Figure 5. FGF21 is associated with beiging of subcutaneous fat depots and acyl-CoA trapping.

(A) In the MMA patient cohort, FGF21 concentrations correlated with the abnormal body composition observed in lower extremities and (B) with an increased energy expenditure per kilogram fat-free mass. (C) Immunoblotting of selected mitochondrial or beige fat markers is depicted in subcutaneous adipose tissues of 2 young adult female control participants undergoing postmortem examinations at the NIH Clinical Center, and 2 female participants with mut⁰ MMA: upper anterior chest wall subcutaneous fat of the index case obtained during a central line removal and the upper arm subcutaneous fat of a woman in Figure 1D, obtained during a postmortem exam at age 34 years. While no significant differences were observed in the expression of PGC-1α, MFN2, and DIO2, higher density bands were evident in patients with mut⁰ MMA for SIRT1, UCP1, SIRT5, and FGF21. (D) Combined PET/CT imaging study showing extensive subcutaneous uptake of ¹⁸F-FDG (yellow arrows), over the shoulders and gluteal area/upper thighs in a 13-year-old girl with mut⁰ MMA. Standard Uptake Values of ¹⁸F-FDG are provided in Supplemental Figure 4. (E) Circulating FGF21 in the MMA patient cohort correlated with the acyl-CoA species accumulation (propionyl-C3 and methylmalonyl-C4DC carnitine) reflected in the increased circulating acyl- to free carnitine plasma ratio. (F) Posttranslational modifications (PTMs), including methylmalonylation, propionylation, acetylation, and succinylation, are shown in subcutaneous tissues of participants with mut⁰ MMA compared with controls. The biggest differences were observed in lysine residue methylmalonyl — PTMs that were completely absent from control WAT.