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.
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.
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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $64.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
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.
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.
Bartelt A, Heeren J. Adipose tissue browning and metabolic health. Nat Rev Endocrinol. 2014;10:24–36.
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.
Lo KA, Sun L. Turning WAT into BAT: a review on regulators controlling the browning of white adipocytes. Biosci Rep. 2013;33:e00065.
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.
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.
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.
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.
Enerback S. Adipose tissue plasticity and new therapeutic targets. Nat Rev Endocrinol. 2013;9:69–70.
Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19:1252–63.
Lee P, Greenfield JR. Non-pharmacological and pharmacological strategies of brown adipose tissue recruitment in humans. Mol Cell Endocrinol. 2015;418:184–90.
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.
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.
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.
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.
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.
Jensen MD. Role of body fat distribution and the metabolic complications of obesity. J Clin Endocrinol Metab. 2008;93:S57–63.
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.
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.
American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. Diabetes Care. 2018;41 Suppl 1:S13–27.
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.
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.
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.
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.
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.
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.
Nedergaard J, Cannon B. How brown is brown fat? It depends where you look. Nat Med. 2013;19:540–1.
Giordano A, Frontini A, Cinti S. Convertible visceral fat as a therapeutic target to curb obesity. Nat Rev Drug Discov. 2016;15:405–24.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Bond LM, Burhans MS, Ntambi JM. Uncoupling protein-1 deficiency promotes brown adipose tissue inflammation and ER stress. PLoS ONE. 2018;13:e0205726.
Kajimura S, Seale P, Spiegelman BM. Transcriptional control of brown fat development. Cell Metab. 2010;11:257–62.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
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