Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Integrative Biology

SIRT1 and CLOCK 3111T>C combined genotype is associated with evening preference and weight loss resistance in a behavioral therapy treatment for obesity

Abstract

Background:

A new negative feedback loop has been proposed, which suggests connections between the circadian clock and SIRTUIN1 (SIRT1)-dependent functions associated with cell survival, development and metabolism.

Objective:

To develop a SIRT1 and circadian locomotor output cycles kaput (CLOCK) combined genotype and to assess its associations with the chronotype of subjects and their potential resistance to weight loss in a behavioral treatment for obesity based on a Mediterranean diet.

Design:

Overweight /obese subjects (n=1465), aged 20-65 years, who attended outpatient obesity clinics, were genotyped for SIRT1 (rs1467568) and CLOCK (3111T>C, rs1801260). Anthropometric, biochemical and dietary-intake variables were analyzed. Effectiveness of the program and weight loss progression during 30 weeks of treatment was assessed.

Results:

We found highly consistent associations between the morning/evening questionnaires across the different genotype categories. Subjects carrying minor alleles at SIRT1 and CLOCK loci (R group) displayed a higher resistance to weight loss and a lower weekly weight loss rate as compared with homozygotes for both major alleles (P group). Significant differences were found across genotypes in weight loss progression during the 30 weeks of treatment (P=0.039). Dietary habits indicated that R carriers had a lower intake of total carbohydrates and monounsaturated fats, and a higher intake of saturated fats than those carrying the intermediate (M) and the P genotype (P=0.02). Plasma ghrelin concentrations were also significantly higher in subjects carrying the R genotype.

Conclusion:

Variants of both SIRT1 and CLOCK have an additive effect on resistance to weight loss that could be related to the chronotype of the subject, higher plasma levels of ghrelin and less adherence to Mediterranean diet patterns.

This is a preview of subscription content, access via your institution

Access options

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

Figure 1
Figure 2

References

  1. Garaulet M, Madrid JA . Chronobiological aspects of nutrition, metabolic syndrome and obesity. Adv Drug Deliv Rev 2010; 62: 967–978.

    Article  CAS  PubMed  Google Scholar 

  2. Maury E, Ramsey KM, Bass J . Circadian rhythms and metabolic syndrome: from experimental genetics to human disease. Circ Res 2010; 106: 447–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wijnen H . Circadian rhythms. A circadian loop asSIRTs itself. Science 2009; 324: 598–599.

    Article  CAS  PubMed  Google Scholar 

  4. Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P . Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett 2008; 582: 46–53.

    Article  CAS  PubMed  Google Scholar 

  5. Doi M, Hirayama J, Sassone-Corsi P . Circadian regulator CLOCK is a histone acetyltransferase. Cell 2006; 125: 497–508.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D et al. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 2008; 134: 329–340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bechtold DA . Energy-responsive timekeeping. J Genet 2008; 87: 447–458.

    Article  CAS  PubMed  Google Scholar 

  9. Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004; 429: 771–776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cakir I, Perello M, Lansari O, Messier NJ, Vaslet CA, Nillni EA . Hypothalamic Sirt1 regulates food intake in a rodent model system. PLoS One 2009; 4: e8322.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zillikens MC, van Meurs JB, Rivadeneira F, Amin N, Hofman A, Oostra BA et al. SIRT1 genetic variation is related to BMI and risk of obesity. Diabetes 2009; 58: 2828–2834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sookoian S, Gemma C, Gianotti TF, Burgueño A, Castaño G, Pirola CJ . Genetic variants of Clock transcription factor are associated with individual susceptibility to obesity. Am J Clin Nutr 2008; 87: 1606–1615.

    Article  CAS  PubMed  Google Scholar 

  13. Garaulet M, Lee YC, Shen J, Parnell LD, Arnett DK, Tsai MY et al. CLOCK genetic variation and metabolic syndrome risk: modulation by monounsaturated fatty acids. Am J Clin Nutr 2009; 90: 1466–1475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Garaulet M, Sánchez-Moreno C, Smith CE, Lee YC, Nicolás F, Ordovás JM . Ghrelin, sleep reduction and evening preference: relationships to CLOCK 3111 T/C SNP and weight loss. PLoS One 2011; 6: e17435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Garaulet M, Pérez-Llamas F, Zamora S, Tebar FJ . Weight loss and possible reasons for dropping out of a dietary/behavioural programme in the treatment of overweight patients. J Hum Nutr Diet 1999; 12: 219–227.

    Article  Google Scholar 

  17. Corbalán MD, Morales EM, Canteras M, Espallardo A, Hernández T, Garaulet M . Effectiveness of cognitive-behavioral therapy based on the Mediterranean diet for the treatment of obesity. Nutrition 2009; 25: 861–869.

    Article  PubMed  Google Scholar 

  18. Serra-Majem L, Aranceta J . Spanish Society of Community Nutrition. Nutritional objectives for the Spanish population. Consensus from the Spanish Society of Community Nutrition. Public Health Nutr 2001; 4: 1409–1413.

    CAS  PubMed  Google Scholar 

  19. Ferrario VF, Sforza C, Schmitz JH, Miani Jr A, Taroni G . Fourier analysis of human soft tissue facial shape: sex differences in normal adults. J Anat 1995; 187 (Part 3): 593–602.

    PubMed  PubMed Central  Google Scholar 

  20. Horne JA, Ostberg O . A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol 1976; 4: 97–110.

    CAS  PubMed  Google Scholar 

  21. Taillard J, Philip P, Chastang JF, Bioulac B . Validation of Horne and Ostberg morningness-eveningness questionnaire in a middle-aged population of French workers. J Biol Rhythms 2004; 19: 76–86.

    Article  PubMed  Google Scholar 

  22. Pérez-Llamas F, Garaulet M, Herrero F, Palma JT, Pérez de Heredia F, Marín R et al. Multivalent informatics application for studies of the nutritional status of the population. Assessment of food intake. Nutr Hosp 2004; 19: 160–166. (Article in Spanish).

    PubMed  Google Scholar 

  23. Mataix J, Mañas M, Llopis J, Martínez M . Table of Composition Of Spanish Foods. Instituto de Nutrición y Tecnología, Universidad de Granada: Granada, Spain, 1996 (Book in Spanish).

    Google Scholar 

  24. Moreiras O, Carvajal A, Cabrera L . Tables of composition of foods. Pirámide SA: Madrid, 1995 (Book in Spanish).

    Google Scholar 

  25. Trichopoulou A, Yiannakouris N, Bamia C, Benetou V, Trichopoulos D, Ordovas JM . Genetic predisposition, nongenetic risk factors, and coronary infarct. Arch Intern Med 2008; 168: 891–896.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Morrison AC, Bare LA, Chambless LE, Ellis SG, Malloy M, Kane JP et al. Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. Am J Epidemiol 2007; 166: 28–35.

    Article  PubMed  Google Scholar 

  27. Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt NP, Roos C et al. Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med 2008; 358: 1240–1249.

    Article  CAS  PubMed  Google Scholar 

  28. Mishima K, Tozawa T, Satoh K, Saitoh H, Mishima Y . The 3111T/C polymorphism of hClock is associated with evening preference and delayed sleep timing in a Japanese population sample. Am J Med Genet B Neuropsychiatr Genet 2005; 133B: 101–104.

    Article  PubMed  Google Scholar 

  29. Dijk DJ, Archer SN . PERIOD3, circadian phenotypes, and sleep homeostasis. Sleep Med Rev 2010; 14: 151–160.

    Article  PubMed  Google Scholar 

  30. Mendlewicz J . Disruption of the circadian timing systems: molecular mechanisms in mood disorders. CNS Drugs 2009; 23 (Suppl 2): 15–26.

    Article  CAS  PubMed  Google Scholar 

  31. Lee KY, Song JY, Kim SH, Kim SC, Joo EJ, Ahn YM et al. Association between CLOCK 3111T/C and preferred circadian phase in Korean patients with bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 1196–1201.

    Article  CAS  PubMed  Google Scholar 

  32. Eng S, Wagstaff DA, Kranz S . Eating late in the evening is associated with childhood obesity in some age groups but not in all children: the relationship between time of consumption and body weight status in US children. Int J Behav Nutr Phys Act 2009; 6: 27.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Striegel-Moore RH, Rosselli F, Wilson GT, Perrin N, Harvey K, DeBar L . Nocturnal eating: association with binge eating, obesity, and psychological distress. Int J Eat Disord 2010; 43: 520–526.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Frescas D, Valenti L, Accili D . Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 2005; 280: 20589–20595.

    Article  CAS  PubMed  Google Scholar 

  35. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P . Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005; 434: 113–118.

    Article  CAS  PubMed  Google Scholar 

  36. Mendoza J, Pévet P, Challet E . High-fat feeding alters the clock synchronization to light. J Physiol 2008; 586 (Part 24): 5901–5910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Deng XQ, Chen LL, Li NX . The expression of SIRT1 in nonalcoholic fatty liver disease induced by high-fat diet in rats. Liver Int 2007; 27: 708–715.

    Article  CAS  PubMed  Google Scholar 

  38. Ramadori G, Lee CE, Bookout AL, Lee S, Williams KW, Anderson J et al. Brain SIRT1: anatomical distribution and regulation by energy availability. J Neurosci 2008; 28: 9989–9996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009; 458: 1056–1060.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Xue B, Kahn BB . AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues. J Physiol 2006; 574 (Part 1): 73–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB . Ghrelin--a hormone with multiple functions. Front Neuroendocrinol 2004; 25: 27–68.

    Article  CAS  PubMed  Google Scholar 

  42. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC et al. Hypothalamic mTOR signaling regulates food intake. Science 2006; 312: 927–930.

    Article  CAS  PubMed  Google Scholar 

  43. Blouet C, Ono H, Schwartz GJ . Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metab 2008; 8: 459–467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Government of Education, Science and Research of Murcia (Project BIO/FFA 07/01-0004) and by the Spanish Government of Science and Innovation (projects AGL2008-01655/ALI) National Heart, Lung, and Blood Institute Grants HL-54776, National Institute of Diabetes and Digestive and Kidney Diseases, Grant Number DK075030 and by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Garaulet.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Garaulet, M., Esteban Tardido, A., Lee, YC. et al. SIRT1 and CLOCK 3111T>C combined genotype is associated with evening preference and weight loss resistance in a behavioral therapy treatment for obesity. Int J Obes 36, 1436–1441 (2012). https://doi.org/10.1038/ijo.2011.270

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2011.270

Keywords

This article is cited by

Search

Quick links