Retinaldehyde represses adipogenesis and diet-induced obesity

Ouliana Ziouzenkova

Gabriela Orasanu

Molly Sharlach

Taro Akiyama

Gregory Dolnikowski+3 authors

^{Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA}

^{Merck Research Laboratories, Rahway, New Jersey 07065, USA}

^{Department of Physiology and Biophysics, Boston University, Boston, Massachusetts, 02118, USA}

^{Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA}

^{Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA}

^{OncoDevelopmental Biology Program, Burnham Institute for Medical Research, La Jolla, California 92037, USA}

Correspondence should be addressed to J.P. (ude.dravrah.hwb.scir@ykztulpj)

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-c 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.

Abstract

Although vitamin A and its metabolite retinoic acid have therapeutic applications, frequent side effects limit their use¹3. In clinical trials involving β-carotene supplementation, worrisome increases in cardiovascular events and mortality have been noted, despite evidence suggesting possible beneficial vascular effects of this treatment³. These variable responses to retinoids probably derive from the fact that β-carotene and vitamin A (retinol) and their major metabolites—retinaldehyde (Rald) and retinoic acid—regulate diverse cellular responses, including development, immune function and vision⁴5. The tight control of retinoid biology is evident in the elaborate system that governs the absorption, formation, transportation and action of these structurally and functionally distinct retinoid metabolites. Despite this, retinoids and their effects remain poorly understood⁴5. Of note, retinoid metabolism can vary among tissues, for instance in terms of the expression and activity of specific families of enzymes that govern the transition from retinol to Rald to retinoic acid (Supplementary Fig. 1 online and ref. 5). Alcohol dehydrogenases (Adh) oxidize retinol to Rald, and retinaldehyde dehydrogenases (Raldh) participate in the determination of cellular concentrations of free Rald by oxidizing Rald to retinoic acid⁵. Differences in the concentrations of specific retinoid metabolites may underlie their effects in various settings.

Retinoic acid, the most studied metabolite in the vitamin A pathway, exerts its broad range of biologic effects in large part by controlling gene expression. Retinoic acid binds to and activates members of the nuclear receptor family, including retinoic acid receptor (RAR) and retinoid X receptor (RXR) - transcription factors that link vitamin A metabolism to the transcriptional regulation of specific gene cassettes⁶8. RXR also controls key metabolic pathways by serving as the obligate heterodimeric partner for several members of the steroid hormone nuclear receptor family, including peroxisome proliferator-activated receptors (PPARs)⁸. Adipogenesis is a differentiation process regulated by the complex interaction of some 11 RXR heterodimeric partners (Supplementary Fig. 1 and ref. 9). In 3T3-L1 adipocyte differentiation assays, retinoic acid effects vary as a function of the stage of adipogenesis and relative RAR, PPAR-γ and RXR expression⁹10. Early in adipogenesis, retinoic acid blocks differentiation, whereas after 48 h of differentiation, it promotes fat cell formation¹⁰. Inhibition of endogenous retinoic acid production by the Raldh inhibitor citral reduces weight in vivo in animal models¹¹12. Moreover, although 9-cis-retinoic acid has been generally accepted as a natural ligand for RXR (refs. ⁷8), its role in adipogenesis and its existence in vivo have been challenged by some biochemical and genetic studies⁵.

Rald is primarily considered to be a precursor for retinoic acid formation⁵13. Although Rald (11-cis-Rald) is essential for molecular signaling in vision, a role for Rald outside the eye remains essentially unknown⁴. We hypothesized that Rald itself might be present in fat in vivo, where it could function as a specific but previously unrecognized regulator of adipogenesis, independent of its conversion to retinoic acid.

Footnotes

Note: Supplementary information is available on the Nature Medicine website.

COMPETING INTERESTS STATEMENT

The authors declare no competing financial interests.

Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions

Footnotes

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