Background Circadian Locomotor Output Cycles Kaput (CLOCK), an essential element of the positive regulatory arm in the human biological clock, is involved in metabolic regulation. The aim was to investigate the behavioral (sleep duration, eating patterns and chronobiological characteristics) and hormonal (plasma ghrelin and leptin concentrations) factors which could explain the previously reported association between the CLOCK 3111T/C SNP and weight loss.Methodology/Principal FindingsWe recruited 1495 overweight/obese subjects (BMI: 25–40 kg/m2) of 20–65 y. who attended outpatient obesity clinics in Murcia, in southeastern Spain. We detected an association between the CLOCK 3111T/C SNP and weight loss, which was particularly evident after 12–14 weeks of treatment (P = 0.038). Specifically, carriers of the minor C allele were more resistant to weight loss than TT individuals (Mean±SEM) (8.71±0.59 kg vs 10.4±0.57 kg) C and TT respectively. In addition, our data show that minor C allele carriers had: 1. shorter sleep duration Mean ± SEM (7.0±0.05 vs 7.3±0.05) C and TT respectively (P = 0.039), 2. higher plasma ghrelin concentrations Mean ± SEM (pg/ml) (1108±49 vs 976±47)(P = 0.034); 3. delayed breakfast time; 4. evening preference and 5. less compliance with a Mediterranean Diet pattern, as compared with TT homozygotes.Conclusions/SignificanceSleep reduction, changes in ghrelin values, alterations of eating behaviors and evening preference that characterized CLOCK 3111C carriers could be affecting weight loss. Our results support the hypothesis that the influence of the CLOCK gene may extend to a broad range of variables linked with human behaviors.

APOA5 is one of the strongest regulators of plasma TG concentrations; nevertheless, its mechanisms of action are poorly characterized. Genetic variability at the APOA5 locus has also been associated with increased cardiovascular disease risk; however, this predisposition could be attenuated in the context of a prudent diet as traditionally consumed in the Mediterranean countries. We have investigated the interaction between a single nucleotide polymorphism (SNP) at the APOA5 gene (-1131T > C) and dietary fat that may modulate TG-rich lipoprotein concentrations and anthropometric measures in overweight and obese participants. We recruited 1465 participants from a Spanish population (20-65 y old; BMI 25-40 kg/m(2)) attending outpatient obesity clinics. Consistent with previous reports, we found an association between the APOA5-1131T > C SNP and TG-rich lipoprotein concentrations that were higher in carriers of the minor allele than in noncarriers (P < 0.001). Moreover, we found a significant genotype-dietary fat interaction for obesity traits. Participants homozygous for the -1131T major allele had a positive association between fat intake and obesity, whereas in those carrying the APOA5-1131C minor allele, higher fat intakes were not associated with higher BMI. Likewise, we found genotype-dietary fat interactions for TG-rich lipoproteins (P < 0.001). In conclusion, we have replicated previous gene-diet interactions between APOA5 -1131T > C SNP and fat intake for obesity traits and detected a novel interaction for TG-rich lipoprotein concentrations. Our data support the hypothesis that the minor C-allele may protect those consuming a high-fat diet from obesity and elevated concentrations of TG-rich lipoproteins.

Background The interaction between apolipoprotein A-II (APOA2) m265 genotype and saturated fat for obesity traits has been more extensively demonstrated than for any other locus, but behavioural and hormonal mechanisms underlying this relationship are unexplored. In this study, we evaluated relationships between APOA2 and obesity risk with particular focus on patterns of eating and ghrelin, a hormonal regulator of food intake. Design Cross-sectional study. Subjects Overweight and obese subjects (n = 1225) were evaluated at baseline in five weight loss clinics in southeastern Spain. Methods Behavioural data were assessed using a checklist of weight loss obstacles. Logistic regression models were fitted to estimate the risk of a specific behaviour associated with APOA2 genotype. Relationships between APOA2 genotype and saturated fat intakes for anthropometric traits and plasma ghrelin were evaluated by analysis of variance. To construct categorical variables to evaluate interactions, saturated fat intake was dichotomized into high and low according to the population median intake or as tertiles. Results Homozygous minor (CC) subjects were more likely to exhibit behaviours that impede weight loss (‘Do you skip meals’, odds ratio (OR) = 2.09, P=0.008) and less likely to exhibit the protective behaviour of ‘Do you plan meals in advance’ (OR = 0.64, P=0.034). Plasma ghrelin for CC subjects consuming low saturated fat was lower compared with (1) CC subjects consuming high saturated fat, (2) TT + TC carriers consuming low saturated fat and (3) TT+TC carriers consuming high saturated fat (all P<0.05). Conclusions APOA2 m265 genotype may be associated with eating behaviours and dietary modulation of plasma ghrelin. Expansion of knowledge of APOA2 and obesity to include modulation of specific behaviours and hormonal mediators not only broadens understanding of gene–diet interactions, but also facilitates the pragmatic, future goal of developing dietary guidelines based on genotype.

In mammals, the molecular circadian clockwork is comprised of interlocked transcriptional-translational feedback loops (TTLs). Three Period (Per1-3) and 2 Dec (Dec1/2) genes interact in regulating the activity of the transcriptional activators CLOCK/NPAS2 and BMAL1. While deletion of Per1 and Per2 in mice results in behavioral arrhythmicity, Dec deletion has less dramatic effects on activity rhythms, affecting primarily phase of entrainment and free-running period. In intact animals, clock gene mutant phenotypes are often masked due to intercellular coupling mechanisms that stabilize cellular rhythms. Therefore, to study Per/Dec genetic interaction at the cellular level, we isolated fibroblasts from different tissues of Per1, Per2, and Dec2 single and double mutant mice. We show that in the cellular TTL, Pers and Dec2 act in a principally synergistic way, but tissue-specific differences in this interaction are seen. A rescue of rhythmicity in Per2 mutant cells after additional deletion of Dec2 was observed, indicating that in the absence of Per2, DEC2 destabilizes TTL function. Rhythm power in Per1/Dec2 and Per2/Dec2 double mutants was strongly reduced, suggesting that interaction of Dec2 with both Per genes is important for stabilizing clock period. Contrary to what was observed for behavior, nonsynergistic effects of Dec2 and Per1/2 mutations were observed on cellular clock phase regulation that do not correlate with period effects. Our data reveal cell type-specific interactions of Per1/2 and Dec2 in the regulation of period, phase, and rhythm sustainment, emphasizing the differential organization of the mammalian clock machinery in different tissues.