc4rΔIntestine compared to Mc4r-KOGlobal mice (2.29 vs. 4.83g) and PYY levels were significantly elevated. Strikingly, re-expression of the intestinal MC4R led to increased energy expenditure relative to body weight. These metabolic effects were transient and returned to baseline levels by day 30.

These findings suggest that intestinal MC4R plays a role in mediating the actions of melanocortin agonists in the periphery, as indicated by its effects on body weight, food intake and energy expenditure. These effects are at least partly influenced by PYY secretion, however, the precise mechanisms the underpinning the diminished appetite will be investigated in future studies.

  1. Panaro B. et al. 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, 1018-1029, 10.1016/j.cmet.2014.10.004 (2014).
  2. Sun EW. et al. A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans. Gastroenterology 161(2), 536-54, 0.1053/j.gastro.2021.04.014 (2021).