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Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis

Laboratory Investigation (2018) | Download Citation

Abstract

Nonalcoholic steatohepatitis (NASH) is the form of nonalcoholic fatty liver disease that can evolve into cirrhosis. Lifestyle modifications achieving 10% weight loss reverse NASH, but there are no effective approved drug treatments. We previously identified defective adaptive thermogenesis as a factor contributing to metabolic syndrome and hepatic steatosis. We have now tested whether increasing nonshivering thermogenesis can improve preexisting NASH in mice. In high-fat diet-fed foz/foz mice with established NASH, treatment with β3AR agonist restored brown adipose tissue (BAT) function, decreased body weight, improved glucose tolerance, and reduced hepatic lipid content compared to untreated counterparts, but had no impact on liver inflammation or on nonalcoholic fatty liver disease activity score (NAS). Similarly, β3AR agonist did not alter liver pathology in other steatohepatitis models, including MCD diet-fed diabetic obese db/db mice. Caloric restriction alone alleviated the hepatic inflammatory signature in foz/foz mice. Addition of a β3AR agonist to mice subjected to caloric restriction enhanced weight loss and glucose tolerance, and improved liver steatosis, hepatocellular injury, and further reduced liver inflammation. These changes contributed to a significantly lower NAS score such as no (0/9) animals in this group fulfilled the criteria for NASH pathology compared to eight out of ten mice under caloric restriction alone. In conclusion, β3AR agonist counteracts features of the metabolic syndrome and alleviates steatosis, but does not reverse NASH. However, when coupled with weight loss therapy, BAT stimulation provides additional therapeutic advantages and reverses NASH.

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References

  1. 1.

    LaBrecque DR, Abbas Z, Anania F, et al. World Gastroenterology Organisation global guidelines: nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Clin Gastroenterol. 2014;48:467–73.

  2. 2.

    Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34:274–85.

  3. 3.

    Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005–23.

  4. 4.

    Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149:367–78.e5.

  5. 5.

    Poekes L, Lanthier N, Leclercq IA. Brown adipose tissue: a potential target in the fight against obesity and the metabolic syndrome. Clin Sci. 2015;129:933–49.

  6. 6.

    Virtanen KA, Lidell ME, Orava J, et al. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360:1518–25.

  7. 7.

    van Marken Lichtenbelt WD, Schrauwen P. Implications of nonshivering thermogenesis for energy balance regulation in humans. AJP Regul Integr Comp Physiol. 2011;301:R285–96.

  8. 8.

    Leitner BP, Huang S, Brychta RJ, Duckworth CJ, Baskin AS, McGehee S, et al. Mapping of human brown adipose tissue in lean and obese young men. Proc Natl Acad Sci. 2017;114:8649–54.

  9. 9.

    Liu X, Wang S, You Y, et al. Brown adipose tissue transplantation reverses obesity in Ob/Ob mice. Endocrinology. 2015;156:2461–9.

  10. 10.

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

  11. 11.

    Poekes L, Legry V, Schakman O, et al. Defective adaptive thermogenesis contributes to metabolic syndrome and liver steatosis in obese mice. Clin Sci. 2017;131:285–96.

  12. 12.

    Larter CZ, Yeh MM, Van Rooyen DM, et al. Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice. J Gastroenterol Hepatol. 2009;24:1658–68.

  13. 13.

    Arsov T, Silva DG, O’Bryan MK, et al. Fat aussie—a new Alström syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesis. Mol Endocrinol. 2006;20:1610–22.

  14. 14.

    Legry V, Van Rooyen DM, Lambert B, et al. Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice. Clin Sci. 2014;127:507–18.

  15. 15.

    Larter CZ, Yeh MM, Haigh WG, et al. Dietary modification dampens liver inflammation and fibrosis in obesity-related fatty liver disease. Obesity. 2013;21:1189–99.

  16. 16.

    Liu J, Xu Y, Hu Y, Wang G. The role of fibroblast growth factor 21 in the pathogenesis of nonalcoholic fatty liver disease and implications for therapy. Metabolism. 2015;64:380–90.

  17. 17.

    Wang GX, Zhao XY, Meng ZX, et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat Med. 2014;20:1436–43.

  18. 18.

    Leclercq IA, Lebrun VA, Stärkel P, Horsmans YJ. Intrahepatic insulin resistance in a murine model of steatohepatitis: effect of PPARγ agonist pioglitazone. Lab Invest. 2007;87:56–65.

  19. 19.

    Romero-Gómez M, Zelber-Sagi S, Trenell M. Treatment of NAFLD with diet, physical activity and exercise. J Hepatol. 2017;67:829–46.

  20. 20.

    Marchesini G, Mazzella N, Forlani G. Weight loss for a healthy liver. Gastroenterology. 2015;149:274–8.

  21. 21.

    Calmasini FB, de Oliveira MG, Alexandre EC. Long-term treatment with the beta-3 adrenoceptor agonist, mirabegron ameliorates detrusor overactivity and restores cyclic adenosine monophosphate (cAMP) levels in obese mice. Neurourol Urodyn. 2017;36:1511–8.

  22. 22.

    Stanford KI, Middelbeek RJ, Townsend KL, et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest. 2013;123:215–23.

  23. 23.

    Hepler C, Shao M, Xia JY, et al. Directing visceral white adipocyte precursors to a thermogenic adipocyte fate improves insulin sensitivity in obese mice. eLife. 2017;6:1–33.

  24. 24.

    Haukeland JW, Konopski Z, Eggesbø HB, et al. Metformin in patients with nonalcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol. 2009;44:853–60.

  25. 25.

    Li Y, Liu L, Wang B, et al. Metformin in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Rep. 2013;1(1):57–64.

  26. 26.

    Shields WW, Thompson KE, Grice GA, et al. The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a Pilot Trial. Ther Adv Gastroenterol. 2009;2:157–63.

  27. 27.

    Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.

  28. 28.

    Lassailly G, Caiazzo R, Buob D, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149:379–88.

  29. 29.

    Liu X, Zheng Z, Zhu X, et al. Brown adipose tissue transplantation improves whole-body energy metabolism. Cell Res. 2013;23:851–4.

  30. 30.

    Wang H, Liu L, Lin JZ, et al. Browning of white adipose tissue with roscovitine induces a distinct population of UCP1+ adipocytes. Cell Metab. 2016;24:835–47.

  31. 31.

    Bartelt A, Bruns OT, Reimer R, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17:200–6.

  32. 32.

    Ghosh PM, Shu Z-J, Zhu B, et al. Role of b-adrenergic receptors in regulation of hepatic fat accumulation during aging. J Endocrinol. 2012;213:251–61.

  33. 33.

    Cypess AM, White AP, Vernochet C, et al. Anatomical localization, gene expression profiling, and functional characterization of adult human neck brown fat. Nat Med. 2013;19:635–9.

  34. 34.

    Yilmaz Y, Ones T, Purnak T, et al. Association between the presence of brown adipose tissue and nonalcoholic fatty liver disease in adult humans. Aliment Pharmacol Ther. 2011;34:318–23.

  35. 35.

    Chondronikola M, Volpi E, Børsheim E, et al. Brown adipose tissue activation is linked to distinct dystemic dffects on lipid metabolism in humans. Cell Metab. 2016;23:1200–6.

  36. 36.

    Cypess AM, Weiner LS, Roberts-toler C, et al. Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. Cell Metab. 2016;21:33–8.

  37. 37.

    Hibi M, Oishi S, Matsushita M, et al. Brown adipose tissue is involved in diet-induced thermogenesis and whole-body fat utilization in healthy humans. Int J Obes. 2016;40:1655–61.

  38. 38.

    Matsushita M, Yoneshiro T, Aita S, et al. Impact of brown adipose tissue on body fatness and glucose metabolism in healthy humans. Int J Obes. 2014;38:812–7.

  39. 39.

    Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.

  40. 40.

    Andrew J. Whittle, Stefania Carobbio, Luís Martins, et al. BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral Actions. Cell 2012;149:871–885.

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Acknowledgments

The authors thank Natacha Feza-Bingi (UCL, Brussels, Belgium) and Mathilde Beka (UCL, Brussels, Belgium) for animal breeding, genotyping, and care; and Anne Bol (UCL, Brussels, Belgium) for PET/CT imaging. The work was financially supported by “Communauté française de Belgique – Actions de Recherche Concertées” (12/17-047) and unrestricted grants from Bristol-Myers Squibb Belgium, MSD Belgium, Gilead Belgium, Janssen Pharmaceutica Belgium, and Abbvie Belgium.

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Affiliations

  1. Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium

    • Laurence Poekes
    • , Justine Gillard
    •  & Isabelle A. Leclercq
  2. Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, ACT, Australia

    • Geoffrey C. Farrell
  3. Gastroenterology Unit, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium

    • Yves Horsmans

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Competing interests

The authors have no conflict of interest in relation to this work to disclose.

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Correspondence to Isabelle A. Leclercq.

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DOI

https://doi.org/10.1038/s41374-018-0120-x