Abstract
Background:
The circadian clock coordinates numerous metabolic processes to adapt physiological responses to light–dark and feeding regimens and is itself regulated by metabolic cues. The implication of the circadian clock in the regulation of energy balance and body weight is widely studied in rodents but not in humans. Here we investigated (1) whether the expression of clock genes in human adipose tissue is changed by weight loss and (2) whether these alterations are associated with metabolic parameters.
Subjects/Methods:
Subcutaneous adipose tissue (SAT) samples were collected before and after 8 weeks of weight loss on an 800 kcal per day hypocaloric diet (plus 200 g per day vegetables) at the same time of the day. Fifty overweight subjects who lost at least 8% weight after 8 weeks were selected for the study. The expression of 10 clock genes and key metabolic and inflammatory genes in adipose tissue was determined by quantitative real-time PCR.
Results:
The expression of core clock genes PER2 and NR1D1 was increased after the weight loss. Correlations of PERIOD expression with body mass index (BMI) and serum total, high-density lipoprotein and low-density lipoprotein (LDL) cholesterol levels and of NR1D1 expression with total and LDL cholesterol were found that became non-significant after correction for multiple testing. Clock gene expression levels and their weight loss-induced changes tightly correlated with each other and with genes involved in fat metabolism (FASN, CPT1A, LPL, PPARG, PGC1A, ADIPOQ), energy metabolism (SIRT1), autophagy (LC3A, LC3B) and inflammatory response (NFKB1, NFKBIA, NLRP3, EMR1).
Conclusion:
Clock gene expression in human SAT is regulated by body weight changes and associated with BMI, serum cholesterol levels and the expression of metabolic and inflammatory genes. Our data confirm the tight crosstalk between molecular clock and metabolic and inflammatory pathways involved in adapting adipose tissue metabolism to changes of the energy intake in humans.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Asher G, Sassone-Corsi P . Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell 2015; 161: 84–92.
Huang W, Ramsey KM, Marcheva B, Bass J . Circadian rhythms, sleep, and metabolism. J Clin Invest 2011; 121: 2133–2141.
Loboda A, Kraft WK, Fine B, Joseph J, Nebozhyn M, Zhang C et al. Diurnal variation of the human adipose transcriptome and the link to metabolic disease. BMC Med Genomics 2009; 2: 7.
Eckel-Mahan KL, Patel VR, de Mateo S, Orozco-Solis R, Ceglia NJ, Sahar S et al. Reprogramming of the circadian clock by nutritional challenge. Cell 2013; 155: 1464–1478.
Keller M, Mazuch J, Abraham U, Eom GD, Herzog ED, Volk HD et al. A circadian clock in macrophages controls inflammatory immune responses. Proc Natl Acad Sci USA 2009; 106: 21407–21412.
Damiola F . Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev 2000; 14: 2950–2961.
Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab 2012; 15: 848–860.
Kohsaka A, Laposky AD, Ramsey KM, Estrada C, Joshu C, Kobayashi Y et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab 2007; 6: 414–421.
Pivovarova O, Jurchott K, Rudovich N, Hornemann S, Lu Y, Mockel S et al. Changes of dietary fat and carbohydrate content alter central and peripheral clock in humans. J Clin Endocrinol Metab 2015; 100: 2291–2302.
Kumar Jha P, Challet E, Kalsbeek A . Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals. Mol Cell Endocrinol 2015; 418: 74–88.
Adamovich Y, Rousso-Noori L, Zwighaft Z, Neufeld-Cohen A, Golik M, Kraut-Cohen J et al. Circadian clocks and feeding time regulate the oscillations and levels of hepatic triglycerides. Cell Metab 2014; 19: 319–330.
Benedict C, Shostak A, Lange T, Brooks SJ, Schioth HB, Schultes B et al. Diurnal rhythm of circulating nicotinamide phosphoribosyltransferase (Nampt/visfatin/PBEF): impact of sleep loss and relation to glucose metabolism. J Clin Endocrinol Metab 2012; 97: E218–E222.
Gavrila A . Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. J Clin Endocrinol Metab 2003; 88: 2838–2843.
Turek FW . Obesity and metabolic syndrome in circadian clock mutant mice. Science 2005; 308: 1043–1045.
Delezie J, Dumont S, Dardente H, Oudart H, Grechez-Cassiau A, Klosen P et al. The nuclear receptor REV-ERB alpha is required for the daily balance of carbohydrate and lipid metabolism. FASEB J 2012; 26: 3321–3335.
Yang S, Liu A, Weidenhammer A, Cooksey RC, McClain D, Kim MK et al. The role of mPer2 clock gene in glucocorticoid and feeding rhythms. Endocrinology 2009; 150: 2153–2160.
Paschos GK, Ibrahim S, Song WL, Kunieda T, Grant G, Reyes TM et al. Obesity in mice with adipocyte-specific deletion of clock component Arntl. Nat Med 2012; 18: 1768–1777.
Garaulet M . PERIOD2 variants are associated with abdominal obesity, psycho-behavioral factors, and attrition in the dietary treatment of obesity. J Am Diet Assoc 2011; 110: 917–921.
Garaulet M, Tardido AE, Lee YC, Smith CE, Parnell LD, Ordovas JM . SIRT1 and CLOCK 3111 T>C combined genotype is associated with evening preference and weight loss resistance in a behavioral therapy treatment for obesity. Int J Obesity 2012; 36: 1436–1441.
Maury E, Ramsey KM, Bass J . Circadian rhythms and metabolic syndrome: from experimental genetics to human disease. Circ Res 2010; 106: 447–462.
Ando H, Takamura T, Matsuzawa-Nagata N, Shima KR, Eto T, Misu H et al. Clock gene expression in peripheral leucocytes of patients with type 2 diabetes. Diabetologia 2009; 52: 329–335.
Gomez-Abellan P, Hernandez-Morante JJ, Lujan JA, Madrid JA, Garaulet M . Clock genes are implicated in the human metabolic syndrome. Int J Obes (Lond) 2008; 32: 121–128.
Gogebakan O, Kohl A, Osterhoff MA, van Baak MA, Jebb SA, Papadaki A et al. Effects of weight loss and long-term weight maintenance with diets varying in protein and glycemic index on cardiovascular risk factors: the diet, obesity, and genes (DiOGenes) study: a randomized, controlled trial. Circulation 2011; 124: 2829–2838.
Rossmeislova L, Malisova L, Kracmerova J, Stich V . Adaptation of human adipose tissue to hypocaloric diet. Int J Obes (Lond) 2013; 37: 640–650.
de Kreutzenberg SV, Ceolotto G, Papparella I, Bortoluzzi A, Semplicini A, Dalla Man C et al. Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Diabetes 2010; 59: 1006–1015.
Kovsan J, Bluher M, Tarnovscki T, Kloting N, Kirshtein B, Madar L et al. Altered autophagy in human adipose tissues in obesity. J Clin Endocrinol Metab 2011; 96: E268–E277.
Dasu MR, Devaraj S, Park S, Jialal I . Increased Toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care 2010; 33: 861–868.
Lumeng CN, Bodzin JL, Saltiel AR . Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007; 117: 175–184.
Gomez-Santos C, Gomez-Abellan P, Madrid JA, Hernandez-Morante JJ, Lujan JA, Ordovas JM et al. Circadian rhythm of clock genes in human adipose explants. Obesity 2009; 17: 1481–1485.
Garaulet M, Gomez-Abellan P, Alburquerque-Bejar JJ, Lee YC, Ordovas JM, Scheer FA . Timing of food intake predicts weight loss effectiveness. Int J Obes (Lond) 2013; 37: 604–611.
Kahleova H, Belinova L, Malinska H, Oliyarnyk O, Trnovska J, Skop V et al. Eating two larger meals a day (breakfast and lunch) is more effective than six smaller meals in a reduced-energy regimen for patients with type 2 diabetes: a randomised crossover study. Diabetologia 2014; 57: 1552–1560.
Li Y, Sato Y, Yamaguchi N . Shift work and the risk of metabolic syndrome: a nested case-control study. Int J Occup Environ Health 2011; 17: 154–160.
Le Martelot G, Claudel T, Gatfield D, Schaad O, Kornmann B, Lo Sasso G et al. REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis. PLoS Biol 2009; 7: e1000181.
Grimaldi B, Bellet MM, Katada S, Astarita G, Hirayama J, Amin RH et al. PER2 controls lipid metabolism by direct regulation of PPARgamma. Cell Metab 2010; 12: 509–520.
Soussi H, Reggio S, Alili R, Prado C, Mutel S, Pini M et al. DAPK2 down-regulation associates with attenuated adipocyte autophagic clearance in human obesity. Diabetes 2015; 64: 3452–3463.
Ma D, Panda S, Lin JD . Temporal orchestration of circadian autophagy rhythm by C/EBPbeta. EMBO J 2011; 30: 4642–4651.
Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P . Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 2009; 324: 654–657.
Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 2009; 326: 437–440.
Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 2009; 324: 651–654.
Acknowledgements
We thank all study participants for their cooperation. We also thank Andreas Wagner, Melanie Hannemann and Anja Henkel for technical assistance. The study was supported by grants of the European Union Food Quality and Safety Priority of the Sixth Framework Program (FP6-2005-513946), of the European Community (contract no. FOOD-CT-2005-513946) and of the German Science Foundation (DFG grant KFO218 PF164/16-1 to OP, AK and AFHP).
Author contributions
AFHP, OG and OP designed the research; OP, SS, JG, VM and KK conducted the research; OP, MO and NR analyzed data and performed the statistical analysis; and OP, AK and AFHP wrote and edited the manuscript; OP had the primary responsibility for the final content. All authors read and approved the final manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on International Journal of Obesity website
Supplementary information
Rights and permissions
About this article
Cite this article
Pivovarova, O., Gögebakan, Ö., Sucher, S. et al. Regulation of the clock gene expression in human adipose tissue by weight loss. Int J Obes 40, 899–906 (2016). https://doi.org/10.1038/ijo.2016.34
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ijo.2016.34
This article is cited by
-
Acute and long-term exercise adaptation of adipose tissue and skeletal muscle in humans: a matched transcriptomics approach after 8-week training-intervention
International Journal of Obesity (2023)
-
Transcriptomic analysis to elucidate the effects of high stocking density on grass carp (Ctenopharyngodon idella)
BMC Genomics (2021)
-
The circadian rhythm in intervertebral disc degeneration: an autophagy connection
Experimental & Molecular Medicine (2020)
-
Chronotype and social jetlag influence human circadian clock gene expression
Scientific Reports (2018)
-
Positive association between physical activity and PER3 expression in older adults
Scientific Reports (2017)