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Identification of the Relationship Between DNA Methylation of Circadian Rhythm Genes and Obesity

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Abstract

In children, teenagers, and young adults, environmental factors and genetic modifications have contributed to the development of obesity. There is a close relationship between obesity and circadian rhythm. To understand the role of CLOCK and BMAL1 in obesity, we analyzed the methylation status of CLOCK and BMAL1 in obese and control subjects. In this paper, we analyzed the methylation status of the CLOCK and BMAL1 genes by using MS-HRM in a total of 55 obese and 54 control subjects. In our study, we demonstrated that the level of fasting glucose and the level of HDL-cholesterol were associated with CLOCK methylation in obesity. We also showed a significant association between BMAL1 gene methylation and waist and hip circumference in obese subjects. This is the first study that shows the methylation of BMAL1 is associated with the obese phenotype. However, we could not show a direct association between CLOCK methylation and the obese phenotype. In this paper, a novel epigenetic interaction between circadian clock genes and obesity was demonstrated.

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Data Availability

The genetics data that support the findings of this study are available on request from the corresponding author (RK).

References

  • Azevedo PG, Miranda LR, Nicolau ES, Alves RB, Bicalho MAC, Couto PP, Ramos AV, Souza RP, Longhi R, Friedman E, Marco L (2021) Bastos-Rodrigues L. Genetic association of the PERIOD3 (PER3) Clock gene with extreme obesity. Obes Res Clin Pract 15(4):334–338

    Article  PubMed  Google Scholar 

  • Barnea M, Chapnik N, Genzer Y, Froy O (2015) The circadian clock machinery controls adiponectin expression. Mol Cell Endocrinol 399:284–287

    Article  CAS  PubMed  Google Scholar 

  • Baron KG, Reid KJ, Kim T et al (2017) Circadian timing and alignment in healthy adults: associations with BMI, body fat, caloric intake and physical activity. Int J Obes (lond) 41(2):203–209

    Article  CAS  PubMed  Google Scholar 

  • Bell-Pedersen D, Cassone VM, Earnest DJ, Golden SS, Hardin PE, Thomas TL, Zoran MJ (2005) Circadian rhythms from multiple oscillators: lessons from divers organisms. Nat Rev Genet 6:544–556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boutari C, Mantzoros CS (2022) A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on. Metabolism 133:155217. https://doi.org/10.1016/j.metabol.2022.155217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, Hogenesch JB, Simon MC, Takahashi JS, Bradfield CA (2000) Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103:1009–1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dyar KA, Ciciliot S, Wright LE, Biensø RS, Tagliazucchi GM, Patel VR, Forcato M, Paz MIP, Gudiksen A, Solagna F et al (2014) Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock. Mol Metab 3:29–41

    Article  CAS  PubMed  Google Scholar 

  • Eide EJ, Woolf MF, Kang H et al (2005) Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Mol Cell Biol 25:2795–2807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garaulet M, Lee YC, Shen J et al (2009) CLOCK genetic variation and metabolic syndrome risk: modulation by monounsaturated fatty acids. Am J Clin Nutr 90:1466–1475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garaulet M, Corbalán MD, Madrid JA, Morales E, Baraza JC, Lee YC, Ordovas JM (2010) CLOCK gene is implicated in weight reduction in obese patients participating in a dietary programme based on the Mediterranean diet. Int J Obes 34(3):516–523

    Article  CAS  Google Scholar 

  • Gibson EM, Wang C, Tjho S, Khattar N, Kriegsfeld LJ (2010) Experimental “jet lag” inhibits adult neurogenesis and produces long-term cognitive deficits in female hamsters. PLoS ONE 5(12):e15267. https://doi.org/10.1371/journal.pone.0015267

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Godinho SI, Maywood ES, Shaw L et al (2007) The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316:897–900

    Article  ADS  CAS  PubMed  Google Scholar 

  • Gooley JJ (2016) Circadian regulation of lipid metabolism. Proc Nutr Soc 75:440–450

    Article  CAS  PubMed  Google Scholar 

  • Grosjean E, Simonneaux V, Challet E (2023) Reciprocal interactions between circadian clocks, food intake, and energy metabolism. Biology 12(4):539. https://doi.org/10.3390/biology12040539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Honma S, Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, Kato Y, Honma K (2002) Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 419:841–844

    Article  ADS  CAS  PubMed  Google Scholar 

  • Kalkan R, Becer E (2019) RANK/RANKL/OPG pathway is an important for the epigenetic regulation of obesity. Mol Biol Rep 46(5):5425–5432. https://doi.org/10.1007/s11033-019-04997-z

    Article  CAS  PubMed  Google Scholar 

  • Kettner NM, Mayo SA, Hua J, Lee C, Moore DD, Fu L (2015) Circadian dysfunction induces leptin resistance in mice. Cell Metab 22(3):448–459. https://doi.org/10.1016/j.cmet.2015.06.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lamia KA, Storch KF, Weitz CJ (2008) Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci USA 105:15172–15177

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Ma J, Yao K, Su W, Tan B, Wu X, Huang X, Li T, Yin Y, Tosini G, Yin J (2020) Circadian rhythms and obesity: timekeeping governs lipid metabolism. J Pineal Res 69(3):e12682. https://doi.org/10.1111/jpi.12682

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Zheng C, Cheng X, Qian L, Peng Z (2017) Nighttime snacking is associated with risk of obesity and hyperglycemia in adults: a cross-sectional survey from Chinese adult teachers. J Biomed Res 31(6):541

    Article  PubMed  PubMed Central  Google Scholar 

  • Loos RJF, Yeo GSH (2022) The genetics of obesity: from discovery to biology. Nat Rev Genet 23(2):120–133. https://doi.org/10.1038/s41576-021-00414-z

    Article  CAS  PubMed  Google Scholar 

  • Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, Ivanova G, Omura C, Mo S, Vitaterna MH et al (2010) Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466:627–631

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Matthews DR, Hosker JP, Rudenski AS et al (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentration in man. Diabetologia 28:412–419

    Article  CAS  PubMed  Google Scholar 

  • Milagro FI, Gómez-Abellán P, Campión J, Martínez JA, Ordovás JM, Garaulet M (2012) CLOCK, PER2 and BMAL1 DNA methylation: association with obesity and metabolic syndrome characteristics and monounsaturated fat intake. Chronobiol Int 29(9):1180–1194. https://doi.org/10.3109/07420528.2012.719967. (Epub 2012 Sep 24 PMID: 23003921)

    Article  CAS  PubMed  Google Scholar 

  • Nguyen KD et al (2013) Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes. Science 341:1483–1488

    Article  ADS  CAS  PubMed  Google Scholar 

  • Pan X, Jiang XC, Hussain MM (2013) Impaired cholesterol metabolism and enhanced atherosclerosis in clock mutant mice. Circulation 128(16):1758–1769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parsons MJ et al (2015) Social jetlag, obesity and metabolic disorder: investigation in a cohort study. Int J Obes (lond) 39:842–848

    Article  CAS  PubMed  Google Scholar 

  • Paschos GK et al (2012) Obesity in mice with adipocyte-specific deletion of clock component BMAL1. Nat Med 18:1768–1777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng H, Zhu Y, Goldberg J, Vaccarino V, Zhao J (2019) DNA methylation of five core circadian genes jointly contributes to glucose metabolism: a gene-set analysis in monozygotic twins. Front Genet 10:329. https://doi.org/10.3389/fgene.2019.00329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qian J, Scheer FA (2016) Circadian system and glucose metabolism: implications for physiology and disease. Trends Endocrinol Metab 27(5):282–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schabler S, Amatobi KM, Horn M et al (2020) Loss of function in the Drosophila clock gene period results in altered intermediary lipid metabolism and increased susceptibility to starvation. Cell Mol Life Sci. https://doi.org/10.1007/s00018-019-03441-6

    Article  PubMed  PubMed Central  Google Scholar 

  • Scott EM, Carter AM, Grant PJ (2008) Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Int J Obes (lond) 32:658–662

    Article  CAS  PubMed  Google Scholar 

  • Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, Zheng B, Kume K, Lee CC, van der Horst GT, Hastings MH, Reppert SM (2000) Interacting molecular loops in the mammalian circadian clock. Science 288(5468):1013–1019. https://doi.org/10.1126/science.288.5468.1013

    Article  ADS  CAS  PubMed  Google Scholar 

  • Shen L, Cui A, Xue Y, Cui Y, Dong X, Gao Y, Yang H, Fang F, Chang Y (2014) Hepatic differentiated embryo-chondrocyte-expressed gene 1 (Dec1) inhibits sterol regulatory element-binding protein-1c (Srebp-1c) expression and alleviates fatty liver phenotype. J Biol Chem 289:23332–23342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shimba S (2013) The roles of clock genes in obesity. Nihon rinsho. Jpn J Clin Med 71(2):244–248

    Google Scholar 

  • Shimba S, Ishii N, Ohta Y, Ohno T, Watabe Y, HayashiM WT, Aoyagi T, Tezuka M (2005) Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. Proc Natl Acad Sci USA 102:12071–12076

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Shimba S, Ogawa T, Hitosugi S, Ichihashi Y, Nakadaira Y, Kobayashi M, Tezuka M, Kosuge Y, Ishige K, Ito Y et al (2011) Deficient of a clock gene, brain and muscle arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation. PLoS ONE 6:e25231

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Shirogane T, Jin J, Ang XL et al (2005) SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein. J Biol Chem 280:26863–26872

    Article  CAS  PubMed  Google Scholar 

  • Siepka SM, Yoo SH, Park J et al (2007) Circadian mutant overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell 129:1011–1023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sookoian S, Gemma C, Gianotti TF et al (2008) Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity. Am J Clin Nutr 87:1606–1615

    Article  CAS  PubMed  Google Scholar 

  • Touitou Y, Reinberg A, Touitou D (2017) Association between light at night, melatonin secretion, sleep deprivation, and the internal clock: health impacts and mechanisms of circadian disruption. Life Sci 173:94–106

    Article  CAS  PubMed  Google Scholar 

  • Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E et al (2005) Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308(5724):1043–1045

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Uemura H, Katsuura-Kamano S, Yamaguchi M et al. (2015) A variant of the CLOCK gene and related haplotypes are associated with the prevalence of type 2 diabetes in the Japanese population. J Diab (Epublication ahead of print version)

  • Villanueva JE, Livelo C, Trujillo AS et al (2019) Time-restricted feeding restores muscle function in Drosophila models of obesity and circadian-rhythm disruption. Nat Commun 10(1):2700

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang S, Lin Y, Gao L, Yang Z, Lin J, Ren S et al (2022) PPAR-γ integrates obesity and adipocyte clock through epigenetic regulation of Bmal1. Theranostics 12(4):1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • WHO European Regional Obesity Report 2022, ISBN: 978–92–890–5773–8.

  • WHO (2016) Word Health Organization (WHO). Obesity and overweight. Geneva: WHO;2016. Available from: http://www.who.int/mediacentre/factsheets/fs311/en/

  • Woon PY, Kaisaki PJ, Braganc AJ, Bihoreau MT, Levy JC, Farrall M, Gauguier D (2007) Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proc Natl Acad Sci USA 104:14412–14417

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Yagawa M, Nagatomo Y, Izumi Y, Mahara K, Tomoike H, Shiraishi Y, Kohno T, Mizuno A, Goda A, Kohsaka S, Yoshikawa T, West Tokyo Heart Failure (WET-HF) Registry Collaborative Group (2017) Effect of obesity on the prognostic impact of atrial fibrillation in heart failure with preserved ejection fraction. Circ J 81(7):966–973. https://doi.org/10.1253/circj.CJ-16-1130

    Article  CAS  PubMed  Google Scholar 

  • Yoo SH, Mohawk JA, Siepka SM et al (2013) Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell 152:1091–1105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang R, Lahens NF, Balance HI, Hughes ME, Hogenesch JB (2014) A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci USA 111(45):16219–16224

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The authors received no specific funding for this work. We would like to thank all the participants involved in this study.

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Contributions

Conceptualization: RK; Methodology: RK and TGJ; Software: RK and TGJ; Validation: RK and TGJ; Formal analysis: RK, TGJ, and EB; Investigation: RK and TGJ; Resources: RK, TGJ, and EB; Data curation: RK, TGJ, and EB; Writing—original draft preparation: RK, TGJ, and EB; Writing—review and editing: RK, TGJ, and EB; Visualization: RK, TGJ, and EB; Supervision: R.K.; Project administration: RK; Funding acquisition: RK.

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Correspondence to Rasime Kalkan.

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All subjects signed written consent forms after being fully informed. The study protocol was approved by the Research Ethics Committee of the Near East University and performed in accordance with the Declaration of Helsinki (YDU-2021/96–1425).

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Jesse, T.G., Becer, E. & Kalkan, R. Identification of the Relationship Between DNA Methylation of Circadian Rhythm Genes and Obesity. Biochem Genet 62, 281–293 (2024). https://doi.org/10.1007/s10528-023-10415-8

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