Cyclophilin B, a molecule chaperone, promotes adipogenesis in 3T3‑L1 preadipocytes via AKT/mTOR pathway

Yoon,Ji-Su; Kim,Sung Soo; Ha,Joohun; Kang,Insug; Choe,Wonchae

doi:10.3892/ijmm.2022.5209

January-2023 Volume 51 Issue 1

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

January-2023 Volume 51 Issue 1

Full Size Image

Article Open Access

Cyclophilin B, a molecule chaperone, promotes adipogenesis in 3T3‑L1 preadipocytes via AKT/mTOR pathway

Authors:
- Ji-Su Yoon
- Sung Soo Kim
- Joohun Ha
- Insug Kang
- Wonchae Choe
View Affiliations / Copyright

Affiliations: Department of Biomedical Science, Graduate School, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea

Copyright: © Yoon et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 6
|
Published online on: December 2, 2022

https://doi.org/10.3892/ijmm.2022.5209
Expand metrics +

Abstract

Cyclophilin is known to act as a molecular chaperone in the endoplasmic reticulum. Recent studies have reported that the expression of cyclophilin B (CypB) is increased in ob/ob mice and its inhibitor suppresses adipocyte differentiation. However, the mechanism of action of CypB in adipocytes remains to be elucidated. The present study investigated the role of CypB in 3T3‑L1 adipocyte differentiation. It showed that the expression level of CypB was increased during 3T3‑L1 adipocyte differentiation by reverse transcription‑quantitative PCR and western blotting analysis. CypB knockdown using short interfering RNA delayed cell cycle progression from the G₁/S to G₂/M phase through the mammalian target of rapamycin (mTOR) signaling pathway and inhibited the expression levels of adipogenic transcription factors including peroxisome proliferator‑activated receptor γ (PPARγ) and CCAAT‑enhancer binding protein (C/EBP)α. Additionally, the accumulation of lipid droplets was inhibited by CypB knockdown. Conversely, overexpression of CypB promoted cell cycle progression from the G₁/S to G₂/M phase by the mTOR signaling pathway and enhanced the expression levels of adipogenic transcription factors including PPARγ and C/EBPα. Finally, the present study showed that CypB downregulated the expression of CHOP, a well‑known negative regulator of adipogenesis. Taken together, the data suggested that CypB might serve important physiological regulatory roles in 3T3‑L1 adipocyte differentiation.

View Figures

View References

1	Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS and Marks JS: Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA. 289:76–79. 2003. View Article : Google Scholar
2	Smith PD, O'Halloran P, Hahn DL, Grasmick M and Radant L: Screening for obesity: Clinical tools in evolution, a WREN study. WMJ. 109:274–278. 2010.PubMed/NCBI
3	Spiegelman BM and Flier JS: Obesity and the regulation of energy balance. Cell. 104:531–543. 2001. View Article : Google Scholar : PubMed/NCBI
4	Tak YJ and Lee SY: Anti-Obesity Drugs: Long-Term efficacy and safety: An updated review. World J Mens Health. 39:208–221. 2021. View Article : Google Scholar :
5	Colman E, Golden J, Roberts M, Egan A, Weaver J and Rosebraugh C: The FDA's assessment of two drugs for chronic weight management. N Engl J Med. 367:1577–1579. 2012. View Article : Google Scholar : PubMed/NCBI
6	Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Aminian A, Brethauer SA, Navaneethan SD, Singh RP, Pothier CE, Nissen SE, et al: Bariatric surgery versus intensive medical therapy for diabetes-5-year outcomes. N Engl J Med. 376:641–651. 2017. View Article : Google Scholar : PubMed/NCBI
7	Every-Palmer S, Romans SE, Stubbs R, Tomlinson A, Gandhi S and Huthwaite M: Experiences of weight-loss surgery in people with serious mental Illness: A qualitative study. Front Psychiatry. 11:4192020. View Article : Google Scholar : PubMed/NCBI
8	Gesta S, Tseng YH and Kahn CR: Developmental origin of fat: Tracking obesity to its source. Cell. 131:242–256. 2007. View Article : Google Scholar : PubMed/NCBI
9	Chang E and Kim CY: Natural products and obesity: A focus on the regulation of mitotic clonal expansion during adipogenesis. Molecules. 24:11572019. View Article : Google Scholar : PubMed/NCBI
10	Mitterberger MC and Zwerschke W: Mechanisms of resveratrol-induced inhibition of clonal expansion and terminal adipogenic differentiation in 3T3-L1 preadipocytes. J Gerontol A Biol Sci Med Sci. 68:1356–1376. 2013. View Article : Google Scholar : PubMed/NCBI
11	Tang QQ, Otto TC and Lane MD: Mitotic clonal expansion: A synchronous process required for adipogenesis. Proc Natl Acad Sci USA. 100:44–49. 2003. View Article : Google Scholar :
12	Jang MK, Yun YR, Kim JH, Park MH and Jung MH: Gomisin N inhibits adipogenesis and prevents high-fat diet-induced obesity. Sci Rep. 7:403452017. View Article : Google Scholar : PubMed/NCBI
13	Ferguson BS, Nam H and Morrison RF: Curcumin Inhibits 3T3-L1 preadipocyte proliferation by mechanisms involving post-transcriptional p27 regulation. Biochem Biophys Rep. 5:16–21. 2016.
14	Maki C, Funakoshi-Tago M, Aoyagi R, Ueda F, Kimura M, Kobata K, Tago K and Tamura H: Coffee extract inhibits adipogenesis in 3T3-L1 preadipocyes by interrupting insulin signaling through the downregulation of IRS1. PLoS One. 12:e01732642017. View Article : Google Scholar : PubMed/NCBI
15	Kang HJ, Seo HA, Go Y, Oh CJ, Jeoung NH, Park KG and Lee IK: Dimethylfumarate suppresses adipogenic differentiation in 3T3-L1 preadipocytes through inhibition of STAT3 activity. PLoS One. 8:e614112013. View Article : Google Scholar : PubMed/NCBI
16	Wu Z, Rosen ED, Brun R, Hauser S, Adelmant G, Troy AE, McKeon C, Darlington GJ and Spiegelman BM: Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell. 3:151–158. 1999. View Article : Google Scholar : PubMed/NCBI
17	Lee JE, Schmidt H, Lai B and Ge K: Transcriptional and epigenomic regulation of adipogenesis. Mol Cell Biol. 39:e00601–18. 2019. View Article : Google Scholar : PubMed/NCBI
18	Ghaben AL and Scherer PE: Adipogenesis and metabolic health. Nat Rev Mol Cell Biol. 20:242–258. 2019. View Article : Google Scholar : PubMed/NCBI
19	Muller C, Calkhoven CF, Sha X and Leutz A: The CCAAT enhancer-binding protein alpha (C/EBPalpha) requires a SWI/SNF complex for proliferation arrest. J Biol Chem. 279:7353–7358. 2004. View Article : Google Scholar
20	Morrison RF and Farmer SR: Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis. J Biol Chem. 274:17088–17097. 1999. View Article : Google Scholar : PubMed/NCBI
21	Price ER, Zydowsky LD, Jin MJ, Baker CH, McKeon FD and Walsh CT: Human cyclophilin B: A second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence. Proc Natl Acad Sci USA. 88:1903–1907. 1991. View Article : Google Scholar : PubMed/NCBI
22	Zhang H, Fan Q, Xie H, Lu L, Tao R, Wang F, Xi R, Hu J, Chen Q, Shen W, et al: Elevated serum cyclophilin B levels are associated with the prevalence and severity of metabolic syndrome. Front Endocrinol (Lausanne). 8:3602017. View Article : Google Scholar
23	Kuo J, Serrano SS, Gronberg A, Massoumi R, Hansson MJ and Gallay P: Cyclophilin inhibitor NV556 reduces fibrosis and hepatocellular carcinoma development in mice with Non-alcoholic steatohepatitis. Front Pharmacol. 10:11292019. View Article : Google Scholar : PubMed/NCBI
24	Zhang L, Li Z, Zhang B, He H and Bai Y: PPIA is a novel adipogenic factor implicated in obesity. Obesity (Silver Spring). 23:2093–2100. 2015. View Article : Google Scholar : PubMed/NCBI
25	Tang QQ and Lane MD: Role of C/EBP homologous protein (CHOP-10) in the programmed activation of CCAAT/enhancer-binding protein-beta during adipogenesis. Proc Natl Acad Sci USA. 97:12446–12450. 2000. View Article : Google Scholar : PubMed/NCBI
26	Batchvarova N, Wang XZ and Ron D: Inhibition of adipogenesis by the stress-induced protein CHOP (Gadd153). EMBO J. 14:4654–4661. 1995. View Article : Google Scholar : PubMed/NCBI
27	Huang X, Ordemann J, Muller JM and Dubiel W: The COP9 signalosome, cullin 3 and Keap1 supercomplex regulates CHOP stability and adipogenesis. Biol Open. 1:705–710. 2012. View Article : Google Scholar : PubMed/NCBI
28	Han J, Murthy R, Wood B, Song B, Wang S, Sun B, Malhi H and Kaufman RJ: ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice. Diabetologia. 56:911–924. 2013. View Article : Google Scholar : PubMed/NCBI
29	Albert V and Hall MN: mTOR signaling in cellular and organismal energetics. Curr Opin Cell Biol. 33:55–66. 2015. View Article : Google Scholar : PubMed/NCBI
30	Bracho-Valdes I, Moreno-Alvarez P, Valencia-Martinez I, Robles-Molina E, Chavez-Vargas L and Vazquez-Prado J: mTORC1- and mTORC2-interacting proteins keep their multifunctional partners focused. IUBMB Life. 63:896–914. 2011. View Article : Google Scholar : PubMed/NCBI
31	Nissley SP, Haskell JF, Sasaki N, De Vroede MA and Rechler MM: Insulin-like growth factor receptors. J Cell Sci Suppl. 3:39–51. 1985. View Article : Google Scholar : PubMed/NCBI
32	Wong RH and Sul HS: Insulin signaling in fatty acid and fat synthesis: A transcriptional perspective. Curr Opin Pharmacol. 10:684–691. 2010. View Article : Google Scholar : PubMed/NCBI
33	Chen J, Crawford R, Chen C and Xiao Y: The key regulatory roles of the PI3K/Akt signaling pathway in the functionalities of mesenchymal stem cells and applications in tissue regeneration. Tissue Eng Part B Rev. 19:516–528. 2013. View Article : Google Scholar : PubMed/NCBI
34	Shockley KR, Rosen CJ, Churchill GA and Lecka-Czernik B: PPARgamma2 regulates a molecular signature of marrow mesenchymal stem cells. PPAR Res. 2007:812192007. View Article : Google Scholar
35	Lieberthal W and Levine JS: The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol. 20:2493–2502. 2009. View Article : Google Scholar : PubMed/NCBI
36	Showkat M, Beigh MA and Andrabi KI: mTOR signaling in protein translation regulation: Implications in cancer genesis and therapeutic interventions. Mol Biol Int. 2014:6869842014. View Article : Google Scholar : PubMed/NCBI
37	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
38	Farmer SR: Transcriptional control of adipocyte formation. Cell Metab. 4:263–273. 2006. View Article : Google Scholar : PubMed/NCBI
39	Hemmings BA and Restuccia DF: PI3K-PKB/Akt pathway. Cold Spring Harb Perspect Biol. 4:a0111892012. View Article : Google Scholar : PubMed/NCBI
40	Jeong K, Kim H, Kim K, Kim SJ, Hahn BS, Jahng GH, Yoon KS, Kim SS, Ha J, Kang I and Choe W: Cyclophilin B is involved in p300-mediated degradation of CHOP in tumor cell adaptation to hypoxia. Cell Death Differ. 21:438–450. 2014. View Article : Google Scholar :
41	Erickson RL, Hemati N, Ross SE and MacDougald OA: p300 coactivates the adipogenic transcription factor CCAAT/enhancer-binding protein alpha. J Biol Chem. 276:16348–16355. 2001. View Article : Google Scholar : PubMed/NCBI
42	Fang F, Zheng J, Galbaugh TL, Fiorillo AA, Hjort EE, Zeng X and Clevenger CV: Cyclophilin B as a co-regulator of prolactin-induced gene expression and function in breast cancer cells. J Mol Endocrinol. 44:319–329. 2010. View Article : Google Scholar : PubMed/NCBI
43	Choi JW, Sutor SL, Lindquist L, Evans GL, Madden BJ, Bergen HR III, Hefferan TE, Yaszemski MJ and Bram RJ: Severe osteogenesis imperfecta in cyclophilin B-deficient mice. PLoS Genet. 5:e10007502009. View Article : Google Scholar : PubMed/NCBI
44	Hu H, Tian M, Ding C and Yu S: The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol. 9:30832019. View Article : Google Scholar : PubMed/NCBI
45	Lei Y, Wang S, Ren B, Wang J, Chen J, Lu J, Zhan S, Fu Y, Huang L and Tan J: CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy. PLoS One. 12:e01836802017. View Article : Google Scholar : PubMed/NCBI
46	El-Chaar D, Gagnon A and Sorisky A: Inhibition of insulin signaling and adipogenesis by rapamycin: Effect on phosphorylation of p70 S6 kinase vs eIF4E-BP1. Int J Obes Relat Metab Disord. 28:191–198. 2004. View Article : Google Scholar : PubMed/NCBI
47	Ahmad B, Serpell CJ, Fong IL and Wong EH: Molecular mechanisms of adipogenesis: The Anti-adipogenic role of AMP-Activated protein kinase. Front Mol Biosci. 7:762020. View Article : Google Scholar : PubMed/NCBI
48	Kang MJ, Kim KK, Son BY, Nam SW, Shin PG and Kim GD: The anti-adipogenic activity of a new cultivar, pleurotus eryngii var. ferulae 'Beesan No. 2', through Down-Regulation of PPAR ү and C/EBP α in 3T3-L1 Cells. J Microbiol Biotechnol. 26:1836–1844. 2016. View Article : Google Scholar : PubMed/NCBI
49	Christodoulides C, Lagathu C, Sethi JK and Vidal-Puig A: Adipogenesis and WNT signalling. Trends Endocrinol Metab. 20:16–24. 2009. View Article : Google Scholar
50	Lee YJ, Choi HS, Seo MJ, Jeon HJ, Kim KJ and Lee BY: Kaempferol suppresses lipid accumulation by inhibiting early adipogenesis in 3T3-L1 cells and zebrafish. Food Funct. 6:2824–2833. 2015. View Article : Google Scholar : PubMed/NCBI
51	Yuan Y, Xi Y, Chen J, Zhu P, Kang J, Zou Z, Wang F and Bu S: STAT3 stimulates adipogenic stem cell proliferation and cooperates with HMGA2 during the early stage of differentiation to promote adipogenesis. Biochem Biophys Res Commun. 482:1360–1366. 2017. View Article : Google Scholar
52	Auld CA, Fernandes KM and Morrison RF: Skp2-mediated p27(Kip1) degradation during S/G2 phase progression of adipocyte hyperplasia. J Cell Physiol. 211:101–111. 2007. View Article : Google Scholar
53	Qu Y, Lin Q, Yuan Y, Sun Z, Li P, Wang F, Jiang H and Chen T: Cyclosporin A inhibits adipogenic differentiation and regulates immunomodulatory functions of murine mesenchymal stem cells. Biochem Biophys Res Commun. 498:516–522. 2018. View Article : Google Scholar : PubMed/NCBI
54	Lee YS, Jeong S, Kim KY, Yoon JS, Kim S, Yoon KS, Ha J, Kang I and Choe W: Honokiol inhibits hepatoma carcinoma cell migration through downregulated Cyclophilin B expression. Biochem Biophys Res Commun. 552:44–51. 2021. View Article : Google Scholar : PubMed/NCBI
55	Ding Y, Zhang L, Yao X, Zhang H, He X, Fan Z and Song Z: Honokiol alleviates high-fat diet-induced obesity of mice by inhibiting adipogenesis and promoting white adipose tissue browning. Animals (Basel). 11:14932021. View Article : Google Scholar : PubMed/NCBI
56	Nakatani Y, Kaneto H, Kawamori D, Yoshiuchi K, Hatazaki M, Matsuoka TA, Ozawa K, Ogawa S, Hori M, Yamasaki Y and Matsuhisa M: Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. J Biol Chem. 280:847–851. 2005. View Article : Google Scholar
57	Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ and Hotamisligil GS: Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 313:1137–1140. 2006. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Cyclophilin B, a molecule chaperone, promotes adipogenesis in 3T3‑L1 preadipocytes via AKT/mTOR pathway

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Related Articles