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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



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.


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.


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.


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.


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.

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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.

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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).

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