A lipomatosis endophenotype in methylmalonic acidemia: evidence from patients and mice. I. Manoli1, J. R. Sysol1, M. K. Crocker2, G. Niu3, J. Storrar1, S. Mendelson1,2, J. L. Sloan1, C. Wang1, Y. Ktena1, P. M. Zerfas4, V. Hoffman4, H. J. Vernon5, A. Hamosh5, J. C. Reynolds6, X. Chen3, O. Gavrilova7, J. A. Yanovski2, C. P. Venditti1 1) Genetics and Molecular Biology Branch, NHGRI, NIH, Bethesda, MD; 2) Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD; 3) Laboratory of Molecular Imaging and Nanomedicine, NIBIB, NIH, Bethesda, MD; 4) Office of Research Services, Division of Veterinary Resources, NIH, Bethesda, MD; 5) McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD; 6) Radiology and Imaging Sciences Department, Clinical Center, NIH, Bethesda, MD; 7) Mouse Metabolism Core, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

   We have discerned that a subset of patients with isolated methylmalonic acidemia (MMA) develop centripetal obesity, yet display a paucity of visceral fat, with wasting of distal upper and lower extremities. Measurements of whole and regional body composition, expressed as fat- (FM) and fat-free body mass (FFM), were obtained by dual energy X-ray absorptiomety (DXA) in 46 individuals with MMA (32 mut, 8 cblA and 6 cblB subtype) and 99 age-, gender-, race/ethnicity-, and BMI-matched controls. Compared to controls, mut0 patients had decreased FFM (P=0.005) and increased proximal/total upper and lower extremity FM (73.6 7.1 vs. 68.6 4.8% in controls, P=0.001 for both extremities). While serum leptin concentrations correlated with FM in both groups, the ratio of proximal/total extremity FM correlated positively with serum adiponectin levels in mut0 patients (r=0.425, P=0.04 for upper and r=0.601, P=0.003 for lower extremity), reminiscent of the hyperadiponectinemia and proximal accumulation of subcutaneous fat observed in the multiple lipomatosis syndromes previously reported in alcoholic subjects and, rarely, in patients with primary mitochondrial disease. To model extrahepatic disease manifestations including brown/white fat pathophysiology in MMA, we generated mice that express the methylmalonyl-CoA mutase (Mut) cDNA (TgINS-Alb-Mut) under the control of a liver-specific promoter on the Mut-/- background. Mut-/-;TgINS-Alb-Mut are rescued from lethality and, similar to MMA patients, display decreased FFM and resting energy expenditure (P=0.05), as well as depressed thermogenesis after 3 adrenergic stimulation (P=0.001), and blunted induction of Ucp1 and Dio2 after 4h of cold exposure. When challenged with a high protein diet (HPD), Mut-/-;TgINS-Alb-Mut mice had suppressed 18F-FDG-glucose uptake in brown fat measured by positron emission tomography (PET), associated with abnormal brown fat mitochondrial ultrastructure. The inclusion of 0.5% bezafibrate in the HPD resulted in improved survival (P=0.042), reversal of the PET findings, and increased Ucp1 expression in the subcutaneous shoulder and inguinal fat depots of treated Mut-/-;TgINS-Alb-Mut mice. Our findings delineate a novel obesity phenotype in MMA distinct from other lipodystrophy syndromes associated with mitochondrial dysfunction, identify regions of inducible subcutaneous fat in mice and patients and suggest new therapeutic targets for this disease.

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