Rare variants in the melanocortin 4 receptor gene (MC4R) are associated with abdominal fat and insulin resistance in youth with obesity

Brittany Galuppo; Prabhath Mannam; Jacopo Bonet; Bridget Pierpont; Domenico Trico'; Carrie Haskell-Luevano; Mark D Ericson; Katie T Freeman; William M Philbrick; Allen E Bale; Sonia Caprio; Nicola Santoro

doi:10.1038/s41366-024-01706-0

Rare variants in the melanocortin 4 receptor gene (MC4R) are associated with abdominal fat and insulin resistance in youth with obesity

Int J Obes (Lond). 2024 Dec 29. doi: 10.1038/s41366-024-01706-0. Online ahead of print.

Authors

Affiliations

¹ Touro College of Osteopathic Medicine, Middletown, NY, USA.
² Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA.
³ Department of Information Engineering, University of Padua, Padova, Italy.
⁴ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
⁵ Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA.
⁶ Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁷ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
⁸ Department of Pediatrics, Yale School of Medicine, New Haven, CT, USA. [email protected].
⁹ Department of Medicine and Health Sciences, "V. Tiberio" University of Molise, Campobasso, Italy. [email protected].

PMID: 39738493
DOI: 10.1038/s41366-024-01706-0

Abstract

Background: Rare variants in melanocortin 4 receptor gene (MC4R) result in a severe form of early-onset obesity; however, it is unclear how these variants may affect abdominal fat distribution, intrahepatic fat accumulation, and related metabolic sequelae.

Methods: Eight hundred seventy-seven youth (6-21 years) with overweight/obesity, recruited from the Yale Pediatric Obesity Clinic in New Haven, CT, underwent genetic analysis to screen for functionally damaging, rare variants (MAF < 0.01) in MC4R. Participants were assigned to a Pathogenic Variant or No Pathogenic Variant group and completed a 10-timepoint 180-min oral glucose tolerance test (OGTT) and abdominal MRI.

Results: Compared to the No Pathogenic Variant group, the Pathogenic Variant group demonstrated significantly greater glucose concentrations (AUC_tot: 24.7 ± 1.22 g/dL × 180 min vs. 21.9 ± 1.41 g/dL × 180 min; p = 0.001), insulin levels (AUC_tot: 57.4 ± 11.5 mU/mL × 180 min vs. 35.5 ± 8.90 mU/mL × 180 min; p = 0.002), and lower insulin sensitivity (WBISI: 1.01 ± 0.137 vs. 1.85 ± 0.036; p = 0.0008) during the OGTT. The Pathogenic Variant group also presented with greater visceral adipose tissue (VAT) (85.1 cm² ± 10.3 vs. 56.1 cm² ± 1.64; p = 0.003) and intrahepatic fat content (HFF%) (19.4% ± 4.94 vs. 8.21% ± 0.495; p = 0.012) than the No Pathogenic Variant group despite the two groups having similar BMI z-scores (p = 0.255), subcutaneous adipose tissue (SAT) (p = 0.643), and total body fat (p = 0.225).

Conclusions: Pathogenic variants in MC4R are associated with increased VAT, HFF%, and insulin resistance, independent from the degree of obesity in youth.