Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.

Autor:	Korobkina ED; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Calejman CM; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Haley JA; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Kelly ME; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA., Li H; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Gaughan M; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Chen Q; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Pepper HL; Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA., Ahmad H; Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA., Boucher A; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Fluharty SM; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Lin TY; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Lotun A; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Peura J; Division of Hematology-Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Trefely S; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Green CR; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA., Vo P; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Semenkovich CF; Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA., Pitarresi JR; Division of Hematology-Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA., Spinelli JB; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Aydemir O; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA., Metallo CM; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.; Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA., Lynes MD; MaineHealth Institute for Research, Scarborough, ME, USA., Jang C; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA., Snyder NW; Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA., Wellen KE; Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Guertin DA; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA. david.guertin@umassmed.edu.; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA. david.guertin@umassmed.edu.
Jazyk:	angličtina
Zdroj:	Nature metabolism [Nat Metab] 2024 Nov; Vol. 6 (11), pp. 2187-2202. Date of Electronic Publication: 2024 Oct 14.
DOI:	10.1038/s42255-024-01143-3
Abstrakt:	Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT. Competing Interests: Competing interests: The authors declare no competing interests. (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu Full text from SpringerLink