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

Author
item GARAULET, MARTA - Universidad De Murcia
item ESTEBAN TARDIDO, ALBERTO - Universidad De Murcia
item LEE, YU-CHI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item SMITH, CAREN E. - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Parnell, Laurence
item ORDOVAS, JOSE M. - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: International Journal of Obesity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/5/2011
Publication Date: 2/7/2012
Citation: Garaulet, M., Esteban Tardido, A., Lee, Y., Smith, C., Parnell, L.D., Ordovas, J. 2012. SIRT1 and CLOCK 3111T greater than C combined genotype is associated with evening preference and weight loss resistance in a behavioral therapy treatment for obesity. International Journal of Obesity. DOI: 10.1038/ijo.2011.270.

Interpretive Summary: Recent evidence has come to light showing that a gene known as SIRT1 participates in regulating the circadian clock, or basic 24-hour rhythms central to life. Importantly, the SIRT1-based regulation of the clock has implications on essential metabolism. This study sought to examine the influence of genetic variants in the SIRT1 and CLOCK genes on both the resistance of persons to lose weight, when following a Mediterranean diet, and their chronotype, or classification as morning type or evening type. Overweight and obese adults, who attended outpatient obesity clinics, were assessed for common genetic variants of the SIRT1 and CLOCK genes, and their body measurement, biochemical and dietary-intake variables were analyzed. Effectiveness of the 30-week weight-loss regimen was also determined. Persons with the less common versions of the SIRT1 and CLOCK genes (R group) displayed greater resistance to weight loss overall and a lower weekly weight loss rate compared to persons with two copies of the more common versions of these two genes (P group). Interestingly, an analysis of dietary patterns showed that the R group tended to have lower intake of total carbohydrates and monounsaturated fats but higher intake of saturated fat than the P group. Blood levels of ghrelin, a hormone affiliated with hunger, were also elevated in the R group. In conclusion, certain genetic variants of the SIRT1 and CLOCK genes in combination have an additive effect on resistance to weight loss, which could stem from whether the person is a morning or evening type, the higher levels of the hunger messenger ghrelin, or reduced adherence to a Mediterranean diet.

Technical 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.