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Vitamin D and energy homeostasis—of mice and men

Nature Reviews Endocrinology volume 10, pages 79–87 (2014)Cite this article

Subjects

Key Points

  • Adipose tissue is a target tissue for vitamin D, as 1,25-dihydroxyvitamin D3 stimulates the expression of typical adipocyte genes, such as leptin, and inhibits the expression of uncoupling proteins in vitro

  • Vdr−/− and Cyp27b1−/− mice display increased energy expenditure and lower fat mass accumulation with ageing, whereas mice overexpressing Vdr in adipocytes become obese

  • Two mechanisms might explain the increased energy expenditure of Vdr−/− and Cyp27b1−/− mice: increased adipocyte expression of uncoupling proteins, such as UCP1 and UCP2, or an increased bile acid pool

  • Bile acids are known stimulators of nuclear receptors, for example, BAR (also known as FXR), CAR, PXR and VDR, and G-protein-coupled receptors, such as GPBAR1 (also known as TGR5), which can act as potent regulators of energy expenditure

  • Cross-sectional and long-term observational studies in different populations worldwide show that human obesity and the metabolic syndrome and its components are associated with poor vitamin D status

  • Vitamin D deficiency generates resistance to diet-induced obesity in mice, whereas in humans poor vitamin D status is strongly associated with obesity: no satisfactory explanation for this discrepancy exists

Abstract

The vitamin D endocrine system has many extraskeletal targets, including adipose tissue. 1,25-Dihydroxyvitamin D3, the active form of vitamin D, not only increases adipogenesis and the expression of typical adipocyte genes but also decreases the expression of uncoupling proteins. Mice with disrupted vitamin D action—owing to gene deletion of the nuclear receptor vitamin D receptor (Vdr) or the gene encoding 1α-hydroxylase (Cyp27b1)—lose fat mass over time owing to an increase in energy expenditure, whereas mice with increased Vdr-mediated signalling in adipose tissue become obese. The resistance to diet-induced obesity in mice with disrupted Vdr signalling is caused at least partially by increased expression of uncoupling proteins in white adipose tissue. However, the bile acid pool is also increased in these animals, and bile acids are known to be potent inducers of energy expenditure through activation of several nuclear receptors, including Vdr, and G-protein-coupled receptors, such as GPBAR1 (also known as TGR5). By contrast, in humans, obesity is strongly associated with poor vitamin D status. A causal link has not been firmly proven, but most intervention studies have failed to demonstrate a beneficial effect of vitamin D supplementation on body weight. The reasons for the major discrepancy between mouse and human data are unclear, but understanding the link between vitamin D status and energy homeostasis could potentially be very important for the human epidemic of obesity and the metabolic syndrome.

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Figure 1: Endocrine feedback loop between the vitamin D endocrine system and adipocytes.
Figure 2: Energy expenditure of Vdr−/− mice.
Figure 3: Feedback control of bile acid metabolism by activation of the vitamin D endocrine system.
Figure 4: Bile acid metabolism of Vdr−/− mice.

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Acknowledgements

The Vdr−/− mice were generated by S. Kato's laboratory and breeder pairs were kindly provided by D. Metzger and P. Chambon. The authors' work was supported by grants from the Fund for Scientific Research (G.0587.09; G.0859.11, G.0573.13), the KU Leuven (GOA 2009/10) and the Swiss National Science Foundation (SNF 310030_143748/1).

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  1. Clinical and Experimental Endocrinology, KU Leuven, O&NI Herestraat 49 - bus 902, Leuven, 3000, Belgium

    Roger Bouillon, Geert Carmeliet, Liesbet Lieben & Annemieke Verstuyf

  2. Health Science Laboratory, Graduate School of Media and Governance, Keio University, 5322 Endo Fujisawa-shi, Kanagawa, 252-0882, Japan

    Mitsuhiro Watanabe

  3. Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Station 15, AI 1149, Lausanne, CH-1015, Switzerland

    Alessia Perino, Johan Auwerx & Kristina Schoonjans

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R. Bouillon, G. Carmeliet, M. Watanabe, A. Perino, J. Auwerx and K. Schoonjans researched the data for the article. R. Bouillon, G. Carmeliet, L. Lieben, J. Auwerx, K. Schoonjans and A. Verstuyf provided a substantial contribution to discussions of the content, contributed equally to writing the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Roger Bouillon.

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Bouillon, R., Carmeliet, G., Lieben, L. et al. Vitamin D and energy homeostasis—of mice and men. Nat Rev Endocrinol 10, 79–87 (2014). https://doi.org/10.1038/nrendo.2013.226

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