Melanocortin 4 receptor gene (MC4R) mutations result in early-onset obesity, but it is unclear how they affect abdominal fat distribution, intrahepatic fat, and related metabolic sequelae. 484 overweight/obese (BMI >85th percentile for age, sex, and height) youth (6-21 years) were screened for functionally damaging, rare variants (minor allele frequency <0.01) in the coding region of MC4R and were assigned to a Pathogenic Variant (n=10) or No Variant (n=474) group. Participants underwent MC4R sequencing, abdominal MRI, and a 180-minute oral glucose tolerance test (OGTT) with mathematical modeling of insulin kinetics and β cell function. Compared to No Variant group, the Pathogenic Variant group showed greater visceral fat (Figure 1A) , intrahepatic fat (Figure 1B) , and higher plasma glucose (Figure 1C) and insulin (Figure 1D) during the OGTT, as well as a delayed glucose peak (65.4 ± 3.71 vs. 58.8 ± 0.417 minutes; P=0.036) , insulin resistance (WBISI: 0.9± 0.163 vs. 1.82 ± 0.051; P=0.0006) , and lower insulin clearance (0.441 ± 0.065 vs. 0.6± 0.012 µU/mL/min; P=0.033) despite similar BMI z-scores (P=0.189) and body fat percentage (P=0.704) between groups. These results show that rare variants in MC4R are associated with increased visceral fat, intrahepatic fat, and insulin resistance, independent from the effect of obesity.


D. Trico: None. A.E. Bale: None. S. Caprio: None. N. Santoro: None.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at