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.