Secreted frizzled‑related protein 4 promotes brown adipocyte differentiation

Guan,Hua; Zheng,Huiyuan; Zhang,Jin; Xiang,Aoqi; Li,Yongxin; Zheng,Huadong; Xu,Lixian; Liu,Enqi; Yu,Qi

doi:10.3892/etm.2021.10069

Secreted frizzled‑related protein 4 promotes brown adipocyte differentiation

Authors:
- Hua Guan
- Huiyuan Zheng
- Jin Zhang
- Aoqi Xiang
- Yongxin Li
- Huadong Zheng
- Lixian Xu
- Enqi Liu
- Qi Yu
View Affiliations

Affiliations: Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases and Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China, Preventive Dentistry, The Fourth Military Medical University Stomatological Hospital, Xi'an, Shaanxi 710032, P.R. China, Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Anesthesiology, The Fourth Military Medical University Stomatological Hospital, Xi'an, Shaanxi 710032, P.R. China, Laboratory Animal Center, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China
Published online on: April 15, 2021 https://doi.org/10.3892/etm.2021.10069
Article Number: 637
Copyright: © Guan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Secreted frizzled‑related protein 4 (SFRP4) is a member of the SFRP family that contains a cysteine‑rich domain homologous to the putative Wnt‑binding site of frizzled proteins. In the present report, the effects of SFRP4 on murine brown adipocyte differentiation were evaluated, which exhibited an intrinsic capacity to differentiate with high efficiency. Brown preadipocytes were isolated from the scapular region of brown adipose tissue, which showed that the overexpression of recombinant active SFRP4 protein at three concentrations (1, 10 and 100 ng/ml) significantly increased the expression of adipocyte differentiation‑associated genes (C/EBPα, C/EBPβ, UCP‑1, PRDM16, PGC1α and GLUT4) in a dose‑dependent manner compared with the control group. Secondly, adiponectin protein expression was significantly inhibited in a dose‑independent manner, while leptin was increased in brown adipocytes by incubation with the high concentration (100 ng/ml) of SFRP4. Thirdly, the role of interleukin‑1β (IL‑1β) was investigated in brown adipocytes and discovered that IL‑1β cannot induce SFRP4 mRNA expression in brown adipocytes, similar to human islet cells. These data suggested that SFRP4‑treated brown adipocytes represent a valuable in vitro model for the study of adipogenesis and indicated that SFRP4 served various functions during brown adipocyte differentiation.

View Figures

View References

1	Murawska-Cialowicz E: Adipose tissue-morphological and biochemical characteristic of different depots. Postepy Hig Med Dosw (Online). 71:466–484. 2017.PubMed/NCBI View Article : Google Scholar
2	Cinti S: The adipose organ at a glance. Dis Model Mech. 5:588–594. 2012.PubMed/NCBI View Article : Google Scholar
3	Ibrahim MM: Subcutaneous and visceral adipose tissue: Structural and functional differences. Obes Rev. 11:11–18. 2010.PubMed/NCBI View Article : Google Scholar
4	Marlatt KL and Ravussin E: Brown adipose tissue: An update on recent findings. Curr Obes Rep. 6:389–396. 2017.PubMed/NCBI View Article : Google Scholar
5	Yu Q, Wang F, Meng X, Gong Y, Wang Y, Xu C and Wang S: Short-term use of atorvastatin affects glucose homeostasis and suppresses the expression of LDL receptors in the pancreas of mice. Mol Med Rep. 18:2780–2788. 2018.PubMed/NCBI View Article : Google Scholar
6	Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerbäck S and Nuutila P: Functional brown adipose tissue in healthy adults. N Engl J Med. 360:1518–1525. 2009.PubMed/NCBI View Article : Google Scholar
7	Ode KL, Frohnert BI and Nathan BM: Identification and treatment of metabolic complications in pediatric obesity. Rev Endocr Metab Disord. 10:167–188. 2009.PubMed/NCBI View Article : Google Scholar
8	Pawar NM and Rao P: Secreted frizzled related protein 4 (sFRP4) update: A brief review. Cell Signal. 45:63–70. 2018.PubMed/NCBI View Article : Google Scholar
9	Mastaitis J, Eckersdorff M, Min S, Xin Y, Cavino K, Aglione J, Okamoto H, Na E, Stitt T, Dominguez MG, et al: Loss of SFRP4 alters body size, food intake and energy expenditure in diet-induced obese male mice. Endocrinology. 156:4502–4510. 2015.PubMed/NCBI View Article : Google Scholar
10	Liu F, Qu H, Li Y, Tang Q, Yang Z, Wang H and Deng H: Relationship between serum secreted frizzled-related protein 4 levels and the first-phase of glucose-stimulated insulin secretion in individuals with different glucose tolerance. Endocr J. 62:733–740. 2015.PubMed/NCBI View Article : Google Scholar
11	Mahdi T, Hänzelmann S, Salehi A, Muhammed SJ, Reinbothe TM, Tang Y, Axelsson AS, Zhou Y, Jing X, Almgren P, et al: Secreted frizzled-related protein 4 reduces insulin secretion and is overexpressed in type 2 diabetes. Cell Metab. 16:625–633. 2012.PubMed/NCBI View Article : Google Scholar
12	Li XJ, Yang H, Li GX, Zhang GH, Cheng J, Guan H and Yang GS: Transcriptome profile analysis of porcine adipose tissue by high-throughput sequencing. Anim Genet. 43:144–152. 2012.PubMed/NCBI View Article : Google Scholar
13	Guan H, Zhang Y, Gao S, Bai L, Zhao S, Cheng XW, Fan J and Liu E: Differential patterns of secreted frizzled-related protein 4 (SFRP4) in adipocyte differentiation: Adipose depot specificity. Cell Physiol Biochem. 46:2149–2164. 2018.PubMed/NCBI View Article : Google Scholar
14	Gao W, Kong X and Yang Q: Isolation, primary culture, and differentiation of preadipocytes from mouse brown adipose tissue. Methods Mol Biol. 1566:3–8. 2017.PubMed/NCBI View Article : Google Scholar
15	Barthold SW, Bayne KA, Davis MA, Everitt JI, Fox JG, Garnett NL, Gauda EB, Kemnitz JW, Clark JAM, McClintock MK, et al: Guide for the care and use of laboratory animals. 8th edition. National Institutes of Health (NIH), 2008.
16	Frontini A and Cinti S: Distribution and development of brown adipocytes in the murine and human adipose organ. Cell Metab. 11:253–256. 2010.PubMed/NCBI View Article : Google Scholar
17	Alomar SY, Zaibi MS, Kępczyńska MA, Gentili A, Alkhuriji A, Mansour L, Dar JA and Trayhurn P: PCR array and protein array studies demonstrate that IL-1β (interleukin-1β) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes. Arch Physiol Biochem. 121:187–193. 2015.PubMed/NCBI View Article : Google Scholar
18	Withrow D and Alter DA: The economic burden of obesity worldwide: A systematic review of the direct costs of obesity. Obes Rev. 12:131–141. 2011.PubMed/NCBI View Article : Google Scholar
19	Hankir MK: Loading and firing the brown adipocyte. Adipocyte. 7:4–11. 2018.PubMed/NCBI View Article : Google Scholar
20	Giralt M and Villarroya F: White, brown, beige/brite: Different adipose cells for different functions? Endocrinology. 154:2992–3000. 2013.PubMed/NCBI View Article : Google Scholar
21	Xiong W, Zhao X, Villacorta L, Rom O, Garcia-Barrio MT, Guo Y, Fan Y, Zhu T, Zhang J, Zeng R, et al: Brown adipocyte-specific PPARγ (peroxisome proliferator-activated receptor γ) deletion impairs perivascular adipose tissue development and enhances atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 38:1738–1747. 2018.PubMed/NCBI View Article : Google Scholar
22	Scheideler M, Herzig S and Georgiadi A: Endocrine and autocrine/paracrine modulators of brown adipose tissue mass and activity as novel therapeutic strategies against obesity and type 2 diabetes. Horm Mol Biol Clin Investig: Aug 29, 2017 (Epub ahead of print). doi: 10.1515/hmbci-2017-0043.
23	White JD, Dewal RS and Stanford KI: The beneficial effects of brown adipose tissue transplantation. Mol Aspects Med. 68:74–81. 2019.PubMed/NCBI View Article : Google Scholar
24	Villarroya F, Cereijo R, Villarroya J and Giralt M: Brown adipose tissue as a secretory organ. Nat Rev Endocrinol. 13:26–35. 2017.PubMed/NCBI View Article : Google Scholar
25	Tsai YS and Maeda N: PPARgamma: A critical determinant of body fat distribution in humans and mice. Trends Cardiovasc Med. 15:81–85. 2005.PubMed/NCBI View Article : Google Scholar
26	Nedergaard J, Petrovic N, Lindgren EM, Jacobsson A and Cannon B: PPARgamma in the control of brown adipocyte differentiation. Biochim Biophys Acta. 1740:293–304. 2005.PubMed/NCBI View Article : Google Scholar
27	Ramji DP and Foka P: CCAAT/enhancer-binding proteins: Structure, function and regulation. Biochem J. 365:561–575. 2002.PubMed/NCBI View Article : Google Scholar
28	Yubero P, Manchado C, Cassard-Doulcier AM, Mampel T, Vinas O, Iglesias R, Giralt M and Villarroya F: CCAAT/enhancer binding proteins alpha and beta are transcriptional activators of the brown fat uncoupling protein gene promoter. Biochem Biophys Res Commun. 198:653–659. 1994.PubMed/NCBI View Article : Google Scholar
29	Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, Tavernier G, Langin D and Spiegelman BM: Transcriptional control of brown fat determination by PRDM16. Cell Meta. 6:38–54. 2007.PubMed/NCBI View Article : Google Scholar
30	Puigserver P, Wu Z, Park CW, Graves R, Wright M and Spiegelman BM: A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 92:829–839. 1998.PubMed/NCBI View Article : Google Scholar
31	Tiraby C, Tavernier G, Lefort C, Larrouy D, Bouillaud F, Ricquier D and Langin D: Acquirement of brown fat cell features by human white adipocytes. J Biol Chem. 278:33370–33376. 2003.PubMed/NCBI View Article : Google Scholar
32	Kiess W, Petzold S, Töpfer M, Garten A, Blüher S, Kapellen T, Körner A and Kratzsch J: Adipocytes and adipose tissue. Best Pract Res Clin Endocrinol Metab. 22:135–153. 2008.PubMed/NCBI View Article : Google Scholar
33	Jash S, Banerjee S, Lee MJ, Farmer SR and Puri V: CIDEA transcriptionally regulates UCP1 for britening and thermogenesis in human fat cells. iScience. 20:73–89. 2019.PubMed/NCBI View Article : Google Scholar
34	Villarroya J, Cereijo R, Gavalda-Navarro A, Peyrou M, Giralt M and Villarroya F: New insights into the secretory functions of brown adipose tissue. J Endocrinol. 243:R19–R27. 2019.PubMed/NCBI View Article : Google Scholar
35	Paz G, Mastronardi CA and Licinio J: Leptin treatment: Facts and expectations. Metabolism. 64:146–156. 2015.PubMed/NCBI View Article : Google Scholar
36	Wang J, Ge J, Cao H, Zhang X, Guo Y, Li X, Xia B, Yang G and Shi X: Leptin promotes white adipocyte browning by inhibiting the HH signaling pathway. Cells. 8(372)2019.PubMed/NCBI View Article : Google Scholar
37	Pandit R, Beerens S and Adan RAH: Role of leptin in energy expenditure: The hypothalamic perspective. Am J Physiol Regul Integr Comp Physiol. 312:R938–R947. 2017.PubMed/NCBI View Article : Google Scholar
38	Qiao L, Yoo HS, Bosco C, Lee B, Feng GS, Schaack J, Chi NW and Shao J: Adiponectin reduces thermogenesis by inhibiting brown adipose tissue activation in mice. Diabetologia. 57:1027–1036. 2014.PubMed/NCBI View Article : Google Scholar
39	Song G, Zong C, Zhang Z, Yu Y, Yao S, Jiao P, Tian H, Zhai L, Zhao H, Tian S, et al: Molecular hydrogen stabilizes atherosclerotic plaque in low-density lipoprotein receptor-knockout mice. Free Radic Biol Med. 87:58–68. 2015.PubMed/NCBI View Article : Google Scholar
40	Jing L, Wang Y, Zhao XM, Zhao B, Han JJ, Qin SC and Sun XJ: Cardioprotective effect of hydrogen-rich saline on isoproterenol-induced myocardial infarction in rats. Heart Lung Circ. 24:602–610. 2015.PubMed/NCBI View Article : Google Scholar
41	Stolarczyk E: Adipose tissue inflammation in obesity: A metabolic or immune response? Curr Opin Pharmacol. 37:35–40. 2017.PubMed/NCBI View Article : Google Scholar
42	Villarroya F, Cereijo R, Gavalda-Navarro A, Villarroya J and Giralt M: Inflammation of brown/beige adipose tissues in obesity and metabolic disease. J Intern Med. 284:492–504. 2018.PubMed/NCBI View Article : Google Scholar
43	Nøhr MK, Bobba N, Richelsen B, Lund S and Pedersen SB: Inflammation downregulates UCP1 expression in brown adipocytes potentially via SIRT1 and DBC1 interaction. Int J Mol Sci. 18(1006)2017.PubMed/NCBI View Article : Google Scholar
44	Goto T, Naknukool S, Yoshitake R, Hanafusa Y, Tokiwa S, Li Y, Sakamoto T, Nitta T, Kim M, Takahashi N, et al: Proinflammatory cytokine interleukin-1β suppresses cold-induced thermogenesis in adipocytes. Cytokine. 77:107–114. 2016.PubMed/NCBI View Article : Google Scholar