Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation
A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
JCI insight - 9(2024), 4 vom: 22. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Manoli, Irini [VerfasserIn] |
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| Links: |
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| Themen: |
62031-54-3 |
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| Anmerkungen: |
Date Completed 24.02.2024 Date Revised 30.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.174097 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367615266 |
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| 100 | 1 | |a Manoli, Irini |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation |
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| 500 | |a Date Revised 30.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Amino acid metabolism | |
| 650 | 4 | |a Genetics | |
| 650 | 4 | |a Mouse models | |
| 650 | 4 | |a Obesity | |
| 650 | 4 | |a Therapeutics | |
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| 700 | 1 | |a Sysol, Justin R |e verfasserin |4 aut | |
| 700 | 1 | |a Head, PamelaSara E |e verfasserin |4 aut | |
| 700 | 1 | |a Epping, Madeline W |e verfasserin |4 aut | |
| 700 | 1 | |a Gavrilova, Oksana |e verfasserin |4 aut | |
| 700 | 1 | |a Crocker, Melissa K |e verfasserin |4 aut | |
| 700 | 1 | |a Sloan, Jennifer L |e verfasserin |4 aut | |
| 700 | 1 | |a Koutsoukos, Stefanos A |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Cindy |e verfasserin |4 aut | |
| 700 | 1 | |a Ktena, Yiouli P |e verfasserin |4 aut | |
| 700 | 1 | |a Mendelson, Sophia |e verfasserin |4 aut | |
| 700 | 1 | |a Pass, Alexandra R |e verfasserin |4 aut | |
| 700 | 1 | |a Zerfas, Patricia M |e verfasserin |4 aut | |
| 700 | 1 | |a Hoffmann, Victoria |e verfasserin |4 aut | |
| 700 | 1 | |a Vernon, Hilary J |e verfasserin |4 aut | |
| 700 | 1 | |a Fletcher, Laura A |e verfasserin |4 aut | |
| 700 | 1 | |a Reynolds, James C |e verfasserin |4 aut | |
| 700 | 1 | |a Tsokos, Maria G |e verfasserin |4 aut | |
| 700 | 1 | |a Stratakis, Constantine A |e verfasserin |4 aut | |
| 700 | 1 | |a Voss, Stephan D |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Kong Y |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Rebecca J |e verfasserin |4 aut | |
| 700 | 1 | |a Hamosh, Ada |e verfasserin |4 aut | |
| 700 | 1 | |a Berry, Gerard T |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xiaoyuan Shawn |e verfasserin |4 aut | |
| 700 | 1 | |a Yanovski, Jack A |e verfasserin |4 aut | |
| 700 | 1 | |a Venditti, Charles P |e verfasserin |4 aut | |
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