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Adipocyte and Cell Biology

Depot-specific UCP1 expression in human white adipose tissue and its association with obesity-related markers

International Journal of Obesity volume 44, pages 697–706 (2020)Cite this article

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Abstract

Background

This study investigated depot-specific mRNA expression of uncoupling protein 1 (UCP1) in human white adipose tissue (WAT) and its association with obesity-related markers.

Methods

We recruited 39 normal-weight, 41 nondiabetic obese, and 22 diabetic obese women. We measured UCP1 mRNA expression in abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), and investigated the associations between UCP1 mRNA expression in VAT and SAT, and obesity-related markers including mRNA expression of leptin, adiponectin, CCAAT-enhancer-binding protein homologous protein (CHOP), and positive regulatory domain-containing protein 16 (PRDM16). We also evaluated UCP1 mRNA expression in differentiated human white adipocytes after treatment with various stressors and metabolic improvement agents in vitro.

Results

UCP1 mRNA in VAT was significantly higher than in SAT in all groups. UCP1 mRNA in SAT was negatively correlated with BMI, total abdominal fat area, visceral fat area, blood pressure, fasting glucose, insulin, HOMA-IR score, triglyceride, hsCRP, fasting leptin levels, and adipocyte size. UCP1 mRNA in SAT was positively correlated with fasting adiponectin levels. UCP1 mRNA in VAT was negatively correlated with visceral-to-subcutaneous fat ratio (VSR), fasting glucose, and triglyceride levels. In SAT, UCP1 mRNA was negatively correlated with mRNA expression of leptin and CHOP, and positively correlated with mRNA expression of adiponectin. The expression of PRDM16 was positively correlated with UCP1 mRNA in both VAT and SAT. UCP1 mRNA expression in differentiated human white adipocytes was significantly reduced after incubation with thapsigargin, tunicamycin, homocysteine, TNF-α, or IL-β, and significantly increased after incubation with exendin 4, dapagliflozin, and telmisartan.

Conclusions

This study demonstrated depot-specific mRNA expression of UCP1 and its association with obesity-related markers in human WAT. UCP1 mRNA in human white adipocytes was suppressed by inflammatory agents and enhanced by metabolic improvement agents. UCP1 in human WAT might participate in the pathogenesis of obesity-related metabolic diseases.

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Fig. 1: UCP1 mRNA expression in the visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of normal-weight control (n = 39), nondiabetic obese (n = 41), and diabetic obese groups (n = 22).
Fig. 2: Correlation of UCP1 mRNA expression in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) with mRNA expression of insulin sensitivity markers (leptin and adiponectin), ER stress markers (CHOP; CCAAT-enhancer-binding protein homologous protein), and beiging-related markers (PRDM16; positive regulatory domain-containing protein 16) in VAT and SAT (n = 102).
Fig. 3: Changes in UCP1 mRNA expression in human differentiated adipocytes in response to ER stress inducer or proinflammatory cytokine treatment.
Fig. 4: Induction of UCP1 mRNA expression by exendin 4, dapagliflozin, and telmisartan in differentiated human adipocytes.

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References

  1. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009;360:1509–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007;293:E444–52.

    CAS  PubMed  Google Scholar 

  3. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360:1518–25.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Himms-Hagen J, Melnyk A, Zingaretti MC, Ceresi E, Barbatelli G, Cinti S. Multilocular fat cells in WAT of CL-316243-treated rats derive directly from white adipocytes. Am J Physiol Cell Physiol. 2000;279:C670–81.

    CAS  PubMed  Google Scholar 

  6. Lo KA, Sun L. Turning WAT into BAT: a review on regulators controlling the browning of white adipocytes. Biosci Rep. 2013;33:e00065.

  7. Cao L, Choi EY, Liu X, Martin A, Wang C, Xu X, et al. White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis. Cell Metab. 2011;14:324–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Shabalina IG, Petrovic N, de Jong JM, Kalinovich AV, Cannon B, Nedergaard J. UCP1 in brite/beige adipose tissue mitochondria is functionally thermogenic. Cell Rep. 2013;5:1196–203.

    CAS  PubMed  Google Scholar 

  9. Poher AL, Altirriba J, Veyrat-Durebex C, Rohner-Jeanrenaud F. Brown adipose tissue activity as a target for the treatment of obesity/insulin resistance. Front Physiol. 2015;6:4.

    PubMed  PubMed Central  Google Scholar 

  10. Sidossis L, Kajimura S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J Clin Investig. 2015;125:478–86.

    PubMed  Google Scholar 

  11. Enerback S. Adipose tissue plasticity and new therapeutic targets. Nat Rev Endocrinol. 2013;9:69–70.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Lee P, Greenfield JR. Non-pharmacological and pharmacological strategies of brown adipose tissue recruitment in humans. Mol Cell Endocrinol. 2015;418:184–90.

    CAS  PubMed  Google Scholar 

  14. Poher AL, Veyrat-Durebex C, Altirriba J, Montet X, Colin DJ, Caillon A, et al. Ectopic UCP1 overexpression in white adipose tissue improves insulin sensitivity in Lou/C rats, a model of obesity resistance. Diabetes. 2015;64:3700–12.

    CAS  PubMed  Google Scholar 

  15. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Investig. 2011;121:96–105.

    CAS  PubMed  Google Scholar 

  16. Li X, Liu J, Wang G, Yu J, Sheng Y, Wang C, et al. Determination of UCP1 expression in subcutaneous and perirenal adipose tissues of patients with hypertension. Endocrine. 2015;50:413–23.

    CAS  PubMed  Google Scholar 

  17. Chechi K, Voisine P, Mathieu P, Laplante M, Bonnet S, Picard F, et al. Functional characterization of the Ucp1-associated oxidative phenotype of human epicardial adipose tissue. Sci Rep. 2017;7:15566.

    PubMed  PubMed Central  Google Scholar 

  18. Lee JH, Kim JM, Choi MJ, Kang YE, Joung KH, Yi HS, et al. Clinical implications of UCP1 mRNA expression in human cervical adipose tissue under physiological conditions. Obesity. 2018;26:1008–16.

    CAS  PubMed  Google Scholar 

  19. Jensen MD. Role of body fat distribution and the metabolic complications of obesity. J Clin Endocrinol Metab. 2008;93:S57–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kaess BM, Pedley A, Massaro JM, Murabito J, Hoffmann U, Fox CS. The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk. Diabetologia. 2012;55:2622–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang C, Rexrode KM, van Dam RM, Li TY, Hu FB. Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality: sixteen years of follow-up in US women. Circulation. 2008;117:1658–67.

    PubMed  Google Scholar 

  22. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. Diabetes Care. 2018;41 Suppl 1:S13–27.

    Google Scholar 

  23. Chang EJ, Lee SK, Song YS, Jang YJ, Park HS, Hong JP, et al. IL-34 is associated with obesity, chronic inflammation, and insulin resistance. J Clin Endocrinol Metab. 2014;99:E1263–71.

    CAS  PubMed  Google Scholar 

  24. Kim J, Lee SK, Jang YJ, Park HS, Kim JH, Hong JP, et al. Enhanced ANGPTL2 expression in adipose tissues and its association with insulin resistance in obese women. Sci Rep. 2018;8:13976.

    PubMed  PubMed Central  Google Scholar 

  25. Dubois SG, Floyd EZ, Zvonic S, Kilroy G, Wu X, Carling S, et al. Isolation of human adipose-derived stem cells from biopsies and liposuction specimens. Methods Mol Biol. 2008;449:69–79.

    PubMed  Google Scholar 

  26. Zuriaga MA, Fuster JJ, Gokce N, Walsh K. Humans and mice display opposing patterns of “Browning” gene expression in visceral and subcutaneous white adipose tissue depots. Front Cardiovasc Med. 2017;4:27.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Lidell ME, Betz MJ, Dahlqvist Leinhard O, Heglind M, Elander L, Slawik M, et al. Evidence for two types of brown adipose tissue in humans. Nat Med. 2013;19:631–4.

    CAS  PubMed  Google Scholar 

  29. Nedergaard J, Cannon B. How brown is brown fat? It depends where you look. Nat Med. 2013;19:540–1.

    CAS  PubMed  Google Scholar 

  30. Giordano A, Frontini A, Cinti S. Convertible visceral fat as a therapeutic target to curb obesity. Nat Rev Drug Discov. 2016;15:405–24.

    CAS  PubMed  Google Scholar 

  31. Bettini S, Favaretto F, Compagnin C, Belligoli A, Sanna M, Fabris R, et al. Resting energy expenditure, insulin resistance and UCP1 expression in human subcutaneous and visceral adipose tissue of patients with obesity. Front Endocrinol. 2019;10:548.

    Google Scholar 

  32. Barquissau V, Leger B, Beuzelin D, Martins F, Amri EZ, Pisani DF, et al. Caloric restriction and diet-induced weight loss do not induce browning of human subcutaneous white adipose tissue in women and men with obesity. Cell Rep. 2018;22:1079–89.

    CAS  PubMed  Google Scholar 

  33. Labbe SM, Caron A, Chechi K, Laplante M, Lecomte R, Richard D. Metabolic activity of brown, “beige,” and white adipose tissues in response to chronic adrenergic stimulation in male mice. Am J Physiol Endocrinol Metab. 2016;311:E260–8.

    PubMed  PubMed Central  Google Scholar 

  34. Carey AL, Vorlander C, Reddy-Luthmoodoo M, Natoli AK, Formosa MF, Bertovic DA, et al. Reduced UCP-1 content in in vitro differentiated beige/brite adipocytes derived from preadipocytes of human subcutaneous white adipose tissues in obesity. PLoS ONE. 2014;9:e91997.

    PubMed  PubMed Central  Google Scholar 

  35. Jorge AS, Jorge GC, Paraiso AF, Franco RM, Vieira LJ, Hilzenderger AM, et al. Brown and white adipose tissue expression of IL6, UCP1 and SIRT1 are associated with alterations in clinical, metabolic and anthropometric parameters in obese humans. Exp Clin Endocrinol Diabetes. 2017;125:163–70.

    CAS  PubMed  Google Scholar 

  36. Nascimento EBM, Sparks LM, Divoux A, van Gisbergen MW, Broeders EPM, Jorgensen JA, et al. Genetic markers of brown adipose tissue identity and in vitro brown adipose tissue activity in humans. Obesity. 2018;26:135–40.

    CAS  PubMed  Google Scholar 

  37. Kern PA, Finlin BS, Zhu B, Rasouli N, McGehee RE Jr, Westgate PM, et al. The effects of temperature and seasons on subcutaneous white adipose tissue in humans: evidence for thermogenic gene induction. J Clin Endocrinol Metab. 2014;99:E2772–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Chechi K, Blanchard PG, Mathieu P, Deshaies Y, Richard D. Brown fat like gene expression in the epicardial fat depot correlates with circulating HDL-cholesterol and triglycerides in patients with coronary artery disease. Int J Cardiol. 2013;167:2264–70.

    PubMed  Google Scholar 

  39. Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med. 2011;17:200–5.

    CAS  PubMed  Google Scholar 

  40. Okamatsu-Ogura Y, Nio-Kobayashi J, Iwanaga T, Terao A, Kimura K, Saito M. Possible involvement of uncoupling protein 1 in appetite control by leptin. Exp Biol Med. 2011;236:1274–81.

    CAS  Google Scholar 

  41. Masaki T, Chiba S, Yasuda T, Tsubone T, Kakuma T, Shimomura I, et al. Peripheral, but not central, administration of adiponectin reduces visceral adiposity and upregulates the expression of uncoupling protein in agouti yellow (Ay/a) obese mice. Diabetes. 2003;52:2266–73.

    CAS  PubMed  Google Scholar 

  42. Bond LM, Burhans MS, Ntambi JM. Uncoupling protein-1 deficiency promotes brown adipose tissue inflammation and ER stress. PLoS ONE. 2018;13:e0205726.

    PubMed  PubMed Central  Google Scholar 

  43. Kajimura S, Seale P, Spiegelman BM. Transcriptional control of brown fat development. Cell Metab. 2010;11:257–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Iida S, Chen W, Nakadai T, Ohkuma Y, Roeder RG. PRDM16 enhances nuclear receptor-dependent transcription of the brown fat-specific Ucp1 gene through interactions with mediator subunit MED1. Genes Dev. 2015;29:308–21.

    PubMed  PubMed Central  Google Scholar 

  45. Harms MJ, Ishibashi J, Wang W, Lim HW, Goyama S, Sato T, et al. Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice. Cell Metab. 2014;19:593–604.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Cohen P, Levy JD, Zhang Y, Frontini A, Kolodin DP, Svensson KJ, et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell. 2014;156:304–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Liu Z, Gu H, Gan L, Xu Y, Feng F, Saeed M, et al. Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue. Oncotarget. 2017;8:9267–79.

    PubMed  Google Scholar 

  48. Valladares A, Roncero C, Benito M, Porras A. TNF-alpha inhibits UCP-1 expression in brown adipocytes via ERKs. Opposite effect of p38MAPK. FEBS Lett. 2001;493:6–11.

    CAS  PubMed  Google Scholar 

  49. Nohr MK, Bobba N, Richelsen B, Lund S, Pedersen SB. Inflammation downregulates UCP1 expression in brown adipocytes potentially via SIRT1 and DBC1 interaction. Int J Mol Sci. 2017;18:1006.

    PubMed Central  Google Scholar 

  50. Beiroa D, Imbernon M, Gallego R, Senra A, Herranz D, Villarroya F, et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes. 2014;63:3346–58.

    CAS  PubMed  Google Scholar 

  51. Xu F, Lin B, Zheng X, Chen Z, Cao H, Xu H, et al. GLP-1 receptor agonist promotes brown remodelling in mouse white adipose tissue through SIRT1. Diabetologia. 2016;59:1059–69.

    CAS  PubMed  Google Scholar 

  52. Xu L, Nagata N, Nagashimada M, Zhuge F, Ni Y, Chen G, et al. SGLT2 inhibition by empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced obese mice. EBioMedicine. 2017;20:137–49.

    PubMed  PubMed Central  Google Scholar 

  53. Araki K, Masaki T, Katsuragi I, Tanaka K, Kakuma T, Yoshimatsu H. Telmisartan prevents obesity and increases the expression of uncoupling protein 1 in diet-induced obese mice. Hypertension. 2006;48:51–7.

    CAS  PubMed  Google Scholar 

  54. Taube M, Andersson-Assarsson JC, Lindberg K, Pereira MJ, Gabel M, Svensson MK, et al. Evaluation of reference genes for gene expression studies in human brown adipose tissue. Adipocyte. 2015;4:280–5.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study was supported by the Basic Science Research Program, through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2017R1D1A1B03030666) and by the Ministry of Science, ICT and Future Planning (2017R1A2B4008673).

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Author notes

  1. These authors contributed equally: Hye Soon Park, Yeon Jin Jang

Authors and Affiliations

  1. Department of Family Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Jisun Lim & Hye Soon Park

  2. Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Jimin Kim & Yeon Jin Jang

  3. Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Jong-Hyeok Kim

  4. Department of Family Medicine, College of Medicine, Inha University, Incheon, Republic of Korea

    YeonJi Lee

  5. Department of General Surgery, College of Medicine, Inha University, Incheon, Republic of Korea

    Yoonseok Heo

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Contributions

JL wrote the paper and analyzed the data. HSP and YJJ conceived the idea of the study and reviewed and edited the paper. JK performed experiments and analyzed the data. J-HK and YH provided samples and reviewed the paper. YJL interpreted the data and reviewed the paper. All authors interpreted the data and provided valuable input at all stages. All authors have approved the final version of the article for publication.

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Correspondence to Hye Soon Park or Yeon Jin Jang.

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Lim, J., Park, H.S., Kim, J. et al. Depot-specific UCP1 expression in human white adipose tissue and its association with obesity-related markers. Int J Obes 44, 697–706 (2020). https://doi.org/10.1038/s41366-020-0528-4

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