Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Mensah, G.A. et al. Obesity, metabolic syndrome, and type 2 diabetes: emerging epidemics and their cardiovascular implications. Cardiol. Clin. 22, 485–504 (2004).

    Article  Google Scholar 

  2. 2

    Bray, G.A. & Bellanger, T. Epidemiology, trends, and morbidities of obesity and the metabolic syndrome. Endocrine 29, 109–117 (2006).

    CAS  Article  Google Scholar 

  3. 3

    Klein, S. et al. Waist circumference and cardiometabolic risk: a consensus statement from shaping America's health: Association for Weight Management and Obesity Prevention; NAASO, the Obesity Society; the American Society for Nutrition; and the American Diabetes Association. Diabetes Care 30, 1647–1652 (2007).

    Article  Google Scholar 

  4. 4

    Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Farmer, S.R. Molecular determinants of brown adipocyte formation and function. Genes Dev. 22, 1269–1275 (2008).

    CAS  Article  Google Scholar 

  6. 6

    Seale, P., Kajimura, S. & Spiegelman, B.M. Transcriptional control of brown adipocyte development and physiological function—of mice and men. Genes Dev. 23, 788–797 (2009).

    CAS  Article  Google Scholar 

  7. 7

    Cypess, A.M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).

    CAS  Article  Google Scholar 

  8. 8

    Tseng, Y.H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008).

    CAS  Article  Google Scholar 

  9. 9

    Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).

    CAS  Article  Google Scholar 

  10. 10

    Vegiopoulos, A. et al. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 328, 1158–1161 (2010).

    CAS  Article  Google Scholar 

  11. 11

    Hansen, J.B. et al. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc. Natl. Acad. Sci. USA 101, 4112–4117 (2004).

    CAS  Article  Google Scholar 

  12. 12

    Fang, S. et al. Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance. Proc. Natl. Acad. Sci. USA 108, 3412–3417 (2011).

    CAS  Article  Google Scholar 

  13. 13

    Cinti, S. Between brown and white: novel aspects of adipocyte differentiation. Ann. Med. 43, 104–115 (2011).

    Article  Google Scholar 

  14. 14

    Park, K.W., Halperin, D.S. & Tontonoz, P. Before they were fat: adipocyte progenitors. Cell Metab. 8, 454–457 (2008).

    CAS  Article  Google Scholar 

  15. 15

    Schwarz, E.J., Reginato, M.J., Shao, D., Krakow, S.L. & Lazar, M.A. Retinoic acid blocks adipogenesis by inhibiting C/EBPβ-mediated transcription. Mol. Cell. Biol. 17, 1552–1561 (1997).

    CAS  Article  Google Scholar 

  16. 16

    Ziouzenkova, O. et al. Retinaldehyde represses adipogenesis and diet-induced obesity. Nat. Med. 13, 695–702 (2007).

    CAS  Article  Google Scholar 

  17. 17

    Kane, M.A. et al. CrbpI modulates glucose homeostasis and pancreas 9-cis-retinoic acid concentrations. Mol. Cell. Biol. 31, 3277–3285 (2011).

    CAS  Article  Google Scholar 

  18. 18

    Altucci, L., Leibowitz, M.D., Ogilvie, K.M., de Lera, A.R. & Gronemeyer, H. RAR and RXR modulation in cancer and metabolic disease. Nat. Rev. Drug Discov. 6, 793–810 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Villarroya, F., Iglesias, R. & Giralt, M. Retinoids and retinoid receptors in the control of energy balance: novel pharmacological strategies in obesity and diabetes. Curr. Med. Chem. 11, 795–805 (2004).

    CAS  Article  Google Scholar 

  20. 20

    Ross, A.C. Overview of retinoid metabolism. J. Nutr. 123, 346–350 (1993).

    CAS  Article  Google Scholar 

  21. 21

    Ziouzenkova, O. & Plutzky, J. Retinoid metabolism and nuclear receptor responses: New insights into coordinated regulation of the PPAR-RXR complex. FEBS Lett. 582, 32–38 (2008).

    CAS  Article  Google Scholar 

  22. 22

    Duester, G., Mic, F.A. & Molotkov, A. Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to retinaldehyde followed by tissue-specific metabolism to retinoic acid. Chem. Biol. Interact. 143–144, 201–210 (2003).

    Article  Google Scholar 

  23. 23

    Molotkov, A. & Duester, G. Genetic evidence that retinaldehyde dehydrogenase Raldh1 (Aldh1a1) functions downstream of alcohol dehydrogenase Adh1 in metabolism of retinol to retinoic acid. J. Biol. Chem. 278, 36085–36090 (2003).

    CAS  Article  Google Scholar 

  24. 24

    Wiegand, G. & Remington, S.J. Citrate synthase: structure, control, and mechanism. Annu. Rev. Biophys. Biophys. Chem. 15, 97–117 (1986).

    CAS  Article  Google Scholar 

  25. 25

    Trounce, I.A., Kim, Y.L., Jun, A.S. & Wallace, D.C. Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines. Methods Enzymol. 264, 484–509 (1996).

    CAS  Article  Google Scholar 

  26. 26

    Tang, Q.Q., Otto, T.C. & Lane, M.D. Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc. Natl. Acad. Sci. USA 101, 9607–9611 (2004).

    CAS  Article  Google Scholar 

  27. 27

    Chute, J.P. et al. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc. Natl. Acad. Sci. USA 103, 11707–11712 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Johnson, A.T., Wang, L., Gillett, S.J. & Chandraratna, R.A. High affinity retinoic acid receptor antagonists: analogs of AGN 193109. Bioorg. Med. Chem. Lett. 9, 573–576 (1999).

    CAS  Article  Google Scholar 

  29. 29

    Takahashi, B. et al. Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimer actions. J. Med. Chem. 45, 3327–3330 (2002).

    CAS  Article  Google Scholar 

  30. 30

    Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998).

    CAS  Article  Google Scholar 

  31. 31

    Alvarez, R. et al. A novel regulatory pathway of brown fat thermogenesis. Retinoic acid is a transcriptional activator of the mitochondrial uncoupling protein gene. J. Biol. Chem. 270, 5666–5673 (1995).

    CAS  Article  Google Scholar 

  32. 32

    Cypess, A.M. & Kahn, C.R. Brown fat as a therapy for obesity and diabetes. Curr. Opin. Endocrinol. Diabetes Obes. 17, 143–149 (2010).

    CAS  Article  Google Scholar 

  33. 33

    Langin, D. Recruitment of brown fat and conversion of white into brown adipocytes: strategies to fight the metabolic complications of obesity? Biochim. Biophys. Acta 1801, 372–376 (2010).

    CAS  Article  Google Scholar 

  34. 34

    Guerra, C., Koza, R.A., Yamashita, H., Walsh, K. & Kozak, L.P. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J. Clin. Invest. 102, 412–420 (1998).

    CAS  Article  Google Scholar 

  35. 35

    Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).

    CAS  Article  Google Scholar 

  36. 36

    Silva, J.E. & Rabelo, R. Regulation of the uncoupling protein gene expression. Eur. J. Endocrinol. 136, 251–264 (1997).

    CAS  Article  Google Scholar 

  37. 37

    Repa, J.J., Hanson, K.K. & Clagett-Dame, M. All-trans-retinol is a ligand for the retinoic acid receptors. Proc. Natl. Acad. Sci. USA 90, 7293–7297 (1993).

    CAS  Article  Google Scholar 

  38. 38

    Schug, T.T., Berry, D.C., Shaw, N.S., Travis, S.N. & Noy, N. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 129, 723–733 (2007).

    CAS  Article  Google Scholar 

  39. 39

    Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Yang, Q. et al. Nature 436, 356–362 (2005).

    CAS  Article  Google Scholar 

  40. 40

    Crooke, S.T. Progress in antisense technology. Annu. Rev. Med. 55, 61–95 (2004).

    CAS  Article  Google Scholar 

  41. 41

    Baker, B.F. et al. 2′-O-(2-methoxy)ethyl-modified anti-intercellular adhesion molecule 1 (ICAM-1) oligonucleotides selectively increase the ICAM-1 mRNA level and inhibit formation of the ICAM-1 translation initiation complex in human umbilical vein endothelial cells. J. Biol. Chem. 272, 11994–12000 (1997).

    CAS  Article  Google Scholar 

  42. 42

    Wernstedt, I. et al. Reduced stress- and cold-induced increase in energy expenditure in interleukin-6-deficient mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R551–R557 (2006).

    CAS  Article  Google Scholar 

  43. 43

    Hodges, M.R. et al. Defects in breathing and thermoregulation in mice with near-complete absence of central serotonin neurons. J. Neurosci. 28, 2495–2505 (2008).

    CAS  Article  Google Scholar 

  44. 44

    Kennedy, A.R. et al. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am. J. Physiol. Endocrinol. Metab. 292, E1724–E1739 (2007).

    CAS  Article  Google Scholar 

  45. 45

    Xu, J. Preparation, culture and immortalization of mouse embryonic fibroblasts. Curr. Protoc. Mol. Biol. 70, 28.1.1–28.1.8 (2005).

    Google Scholar 

  46. 46

    Brown, J.D., Oligino, E., Rader, D.J., Saghatelian, A. & Plutzky, J. VLDL hydrolysis by hepatic lipase regulates PPARδ transcriptional responses. PLoS ONE 6, e21209 (2011).

    CAS  Article  Google Scholar 

  47. 47

    Yehuda-Shnaidman, E., Buehrer, B., Pi, J., Kumar, N. & Collins, S. Acute stimulation of white adipocyte respiration by PKA-induced lipolysis. Diabetes 59, 2474–2483 (2010).

    CAS  Article  Google Scholar 

  48. 48

    Wu, M. et al. Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. Am. J. Physiol. Cell Physiol. 292, C125–C136 (2007).

    CAS  Article  Google Scholar 

Download references

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.).

Author information

Affiliations

Authors

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.

Corresponding author

Correspondence to Jorge Plutzky.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 (PDF 3136 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing