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Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue

Nature Medicine volume 18, pages 918–925 (2012)Cite this article

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Abstract

Promoting brown adipose tissue (BAT) formation and function may reduce obesity. Recent data link retinoids to energy balance, but a specific role for retinoid metabolism in white versus brown fat is unknown. Retinaldehyde dehydrogenases (Aldhs), also known as aldehyde dehydrogenases, are rate-limiting enzymes that convert retinaldehyde (Rald) to retinoic acid. Here we show that Aldh1a1 is expressed predominately in white adipose tissue (WAT), including visceral depots in mice and humans. Deficiency of the Aldh1a1 gene induced a BAT-like transcriptional program in WAT that drove uncoupled respiration and adaptive thermogenesis. WAT-selective Aldh1a1 knockdown conferred this BAT program in obese mice, limiting weight gain and improving glucose homeostasis. Rald induced uncoupling protein-1 (Ucp1) mRNA and protein levels in white adipocytes by selectively activating the retinoic acid receptor (RAR), recruiting the coactivator PGC-1α and inducing Ucp1 promoter activity. These data establish Aldh1a1 and its substrate Rald as previously unrecognized determinants of adipocyte plasticity and adaptive thermogenesis, which may have potential therapeutic implications.

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Figure 1: Aldh1a1 is present primarily in visceral fat, and its expression correlates with obesity.
Figure 2: Aldh1a1 deficiency is characterized by increased transcription of brown fat markers in white fat.
Figure 3: Aldh1a1 deficiency activates a thermogenic program in white fat.
Figure 4: Rald induces Ucp1 expression in white adipocytes.
Figure 5: Rald-mediated Ucp1 expression is RAR-dependent and involves PGC-1α recruitment.
Figure 6: ASO-mediated Aldh1a1 knockdown in GWAT promotes white-fat thermogenesis and limits diet-induced obesity.

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Acknowledgements

We thank H. Wang, G. Sukhova, E. Shvartz, T.A. Dang and V. Demchev for excellent technical support, R. Koza (Pennington Biomedical Research Center) for providing the Ucp1 promoter luciferase construct, H. Kagechika (University of Tokyo) for providing HX531 and G. Duester (Burnham Medical Research Institute) for the Aldh1a1−/− mice and helpful discussions. This work was supported by the US National Institutes of Health grants HL048743, AR054604-03S1, 5P30DK057521-12 (J.P.); Mary K. Iacocca Professorship DK082659 and the National Institute of Diabetes and Digestive and Kidney Diseases DK056626 (C.R.K.); DK048873 and DK048873-14S2 (D.E.C.); the Austrian Science Fund (FWF); J3107-B19 (F.W.K.).

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Authors and Affiliations

  1. Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Florian W Kiefer, Patrick O'Brien, Steffen Spoerl, Jonathan D Brown, Shriram Nallamshetty & Jorge Plutzky

  2. Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA

    Cecile Vernochet & C Ronald Kahn

  3. Christian Doppler-Laboratory for Cardio-Metabolic Immunotherapy, Vienna, Austria

    Maximilian Zeyda & Thomas M Stulnig

  4. Clinical Division of Endocrinology and Metabolism, Department of Medicine, Medical University of Vienna, Austria

    Maximilian Zeyda & Thomas M Stulnig

  5. Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    David E Cohen

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Contributions

F.W.K. and J.P. designed the study; F.W.K., C.V., P.O., S.S., J.D.B., S.N. and M.Z. researched data; F.W.K. wrote the manuscript; C.V., J.D.B., S.N., M.Z., T.M.S., D.E.C., C.R.K. and J.P. reviewed the manuscript; D.E.C. and C.R.K. contributed to discussion.

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Correspondence to Jorge Plutzky.

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Kiefer, F., Vernochet, C., O'Brien, P. et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat Med 18, 918–925 (2012). https://doi.org/10.1038/nm.2757

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