Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation

Area of Science:

• Biochemistry
• Metabolic Disorders
• Adipose Tissue Biology

Background:

• Methylmalonyl-CoA mutase (MCM) deficiency, or methylmalonic acidemia (MMA), is an inborn error of branched-chain amino acid (BCAA) metabolism.
• Patients with MMA exhibit an unusual adipose tissue distribution: centripetal obesity with fat accumulation in the limbs and minimal visceral fat, mimicking familial multiple lipomatosis.

Purpose of the Study:

• To investigate the physiology of brown and white adipose tissue in methylmalonic acidemia (MMA).
• To explore the relationship between fibroblast growth factor 21 (FGF21), acyl-CoA accretion, and inflammation in MMA.
• To evaluate the therapeutic potential of bezafibrate in an MMA mouse model.

Main Methods:

• Body composition, adipokines, and inflammatory markers were analyzed in 46 MMA patients and 99 controls.
• Adipose tissue and thermogenesis were studied in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut).
• MMA mice were treated with bezafibrate to assess clinical and metabolic changes.

Main Results:

• MMA patients displayed a distinct lipodystrophy phenotype.
• FGF21 levels correlated with acyl-CoA accumulation, adipose tissue methylmalonylation, and reduced inflammation.
• MMA mice showed impaired thermogenesis, whitened brown fat, and poor response to cold, which improved with bezafibrate treatment, including subcutaneous fat beiging.

Conclusions:

• Defects in BCAA oxidation lead to a novel lipodystrophy phenotype in MMA.
• Subcutaneous adipose tissue beiging in MMA is inducible with small molecules, presenting a potential therapeutic avenue.