Skip to main content
SpringerLink
Log in

Effects of resveratrol and its derivative pterostilbene on brown adipose tissue thermogenic activation and on white adipose tissue browning process

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

The main function of brown adipose tissue (BAT) is thermogenesis, a process mediated by uncoupling protein 1 (UCP1), which is located in the inner mitochondrial membrane and acts uncoupling oxidative phosphorylation from ATP production, thereby dissipating energy as heat. White adipose tissue can also express UCP1 positive cells due to a process known as browning. This phenomenon could also increase the thermogenic effect in the classical brown adipose depots. BAT thermogenesis depends, among other factors on both, nutritional conditions and food availability. Indeed, some studies have found that BAT recruitment and function are enhanced by some food components. The present study focuses on the effects of resveratrol and pterostilbene, two phenolic compounds belonging to the stilbene group, on BAT thermogenic activation and white adipose tissue browning process. The reported studies, carried out in cell cultures and animal models, show that both resveratrol and pterostilbene induce thermogenic capacity in interscapular BAT by increasing mitochondriogenesis, as well as enhancing fatty acid oxidation and glucose disposal. In addition, resveratrol seems to promote browning by activating peroxisome proliferator-activated receptor (PPAR), while the lack of changes in mitochondrial biogenesis suggests that probably the browning process occurs by direct resveratrol-mediated upregulation of ucp1 mRNA expression.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Aguirre L, Portillo MP, Hijona E, Bujanda L (2014) Effects of resveratrol and other polyphenols in hepatic steatosis. World J Gastroenterol 20:7366–7380

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Aguirre L, Milton-Laskibar I, Hijona E, Bujanda L, Rimando AM, Portillo MP (2017) Effects of pterostilbene in brown adipose tissue from obese rats. J Physiol Biochem 73:457–464

    Article  CAS  Google Scholar 

  3. Alberdi G, Rodríguez VM, Miranda J, Macarulla MT, Churruca I, Portillo MP (2013) Thermogenesis is involved in the body-fat lowering effects of resveratrol in rats. Food Chem 141:1530–1535

    Article  CAS  PubMed  Google Scholar 

  4. Andrade JMO, Frade ACM, Guimarães JB, Freitas KM, Lopes MTP, Guimarães ALS, de Paula AMB, Coimbra CC, Santos SHS (2014) Resveratrol increases brown adipose tissue thermogenesis markers by increasing SIRT1 and energy expenditure and decreasing fat accumulation in adipose tissue of mice fed a standard diet. Eur J Nutr 53:1503–1510

    Article  CAS  PubMed  Google Scholar 

  5. Andrade JMO, Barcala-Jorge AS, Batista-Jorge GC, Paraíso AF, Freitas KM, Lelis DF, Guimarães ALS, de Paula AMB, Santos SHS (2019) Effect of resveratrol on expression of genes involved thermogenesis in mice and humans. Biomed Pharmacother 112:108634

  6. Andres-Lacueva C, Macarulla MT, Rotches-Ribalta M, Boto-Ordóñez M, Urpi-Sarda M, Rodríguez VM, Portillo MP (2012) Distribution of resveratrol metabolites in liver, adipose tissue, and skeletal muscle in rats fed different doses of this polyphenol. J Agric Food Chem 60:4833–4840

    Article  CAS  PubMed  Google Scholar 

  7. Bhatt JK, Thomas S, Nanjan MJ (2012) Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr Res 32:537–541

    Article  CAS  PubMed  Google Scholar 

  8. Bode LM, Bunzel D, Huch M, Cho GS, Ruhland D, Bunzel M, Bub A, Franz CM, Kulling SE (2013) In vivo and in vitro metabolism of trans-resveratrol by human gut microbiota. Am J Clin Nutr 97:295–309

    Article  CAS  PubMed  Google Scholar 

  9. Boekelheide K, Blumberg B, Chapin RE, Cote I, Graziano JH, Janesick A, Lane R, Lillycrop K, Myatt L, States JC et al (2012) Predicting later-life outcomes of early-life exposures. Environ Health Perspect 120:1353–1361

    Article  PubMed  PubMed Central  Google Scholar 

  10. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spiegelman BM (2012) A PGC1α-dependent myokine that drives browning of white fat and thermogenesis. Nature 481:463–468

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Boyle KE, Patinkin ZW, Shapiro AL, Baker PR, Dabelea D, Friedman JE (2016) Mesenchymal stem cells from infants born to obese mothers exhibit greater potential for adipogenesis: the healthy start BabyBUMP project. Diabetes 65:647–659

    Article  CAS  PubMed  Google Scholar 

  12. Brand MD, Esteves TC (2005) Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab 2:85–93

    Article  CAS  PubMed  Google Scholar 

  13. Bray GA, Heisel WE, Afshin A, Jensen MD, Dietz WH, Long M, Kushner RF, Daniels SR, Wadden TA, Tsai AG et al (2018) The science of obesity management: an Endocrine Society Scientific Statement. Endocr Rev 239:79–132

    Article  Google Scholar 

  14. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360:1509–1517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Darby JRT, Mohd Dollah MHB, Regnault TRH, Williams MT, Morrison JL (2019) Systematic review: impact of resveratrol exposure during pregnancy on maternal and fetal outcomes in animal models of human pregnancy complications—are we ready for the clinic? Pharmacol Res 144:264–278

    Article  CAS  PubMed  Google Scholar 

  16. Del Rio D, Rodriguez-Mateos A, Spencer JP, Tognolini M, Borges G, Crozier A (2013) Dietary (poly)phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid Redox Signal 18:1818–1892

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, Smith RJ, Smith SR (2011) Obesity and type 2 diabetes: what can be unified and what needs to be individualized? J Clin Endocrinol Metab 96:1654–1663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fabbrini E, Sullivan S, Klein S (2010) Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 2010(51):679–689

    Article  CAS  Google Scholar 

  19. Gómez-Zorita S, Fernández-Quintela A, Lasa A, Aguirre L, Rimando AM, Portillo MP (2014) Pterostilbene, a dimethyl ether derivative of resveratrol, reduces fat accumulation in rats fed an obesogenic diet. J Agric Food Chem 62:8371–8378

    Article  PubMed  CAS  Google Scholar 

  20. Gómez-Zorita S, Milton-Laskíbar I, Aguirre L, Fernández-Quintela A, Xiao J, Portillo PM (2019) Effects of pterostilbene on diabetes, liver steatosis and serum lipids. Curr Med Chem. https://doi.org/10.2174/0929867326666191029112626

  21. Hill JO, Wyatt HR, Peters JC (2012) Energy balance and obesity. Circulation 126:126–132

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ikeda K, Maretich P, Kajimura S (2018) The common and distinct features of brown and beige adipocytes. Trends Endocrinol Metab 29:191–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kapetanovic IM, Muzzio M, Huang Z, Thompson TN, McCormick DL (2011) Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother Pharmacol 68:593–601

    Article  CAS  PubMed  Google Scholar 

  24. Kim SH, Després JP, Koh KK (2016) Obesity and cardiovascular disease: friend or foe? Eur Heart J 37:3560–3568

    Article  PubMed  Google Scholar 

  25. Kosuru R, Rai U, Prakash S, Singh A, Singh S (2016) Promising therapeutic potential of pterostilbene and its mechanistic insight based on preclinical evidence. Eur J Pharmacol 789:229–243

    Article  CAS  PubMed  Google Scholar 

  26. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109–1122

    Article  CAS  PubMed  Google Scholar 

  27. Langcake P, Pryce RJ (1977) A new class of phytoalexins from grapevines. Experientia 33:151–152

    Article  CAS  PubMed  Google Scholar 

  28. Lemstra M, Bird Y, Nwankow C, Rogers M, Moraros J (2016) Weight loss intervention adherence and factors promoting adherence: a meta-analysis. Patient Prefer Adherence 10:1547–1559

    Article  PubMed  PubMed Central  Google Scholar 

  29. Leung AWY, Chan RSM, Sea MMM, Woo J (2017) An overview of factors associated with adherence to lifestyle modification programs for weight management in adults. Int J Environ Res Public Health 14:E922

    Article  PubMed  Google Scholar 

  30. Liao W, Yin X, Li Q, Zhang H, Liu Z, Zheng X, Zheng L, Feng X (2018) Resveratrol-induced white adipose tissue browning in obese mice by remodeling fecal microbiota. Molecules 23:E3356

    Article  PubMed  CAS  Google Scholar 

  31. Louie SM, Roberts LS, Nomura DK (2013) Mechanisms linking obesity and cancer. Biochim Biophys Acta 1831:1499–1508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Marier JF, Vachon P, Gritsas A, Zhang J, Moreau JP, Ducharme MP (2002) Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. J Pharmacol Exp Ther 302:369–373

    Article  CAS  PubMed  Google Scholar 

  33. Marlatt KL, Chen KY, Ravussin E (2018) Is activation of human brown adipose tissue a viable target for weight management? Am J Phys Regul Integr Comp Phys 315:R479–R483

    CAS  Google Scholar 

  34. Mele L, Bidault G, Mena P, Crozier A, Brighenti F, Vidal-Puig A, Del Rio D (2017) Dietary (poly)phenols, brown adipose tissue activation, and energy expenditure: a narrative review. Adv Nutr 8:694–704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Milton-Laskibar I, Aguirre L, Etxeberria U, Milagro FI, Martínez JA, Portillo MP (2018) Do the effects of resveratrol on thermogenic and oxidative capacities in IBAT and skeletal muscle depend on feeding conditions? Nutrients 10:E1446

    Article  PubMed  CAS  Google Scholar 

  36. Mirbolooki MR, Constantinescu CC, Pan ML, Mukherjee J (2011) Quantitative assessment of brown adipose tissue metabolic activity and volume using 18F-FDG PET/CT and β3-adrenergic receptor activation. EJNMMI Res 1:30

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, Scheinin M, Taittonen M, Niemi T, Enerbäck S, Virtanen KA (2011) Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab 14:272–279

    Article  CAS  PubMed  Google Scholar 

  38. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J (2010) Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem 285:7153–7164

    Article  CAS  PubMed  Google Scholar 

  39. Poston L (2012) Maternal obesity, gestational weight gain and diet as determinants of offspring long term health. Best Pract Res Clin Endocrinol Metab 26:627–639

    Article  PubMed  Google Scholar 

  40. Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, Rosenbaum M, Zhao Y, Gu W, Farmer SR, Accili D (2012) Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. Cell 150:620–632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rangel-Huerta OD, Pastor-Villaescusa B, Gil A (2019) Are we close to defining a metabolomic signature of human obesity? A systematic review of metabolomics studies. Metabolomics 15:93

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Rotches-Ribalta M, Urpi-Sarda M, Llorach R, Boto-Ordoñez M, Jauregui O, Chiva-Blanch G, Perez-Garcia L, Jaeger W, Guillen M, Corella D, Tinahones FJ, Estruch R, Andres-Lacueva C (2012) Gut and microbial resveratrol metabolite profiling after moderate long-term consumption of red wine versus dealcoholized red wine in humans by an optimized ultra-high-pressure liquid chromatography tandem mass spectrometry method. J Chromatogr A 1265:105–113

    Article  CAS  PubMed  Google Scholar 

  43. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, Iwanaga T, Miyagawa M, Kameya T, Nakada K, Kawai Y, Tsujisaki M (2009) High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58:1526–1531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Saltiel AR (2016) New therapeutic approaches for the treatment of obesity. Sci Transl Med 8:323rv322

    Article  CAS  Google Scholar 

  45. Schrauwen P, Hardie DG, Roorda B, Clapham JC, Abuin A, Thomason-Hughes M, Green K, Frederik PM, Hesselink MK (2004) Improved glucose homeostasis in mice overexpressing human UCP3: a role for AMP-kinase? Int J Obes Relat Metab Disord 28:824–828

    Article  CAS  PubMed  Google Scholar 

  46. Serrano A, Asnani-Kishnani M, Rodríguez AM, Palou A, Ribot J, Bonet ML (2018) Programming of the beige phenotype in white adipose tissue of adult mice by mild resveratrol and nicotinamide riboside supplementations in early postnatal life. Mol Nutr Food Res 62:e1800463

  47. Srivastava S, Veech RL (2019) Brown and brite: the fat soldiers in the anti-obesity fight. Front Physiol 10:38

    Article  PubMed  PubMed Central  Google Scholar 

  48. Szkudelski T, Szkudelska K (2015) Resveratrol and diabetes: from animal to human studies. Biochim Biophys Acta 1852:1145–1154

    Article  CAS  PubMed  Google Scholar 

  49. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360:1500–1508

    Article  PubMed  Google Scholar 

  50. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerbäck S, Nuutila P (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360:1518–1525

    Article  CAS  PubMed  Google Scholar 

  51. Waldén TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J (2012) Recruited vs. nonrecruited molecular signatures of brown, “brite,” and white adipose tissues. Am J Physiol Endocrinol Metab 302:E19–E31

    Article  PubMed  CAS  Google Scholar 

  52. Walle T, Hsieh F, DeLegge MH, Oatis JE, Walle UK (2004) High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos 32:1377–1382

    Article  CAS  PubMed  Google Scholar 

  53. Walle T (2011) Bioavailability of resveratrol. Ann N Y Acad Sci 1215:9–15

    Article  CAS  PubMed  Google Scholar 

  54. Wang S, Liang X, Yang Q, Fu X, Zhu M, Rodgers BD, Jiang Q, Dodson MV, Du M (2017) Resveratrol enhances brown adipocyte formation and function by activating AMP-activated protein kinase (AMPK) α1 in mice fed high-fat diet. Mol Nutr Food Res 61:e1600746

  55. Wang P, Sang S (2018) Metabolism and pharmacokinetics of resveratrol and pterostilbene. Biofactors 44:16–25

    Article  CAS  PubMed  Google Scholar 

  56. Wenzel E, Somoza V (2005) Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res 49:472–481

    Article  CAS  PubMed  Google Scholar 

  57. Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, Nedergaard J, Cinti S (2009) The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 23:3113–3120

    Article  CAS  PubMed  Google Scholar 

  58. Zou T, Chen D, Yang Q, Wang B, Zhu MJ, Nathanielsz PW, Du M (2017) Resveratrol supplementation of high-fat diet-fed pregnant mice promotes brown and beige adipocyte development and prevents obesity in male offspring. J Physiol 595:1547–1562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zu Y, Overby H, Ren G, Fan Z, Zhao L, Wang S (2018) Resveratrol liposomes and lipid nanocarriers: comparison of characteristics and inducing browning of white adipocytes. Colloids Surf B: Biointerfaces 164:414–423

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research has been supported by MINECO (AGL-2015-65719-R), Fondo Europeo de Desarrollo Regional (FEDER), Instituto de Salud Carlos III (CIBERobn) and University of the Basque Country (GIU18-173).

Author information

Author notes

  1. I. Milton-Laskíbar and Gómez-Zorita contributed equally to this work.

Authors and Affiliations

  1. Nutrition and Obesity Group, Department of Nutrition and Food Science, Faculty of Pharmacy, Lucio Lascaray Research Institute, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006, Vitoria, Spain

    I. Milton-Laskíbar, S. Gómez-Zorita, N. Romo-Miguel, A. Fernández-Quintela & M. P. Portillo

  2. CIBERobn Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, 01006, Vitoria-Gasteiz, Spain

    I. Milton-Laskíbar, S. Gómez-Zorita, A. Fernández-Quintela & M. P. Portillo

  3. A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, Saint Louis, MO, USA

    N. Arias

  4. Nutrition and Food Science Department, Faculty of Biochemistry and Biological Sciences, National Council of Scientific and Technological Research (CONICET), National University of the Littoral, Santa Fe, Argentina

    M. González

Authors
  1. I. Milton-Laskíbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Gómez-Zorita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Arias
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N. Romo-Miguel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. González
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Fernández-Quintela
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. P. Portillo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Fernández-Quintela.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key points

• Pre-clinical evidences link resveratrol to an increased thermogenic activity.

• Pterostilbene, a resveratrol derivative, can also activate brown adipose tissue.

• Most of the studies show a preventive effect in high-fat feeding models of obesity.

• When translating these effects to humans, their metabolites must be kept in mind.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Milton-Laskíbar, I., Gómez-Zorita, S., Arias, N. et al. Effects of resveratrol and its derivative pterostilbene on brown adipose tissue thermogenic activation and on white adipose tissue browning process. J Physiol Biochem 76, 269–278 (2020). https://doi.org/10.1007/s13105-020-00735-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-020-00735-3

Keywords

Search

Navigation