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Retinaldehyde represses adipogenesis and diet-induced obesity

Nature Medicine volume 13, pages 695–702 (2007)Cite this article

Abstract

The metabolism of vitamin A and the diverse effects of its metabolites are tightly controlled by distinct retinoid-generating enzymes, retinoid-binding proteins and retinoid-activated nuclear receptors. Retinoic acid regulates differentiation and metabolism by activating the retinoic acid receptor and retinoid X receptor (RXR), indirectly influencing RXR heterodimeric partners. Retinoic acid is formed solely from retinaldehyde (Rald), which in turn is derived from vitamin A. Rald currently has no defined biologic role outside the eye. Here we show that Rald is present in rodent fat, binds retinol-binding proteins (CRBP1, RBP4), inhibits adipogenesis and suppresses peroxisome proliferator-activated receptor-γ and RXR responses. In vivo, mice lacking the Rald-catabolizing enzyme retinaldehyde dehydrogenase 1 (Raldh1) resisted diet-induced obesity and insulin resistance and showed increased energy dissipation. In ob/ob mice, administrating Rald or a Raldh inhibitor reduced fat and increased insulin sensitivity. These results identify Rald as a distinct transcriptional regulator of the metabolic responses to a high-fat diet.

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Figure 1: Rald and Rald-metabolizing enzymes in rodent fat.
Figure 2: Rald and retinoic acid differentially regulate PPAR-γ–induced adipogenic genes.
Figure 3: Rald regulates nuclear receptor responses in vitro.
Figure 4: Raldh1 deficiency is associated with suppressed adipogenesis in vitro and increased Rald and reduced adipocyte size in vivo.
Figure 5: Raldh1−/− mice resist high-fat diet–induced obesity.
Figure 6: Raldh1 deficiency and direct Rald administration protect against insulin resistance.

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Acknowledgements

We thank G. Sukhova (Brigham and Women's Hospital), J. Kirkland and T. Tchkonia (Boston University), N. Krinsky and R. Russell (Tufts University) for helpful discussions; P. Scherer, S. Kliewer, D. Mangelsdorf (University of Texas), C.H. Lee (Harvard University) and T. Willson for reagents; and E. Shvarz, K. Volz, J. Qin, T. Archibald, N. Sharma, S. Laclair and R. Driscoll for technical support. This research was supported by the Boston Obesity Nutrition Research Center 5P30DK046200 and K12 HD051959-01 NICHD BIRCWH, the American Heart Association SDG 0530101N (O.Z.); the US National Institutes of Health (R01 HL071745 and P01 HL48743) and the Donald W. Reynolds Foundation (J.P.).

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Authors and Affiliations

  1. Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Ouliana Ziouzenkova, Gabriela Orasanu, Molly Sharlach & Jorge Plutzky

  2. Merck Research Laboratories, Rahway, 07065, New Jersey, USA

    Taro E Akiyama & Joel P Berger

  3. Department of Physiology and Biophysics, Boston University, Boston, 02118, Massachusetts, USA

    Jason Viereck & James A Hamilton

  4. Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, 02111, USA

    Guangwen Tang & Gregory G Dolnikowski

  5. Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, 10032, New York, USA

    Silke Vogel

  6. OncoDevelopmental Biology Program, Burnham Institute for Medical Research, La Jolla, 92037, California, USA

    Gregg Duester

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  1. Ouliana Ziouzenkova
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Correspondence to Jorge Plutzky.

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Supplementary information

Supplementary Fig. 1

The metabolism of vitamin A generates Rald and retinoic acid. (PDF 56 kb)

Supplementary Fig. 2

Chromatograms of Rald oxime extracts from lean and obese mice as compared with vitamin A and Rald standards. (PDF 119 kb)

Supplementary Fig. 3

Rald inhibits PPAR-γ–regulated adipogenic genes. (PDF 62 kb)

Supplementary Fig. 4

Additional metabolic characteristics of Raldh1−/− and wild-type mice after high-fat diet feeding. (PDF 49 kb)

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Ziouzenkova, O., Orasanu, G., Sharlach, M. et al. Retinaldehyde represses adipogenesis and diet-induced obesity. Nat Med 13, 695–702 (2007). https://doi.org/10.1038/nm1587

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