Abstract
A strong association between leucine and obesity has been well established; however, the role of leucine catabolic enzymes in adipose tissue remains largely unknown. Here, we show that knockdown of the leucine catabolic enzyme AU RNA-binding methylglutaconyl-CoA hydratase (AUH) in brown adipocytes reduces thermogenesis, while AUH over-expression has the opposite effect both in vivo and in vitro. Mechanistically, AUH partially promotes uncoupling protein 1 (UCP1) expression through its metabolite 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). HMG-CoA directly HMGylates peroxisome proliferator-activated receptor gamma (PPARγ) on lysine 386, enhancing its transcriptional activity to increase UCP1 expression. In addition, AUH binds to and stabilizes Ucp1 mRNA via its RNA-binding function. Moreover, we discovered that AUH promotes white adipose tissue browning; AUH expression in human white adipose tissue is inversely correlated with adiposity, and over-expression of AUH in adipose tissue protects male mice against high-fat diet-induced obesity. Collectively, these results provide new insights into the crosstalk between amino acid metabolism and thermogenesis and identify a novel post-translational modification of PPARγ.
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Data availability
Data supporting the findings of this study are available within this paper and its Supplementary Files. The RIP-Seq data generated in this study have been deposited into the Sequence Read Archive (SRA) in the National Center for Biotechnology Information (NCBI) under the accession codes PRJNA1301336. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository with the dataset identifier PXD075390. The RNA-Seq data used in this study are available in the NCBI Gene Expression Omnibus (GEO) database under accession codes GSE152991 and GSE166047. Source data are provided with this paper.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (82430030, 82495182, 92357304, and 91957207 to F.G., 82270905 to F.X., 82401017 to H.J., 82370811 to F.Y., 82300939 to X.J., 82300940 to Y.N.), the National Key R&D Program of China (2018YFA0800600 to F.G.), Shanghai leading talent program to F.G, and Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (GZC20230478 to H.J.). F.X. was sponsored by the Youth Innovation Promotion Association of CAS, the Shanghai Rising Star Program, and the Sanofi-Aventis SIBS scholarship. H.J. was sponsored by the Fudan University Super Postdoctoral Fellowship.
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H.J. and F.X. designed and carried out overall experiments, analyzed data, wrote, reviewed, and edited the manuscript. S.N., S.C., X.J., P.L., F.Y. and K.T. assisted with mouse experiments and cultured cell studies. Z.L. developed the LC-MS/MS platform to measure the HMG-CoA levels. X.L., H.Z., W.S. and Y.S. provided research materials and contributed to the discussion. F.G. directed the research, contributed to the discussion, wrote, reviewed, and edited the manuscript.
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Jiang, H., Ni, S., Li, Z. et al. Leucine catabolic enzyme AUH regulates BAT thermogenesis via PPARγ HMGylation and RNA-binding function in male mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71581-y
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DOI: https://doi.org/10.1038/s41467-026-71581-y
