Download PDF
Horm Metab Res 2020; 52(12): 869-876
DOI: 10.1055/a-1301-2378
Endocrine Research

The Role of Brown Adipose Tissue in the Development and Treatment of Nonalcoholic Steatohepatitis: An Exploratory Gene Expression Study in Mice

Toon J.I. De Munck‡
1   Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
2   School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
,
Pan Xu‡
1   Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
2   School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
,
Brechtje L.J. Vanderfeesten
1   Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
,
Montserrat Elizalde
2   School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
,
Ad A.M. Masclee
1   Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
2   School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
,
Frederik Nevens
3   Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
,
David Cassiman
3   Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
,
Frank G. Schaap
2   School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
4   Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
5   Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, Aachen, Germany
,
Daisy M.A.E. Jonkers
1   Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands
2   School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, The Netherlands
,
Jef Verbeek
3   Department of Gastroenterology and Hepatology, University Hospitals KU Leuven, Leuven, Belgium
› Author Affiliations Funding Information This research was funded by a seeding grant of the School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, The Netherlands.
› Further Information
Also available at
    Permissions and Reprints

Abstract

Brown adipose tissue (BAT) might be a beneficial mediator in the development and treatment of nonalcoholic steatohepatitis (NASH). We aim to evaluate the gene expression of BAT activity-related genes during the development and the dietary and surgical treatment of NASH. BAT was collected from male C57BL/6J mice that received a high fat-high sucrose diet (HF-HSD) or a normal chow diet (NCD) for 4 and 20 weeks (n=8–9 per dietary group and timepoint) and from mice that underwent dietary intervention (return to NCD) (n=8), roux-en-y gastric bypass (RYGB) (n=6), or sham procedure (n=6) after 12 weeks HF-HSD. Expression of BAT genes involved in lipid metabolism (Cd36 and Cpt1b; p<0.05) and energy expenditure (Ucp1 and Ucp3; p<0.05) were significantly increased after 4 weeks HF-HSD compared with NCD, whereas in the occurrence of NASH after 20 weeks HF-HSD no difference was observed. We observed no differences in gene expression regarding lipid metabolism or energy expenditure at 8 weeks after dietary intervention (no NASH) compared with HF-HSD mice (NASH), nor in mice that underwent RYGB compared with SHAM. However, dietary intervention and RYGB both decreased the BAT gene expression of inflammatory cytokines (Il1b, Tnf-α and MCP-1; p<0.05). Gene expression of the batokine neuregulin 4 was significantly decreased after 20 weeks HF-HSD (p<0.05) compared with NCD, but was restored by dietary intervention and RYGB (p<0.05). In conclusion, BAT is hallmarked by dynamic alterations in the gene expression profile during the development of NASH and can be modulated by dietary intervention and bariatric surgery.

Key words

nonalcoholic fatty liver disease, NAFLD, Nrg4, Ucp1, obesity

Supplementary Material



Publication History

Received: 14 April 2020

Accepted after revision: 21 October 2020

Article published online:
01 December 2020

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Younossi ZM, Koenig AB, Abdelatif D. et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64: 73-84
    CrossrefPubMedSearch in Google Scholar
  • 2 Lonardo A, Nascimbeni F, Mantovani A. et al. Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence?. Journal of Hepatology 2018; 68: 335-352
    CrossrefPubMedSearch in Google Scholar
  • 3 Calzadilla Bertot L, Adams LA. The natural course of non-alcoholic fatty liver disease. Int J Mol Sci 2016; 17: 774
    CrossrefPubMedSearch in Google Scholar
  • 4 Wong RJ, Aguilar M, Cheung R. et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015; 148: 547-555
    CrossrefPubMedSearch in Google Scholar
  • 5 Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol 2018; 53: 362-376
    CrossrefPubMedSearch in Google Scholar
  • 6 Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol 2015; 62: S47-S64
    CrossrefPubMedSearch in Google Scholar
  • 7 Scheja L, Heeren J. Metabolic interplay between white, beige, brown adipocytes and the liver. J Hepatol 2016; 64: 1176-1186
    CrossrefPubMedSearch in Google Scholar
  • 8 Busiello RA, Savarese S, Lombardi A. Mitochondrial uncoupling proteins and energy metabolism. Front Physiol 2015; 6: 36
    CrossrefPubMedSearch in Google Scholar
  • 9 Tutunchi H, Ostadrahimi A, Hosseinzadeh-Attar M-J. et al. A systematic review of the association of neuregulin 4, a brown fat–enriched secreted factor, with obesity and related metabolic disturbances. Obes Rev 2020; 21: e12952
    CrossrefPubMedSearch in Google Scholar
  • 10 Liu J, Xu Y, Hu Y. et al. The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy. Metabolism 2015; 64: 380-390
    CrossrefPubMedSearch in Google Scholar
  • 11 Poekes L, Gillard J, Farrell GC. et al. Activation of brown adipose tissue enhances the efficacy of caloric restriction for treatment of nonalcoholic steatohepatitis. Lab Invest 2019; 99: 4-16
    CrossrefPubMedSearch in Google Scholar
  • 12 van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM. et al. Cold-activated brown adipose tissue in healthy men. N Eng J Med 2009; 360: 1500-1508
    CrossrefPubMedSearch in Google Scholar
  • 13 Cypess AM, Lehman S, Williams G. et al. Identification and Importance of Brown Adipose Tissue in Adult Humans. N Eng J Med 2009; 360: 1509-1517
    CrossrefPubMedSearch in Google Scholar
  • 14 Yilmaz Y, Ones T, Purnak T. et al. Association between the presence of brown adipose tissue and non-alcoholic fatty liver disease in adult humans. Aliment Pharmacol Ther 2011; 34: 318-323
    CrossrefPubMedSearch in Google Scholar
  • 15 Baskin AS, Linderman JD, Brychta RJ. et al. Regulation of human adipose tissue activation, gallbladder size, and bile acid metabolism by a beta3-adrenergic receptor agonist. Diabetes 2018; 67: 2113-2125
    CrossrefPubMedSearch in Google Scholar
  • 16 Verbeek J, Jacobs A, Spincemaille P. et al. Development of a representative mouse model with nonalcoholic steatohepatitis. Curr Protoc Mouse. Biol 2016; 6: 201-210
    PubMedSearch in Google Scholar
  • 17 Verbeek J, Lannoo M, Pirinen E. et al. Roux-en-y gastric bypass attenuates hepatic mitochondrial dysfunction in mice with non-alcoholic steatohepatitis. Gut 2015; 64: 673-683
    CrossrefPubMedSearch in Google Scholar
  • 18 Verbeek J, Spincemaille P, Vanhorebeek I. et al. Dietary intervention, but not losartan, completely reverses non-alcoholic steatohepatitis in obese and insulin resistant mice. Lipids Health Dis 2017; 16: 46
    CrossrefPubMedSearch in Google Scholar
  • 19 Bartelt A, Bruns OT, Reimer R. et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med 2011; 17: 200
    CrossrefPubMedSearch in Google Scholar
  • 20 Townsend KL, Tseng Y-H. Brown Fat Fuel Utilization and Thermogenesis. Trends Endocrinol Metab 2014; 25: 168-177
    CrossrefPubMedSearch in Google Scholar
  • 21 Arrojo EDR, Fonseca TL, Werneck-de-Castro JP. et al. Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. Biochim Biophys Acta 2013; 1830: 3956-3964
    CrossrefPubMedSearch in Google Scholar
  • 22 Gill JA, La Merrill MA. An emerging role for epigenetic regulation of Pgc-1α-expression in environmentally stimulated brown adipose thermogenesis. Environ Epigenet 2017; 3: dvx009
    PubMedSearch in Google Scholar
  • 23 Hu J, Zhou H, Smyth A. et al. Polymorphism of the bovine ADRB3 gene. Mol Biol Rep 2010; 37: 3389-3392
    CrossrefPubMedSearch in Google Scholar
  • 24 Chan MY, Zhao Y, Heng CK. Sequential responses to high-fat and high-calorie feeding in an obese mouse model. Obesity (Silver Spring) 2008; 16: 972-978
    CrossrefPubMedSearch in Google Scholar
  • 25 Ohtomo T, Ino K, Miyashita R. et al. Chronic high-fat feeding impairs adaptive induction of mitochondrial fatty acid combustion-associated proteins in brown adipose tissue of mice. Biochem Biophys Rep 2017; 10: 32-38
    PubMedSearch in Google Scholar
  • 26 Poekes L, Legry V, Schakman O. et al. Defective adaptive thermogenesis contributes to metabolic syndrome and liver steatosis in obese mice. Clin Sci (Lond) 2017; 131: 285-296
    CrossrefPubMedSearch in Google Scholar
  • 27 Fujita M, Momose A, Ohtomo T. et al. Upregulation of fatty acyl-CoA thioesterases in the heart and skeletal muscle of rats fed a high-fat diet. Biol Pharm Bull 2011; 34: 87-91
    CrossrefPubMedSearch in Google Scholar
  • 28 Mosca A, Nobili V, De Vito R. et al. Serum uric acid concentrations and fructose consumption are independently associated with NASH in children and adolescents. J Hepatol 2017; 66: 1031-1036
    CrossrefPubMedSearch in Google Scholar
  • 29 Roberts-Toler C, O'Neill BT, Cypess AM. Diet-induced obesity causes insulin resistance in mouse brown adipose tissue. Obesity (Silver Spring, Md) 2015; 23: 1765-1770
    CrossrefPubMedSearch in Google Scholar
  • 30 Dinh CHL, Szabo A, Yu Y. et al. Bardoxolone methyl prevents fat deposition and inflammation in brown adipose tissue and enhances sympathetic activity in mice fed a high-fat diet. Nutrients 2015; 7: 4705-4723
    CrossrefPubMedSearch in Google Scholar
  • 31 Koves TR, Ussher JR, Noland RC. et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 2008; 7: 45-56
    CrossrefPubMedSearch in Google Scholar
  • 32 Nøhr MK, Bobba N, Richelsen B. et al. Inflammation Downregulates UCP1 Expression in Brown Adipocytes Potentially via SIRT1 and DBC1 Interaction. Int J Mol Sci 2017; 18: 1006
    CrossrefPubMedSearch in Google Scholar
  • 33 Faria SL, Faria OP, Buffington C. et al. Energy expenditure before and after Roux-en-Y gastric bypass. Obes Surg 2012; 22: 1450-1455
    CrossrefPubMedSearch in Google Scholar
  • 34 GHEJ Vijgen, Bouvy ND, GJJ Teule. et al. Increase in Brown Adipose Tissue Activity after Weight Loss in Morbidly Obese Subjects. J Clin Endocrinol Metab 2012; 97: E1229-E1233
    CrossrefPubMedSearch in Google Scholar
  • 35 Hankir M, Bueter M, Gsell W. et al. Increased energy expenditure in gastric bypass rats is not caused by activated brown adipose tissue. Obes Facts 2012; 5: 349-358
    CrossrefPubMedSearch in Google Scholar
  • 36 Chen Y, Yang J, Nie X. et al. Effects of Bariatric Surgery on Change of Brown Adipocyte Tissue and Energy Metabolism in Obese Mice. Obes Surg 2018; 28: 820-830
    CrossrefPubMedSearch in Google Scholar
  • 37 Abegg K, Corteville C, Bueter M. et al. Alterations in energy expenditure in Roux-en-Y gastric bypass rats persist at thermoneutrality. Int J Obes 2016; 40: 1215
    CrossrefPubMedSearch in Google Scholar
  • 38 Chartoumpekis DV, Habeos IG, Ziros PG. et al. Brown adipose tissue responds to cold and adrenergic stimulation by induction of FGF21. Mol Med 2011; 17: 736-740
    CrossrefPubMedSearch in Google Scholar
  • 39 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: 1436-1443
    CrossrefPubMedSearch in Google Scholar
  • 40 Guo L, Zhang P, Chen Z. et al. Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J Clin Invest 2017; 127: 4449-4461
    CrossrefPubMedSearch in Google Scholar
  • 41 Chen Z, Wang G-X, Ma SL. et al. Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders. Mol Metab 2017; 6: 863-872
    CrossrefPubMedSearch in Google Scholar
  • 42 Rao SR. Inflammatory markers and bariatric surgery: A meta-analysis. Inflamm Res 2012; 61: 789-807
    CrossrefPubMedSearch in Google Scholar
  • 43 Christiansen T, Paulsen SK, Bruun JM. et al. Exercise training versus diet-induced weight-loss on metabolic risk factors and inflammatory markers in obese subjects: a 12-week randomized intervention study. Am J Physiol Endocrinol Metab 2010; 298: E824-E831
    CrossrefPubMedSearch in Google Scholar