Animal Models

Resveratrol enhances brown adipose tissue activity and white adipose tissue browning in part by regulating bile acid metabolism via gut microbiota remodeling

Abstract

Objective

Current evidence has linked dietary resveratrol (RSV) intake to the activation of brown adipose tissue (BAT) and induction of white adipose tissue (WAT) browning, which may be a potential means of improving glucose homeostasis. However, the underlying mechanisms remain unclear.

Methods

A diet containing RSV was fed to db/db mice for 10 weeks, following which the body weight, adipose tissue accumulation, bile acid (BA) profiles, and markers of BA metabolism were analyzed. Oral glucose tolerance testing, immunohistochemistry, and gut microbiota sequencing were also performed.

Results

RSV intervention improved glucose homeostasis in db/db mice, which was linked to the enhanced BAT activity and WAT browning. Moreover, RSV-treated mice exhibited altered plasma and fecal BA compositions and significant remodeling of the gut microbiota, the latter confirmed by a higher level of lithocholic acid (LCA) in the plasma and feces. LCA was identified to be the agonist of Takeda G-protein coupled receptor 5 (TGR5), which mediated the BAT activation and WAT browning by upregulating uncoupling protein 1 (UCP1) expression. Furthermore, depletion of the gut microbiota using antibiotics partially abolished the beneficial effects of RSV against glucose intolerance. Finally, microbiota transplantation experiments demonstrated that the RSV-induced beneficial effects were transferable, indicating that these effects were largely dependent on the gut microbiota.

Conclusions

These data indicate that RSV administration improves glucose homeostasis by enhancing BAT activation and WAT browning, a mechanism that might partially be mediated by the gut microbiota-BA-TGR5/UCP1 pathway.

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Fig. 1: RSV improves glucose homeostasis partially through enhancing the activation of BAT and the induction of WAT browning.
Fig. 2: RSV administration prevents obesity-driven dysbiosis.
Fig. 3: RSV treatment regulates bile acid metabolism.
Fig. 4: Gut microbiota contributes to the beneficial effects of RSV on BAT and IngWAT.
Fig. 5: Gut microbiota contributes to the beneficial effects of RSV on BAT and IngWAT.
Fig. 6: Illustration of the effect of RSV on glucose homeostasis mediated through the gut microbiota-bile acid-TGR5/UCP1 signaling pathway.

References

  1. 1.

    Hill JO, Wyatt HR, Peters JC. Energy balance and obesity. Circulation. 2012;126:126–32.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world–a growing challenge. New Engl J Med. 2007;356:213–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell. 2001;104:531–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Global regional and national age-sex specific mortality for 264 causes of death. 1980-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1151–210.

    Article  Google Scholar 

  5. 5.

    Li G, Xie C, Lu S, Nichols RG, Tian Y, Li L, et al. Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab. 2017;26:801.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Chevalier C, Stojanovic O, Colin DJ, Suarez-Zamorano N, Tarallo V, Veyrat-Durebex C, et al. Gut microbiota orchestrates energy homeostasis during cold. Cell. 2015;163:1360–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Bartelt A, Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol. 2014;10:24–36.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Sayin SI, Wahlstrom A, Felin J, Jantti S, Marschall HU, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab. 2013;17:225–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Jones ML, Tomaro-Duchesneau C, Prakash S. The gut microbiome, probiotics, bile acids axis, and human health. Trends Microbiol. 2014;22:306–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Fiorucci S, Distrutti E. Bile acid-activated receptors, intestinal microbiota, and the treatment of metabolic disorders. Trends Mol Med. 2015;21:702–14.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Hesselink MK, Mensink M, Schrauwen P. Human uncoupling protein-3 and obesity: an update. Obes Res. 2003;11:1429–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439:484–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Prawitt J, Caron S, Staels B. Bile acid metabolism and the pathogenesis of type 2 diabetes. Curr Diabetes Rep. 2011;11:160–6.

    CAS  Article  Google Scholar 

  15. 15.

    Chen M, Hou P, Zhou M, Ren Q, Wang X, Huang L, et al. Resveratrol attenuates high-fat diet-induced non-alcoholic steatohepatitis by maintaining gut barrier integrity and inhibiting gut inflammation through regulation of the endocannabinoid system. Clin Nutr. 2019; S0261–5614(19)30231–6. https://doi.org/10.1016/j.clnu.2019.05.020. [Epub ahead of print].

  16. 16.

    Andrade JM, Frade AC, Guimaraes JB, Freitas KM, Lopes MT, Guimaraes AL, et al. 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. 2014;53:1503–10.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Alberdi G, Rodriguez VM, Miranda J, Macarulla MT, Churruca I, Portillo MP. Thermogenesis is involved in the body-fat lowering effects of resveratrol in rats. Food Chem. 2013;141:1530–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Chen ML, Yi L, Zhang Y, Zhou X, Ran L, Yang J, et al. Resveratrol attenuates Trimethylamine-N-Oxide (TMAO)-induced atherosclerosis by regulating TMAO synthesis and bile acid metabolism via remodeling of the gut microbiota. mBio. 2016;7:e02210–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Anhe FF, Roy D, Pilon G, Dudonne S, Matamoros S, Varin TV, et al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut. 2015;64:872–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Zietak M, Kovatcheva-Datchary P, Markiewicz LH, Stahlman M, Kozak LP, Backhed F. Altered microbiota contributes to reduced diet-induced obesity upon cold exposure. Cell Metab. 2016;23:1216–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Worthmann A, John C, Ruhlemann MC. Cold-induced conversion of cholesterol to bile acids in mice shapes the gut microbiome and promotes adaptive thermogenesis. Nat Med. 2017;23:839–49.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Hui S, Liu Y, Chen M. Capsaicin improves glucose tolerance and insulin sensitivity through modulation of the gut microbiota-bile acid-FXR axis in type 2 diabetic db/db mice. Mol Nutr Food Res. 2019;63:e1900608. https://doi.org/10.1002/mnfr.201900608. Epub 2019 Sep 25.

    Article  CAS  Google Scholar 

  23. 23.

    Huang Y, Zhu X, Chen K, Lang H, Zhang Y, Hou P, et al. Resveratrol prevents sarcopenic obesity by reversing mitochondrial dysfunction and oxidative stress via the PKA/LKB1/AMPK pathway. Aging. 2019;11:2217–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–42.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006;127:1109–22.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med. 2018;24:1919–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Zeng X, Yang J, Hu O, Huang J, Ran L, Chen M, et al. Dihydromyricetin ameliorates nonalcoholic fatty liver disease by improving mitochondrial respiratory capacity and redox homeostasis through modulation of SIRT3 signaling. Antioxid Redox Signal. 2018.

  28. 28.

    Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7:335–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB, et al. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol. 2009;75:7537–41.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Parks DH, Beiko RG. Identifying biologically relevant differences between metagenomic communities. Bioinformatics. 2010;26:715–21.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Langille MG, Zaneveld J, Caporaso JG, McDonald D, Knights D, Reyes JA, et al. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol. 2013;31:814–21.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Xie G, Wang X, Huang F, Zhao A, Chen W, Yan J, et al. Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis. Int J Cancer. 2016;139:1764–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Xie G, Wang Y, Wang X, Zhao A, Chen T, Ni Y, et al. Profiling of serum bile acids in a healthy Chinese population using UPLC-MS/MS. J Proteome Res. 2015;14:850–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Lan K, Su M, Xie G, Ferslew BC, Brouwer KL, Rajani C, et al. Key role for the 12-hydroxy group in the negative ion fragmentation of unconjugated C24 bile acids. Anal Chem. 2016;88:7041–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Zhang Z, Zhang H, Li B, Meng X, Wang J, Zhang Y, et al. Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun. 2014;5:5493.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Peirce V, Vidal-Puig A.Regulation of glucose homoeostasis by brown adipose tissue.Lancet Diabetes Endocrinol. 2013;1:353–60.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Dutchak PA, Katafuchi T, Bookout AL, Choi JH, Yu RT, Mangelsdorf DJ, et al. Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones. Cell. 2012;148:556–67.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab. 2007;5:415–25.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Veniant MM, Sivits G, Helmering J, Komorowski R, Lee J, Fan W, et al. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab. 2015;21:731–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Ullmer C, Alvarez Sanchez R, Sprecher U, Raab S, Mattei P, Dehmlow H, et al. Systemic bile acid sensing by G protein-coupled bile acid receptor 1 (GPBAR1) promotes PYY and GLP-1 release. Br J Pharmacol. 2013;169:671–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Wahlstrom A, Sayin SI, Marschall HU, Backhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24:41–50.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  42. 42.

    Liao W, Yin X, Li Q, Zhang H, Liu Z, Zheng X, et al. Resveratrol-induced white adipose tissue browning in obese mice by remodeling fecal microbiota. Molecules. 2018;23: E3356. https://doi.org/10.3390/molecules23123356.

    PubMed Central  Article  CAS  Google Scholar 

  43. 43.

    Yuan X, Wei G, You Y, Huang Y, Lee HJ, Dong M, et al. Rutin ameliorates obesity through brown fat activation. FASEB J. 2017;31:333–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Bartelt A, Heeren J. The holy grail of metabolic disease: brown adipose tissue. Curr Opin Lipidol. 2012;23:190–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19:1252–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Dulloo AG, Miller DS. Energy balance following sympathetic denervation of brown adipose tissue. Canad J Physiol Pharmacol. 1984;62:235–40.

    CAS  Article  Google Scholar 

  47. 47.

    Anhe FF, Nachbar RT, Varin TV, Trottier J, Dudonne S, Le Barz M, et al. Treatment with camu camu (Myrciaria dubia) prevents obesity by altering the gut microbiota and increasing energy expenditure in diet-induced obese mice. Gut. 2018.

  48. 48.

    Fang S, Suh JM, Reilly SM, Yu E, Osborn O, Lackey D, et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med. 2015;21:159–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Prawitt J, Abdelkarim M, Stroeve JH, Popescu I, Duez H, Velagapudi VR, et al. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes. 2011;60:1861–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Watanabe M, Horai Y, Houten SM, Morimoto K, Sugizaki T, Arita E, et al. Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure. J Biol Chem. 2011;286:26913–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Ridlon JM, Kang DJ, Hylemon PB. Bile salt biotransformations by human intestinal bacteria. J Lipid Res. 2006;47:241–59.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Bianco AC, Sheng XY, Silva JE. Triiodothyronine amplifies norepinephrine stimulation of uncoupling protein gene transcription by a mechanism not requiring protein synthesis. J Biol Chem. 1988;263:18168–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Pathak P, Xie C, Nichols RG, Ferrell JM, Boehme S, Krausz KW, et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology. 2018;68:1574–88.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

The authors thank Changjun Zhao for assistance with animal tissue sample collection. This research was supported by project 81470562 of the National Natural Science Foundation of China (NSFC). The sequences reported in this paper have been deposited in the NCBI database (accession number PRJNA554960).

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SH and LY, MM designed the experiments; SH, YL, LH, LZ, MZ, HL and XW performed the experiments; SH, YL, LH and XW analyzed the data; SH, LY, XW, LY and MM prepared the paper and had primary responsibility for final content. All authors read and approved the final paper.

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Correspondence to Long Yi or Mantian Mi.

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Hui, S., Liu, Y., Huang, L. et al. Resveratrol enhances brown adipose tissue activity and white adipose tissue browning in part by regulating bile acid metabolism via gut microbiota remodeling. Int J Obes (2020). https://doi.org/10.1038/s41366-020-0566-y

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