CLOCK 3111T/C genetic variant influences the daily rhythm of autonomic nervous function: relevance to body weight control.

BACKGROUND/OBJECTIVES: Humans carrying the genetic risk variant C at the circadian CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C have been shown to have more difficulties to achieve desired weight loss than TT carriers. We tested the hypothesis that the daily rhythm of autonomic nervous function differs in CLOCK 3111C carriers, leading to reduced effectiveness in weight control. SUBJECTS/METHODS: We recruited 40 overweight/obese Caucasian women (body mass index>25), 20 carrying CLOCK 3111C (CC and TC) and 20 non-carriers with matched age and body mass index who participated in a dietary obesity treatment program of up to 30 weeks. Following the treatment, ambulatory electrocardiography was continuously monitored for up to 3.5 days when subjects underwent their normal daily activities. To assess autonomic function, heart rate variability analysis (HRV) was performed hourly to obtain mean inter-beat interval between two consecutive R waves (mean RR) and s.d. of normal-to-normal heartbeat intervals (SDNN), and two parasympathetic measures, namely, proportion of differences between adjacent NN intervals that are >50 ms (pNN50), and high-frequency (HF: 0.15-0.4 Hz) power. RESULTS: In the TT carriers, all tested HRV indices showed significant daily rhythms (all P-values <0.0001) with lower mean RR, SDNN, pNN50, and HF during the daytime as compared with the nighttime. The amplitudes of these rhythms except for SDNN were reduced significantly in the C carriers (mean RR: ~19.7%, P=0.001; pNN50: 58.1%, P=0.001; and HF: 41.1%, P=0.001). In addition, subjects with less weight loss during the treatment program had smaller amplitudes in the rhythms of mean RR (P<0.0001), pNN50 (P=0.007) and HF (P=0.003). Furthermore, the rhythmicity-weight loss associations were much stronger in the C carriers as compared to the TT carriers (mean RR: P=0.028, pNN50: P=0.0002; HF: P=0.015). CONCLUSIONS: The daily rhythm of parasympathetic modulation may play a role in the influence of the CLOCK variation on body weight control.

Application of multiparametric procedures for assessing the heritability of circadian health.

At present, the measurement of circadian system status under free-living conditions by the use of sensors is a relatively new technique. The data obtained using these methods are influenced by strong environmental masking factors and artifacts that can affect its recording. Therefore, the use of integrative variables such as TAP, a measure that includes temperature, activity and position that reduces these drawbacks and the number of parameters obtained is necessary. However, the relative genetic contribution to this circadian marker is unknown. The aim of our study was to ascertain the relative importance of genetic influences in TAP, and for each of its components using classical twin models. The study was performed in 53 pairs of female twins [28 monozygotic (MZ) and 25 dizygotic (DZ)] with mean age 52 ± 6 years. Circadian patterns were studied by analyzing temperature, body position and activity for 1 week every 1 min with "Circadianware®.". Genetic influences affecting the variability of each of the measurements were estimated by comparing the observed data in twin pairs. MZ twins showed higher intrapair correlations than DZ twins for most of the parameters. Genetic factors (broad sense heritability) were responsible for about 40-72% of TAP variance in parameters such as mesor, acrophase, amplitude, Rayleigh test, percentage of rhythmicity and circadian function index. We found more homogeneous heritability estimates of the circadian system when using an integrative technique such as TAP than with individual variables alone, suggesting that this measurement can be more reliable and less subject to environmental artifacts.

Meal timing affects glucose tolerance, substrate oxidation and circadian-related variables: A randomized, crossover trial.

BACKGROUND/OBJECTIVES: Timing of food intake associates with body weight regulation, insulin sensitivity and glucose tolerance. However, the mechanism is unknown. The aim of this study was to investigate the effects of changes in meal timing on energy-expenditure, glucose-tolerance and circadian-related variables. SUBJECTS/METHODS: Thirty-two women (aged 24±4 years and body mass index 22.9±2.6 kg m(-2)) completed two randomized, crossover protocols: one protocol (P1) including assessment of resting-energy expenditure (indirect-calorimetry) and glucose tolerance (mixed-meal test) (n=10), the other (P2) including circadian-related measurements based on profiles in salivary cortisol and wrist temperature (Twrist) (n=22). In each protocol, participants were provided with standardized meals (breakfast, lunch and dinner) during the two meal intervention weeks and were studied under two lunch-eating conditions: Early Eating (EE; lunch at 13:00) and Late Eating (LE; lunch 16:30). RESULTS: LE, as compared with EE, resulted in decreased pre-meal resting-energy expenditure (P=0.048), a lower pre-meal protein-corrected respiratory quotient (CRQ) and a changed post-meal profile of CRQ (P=0.019). These changes reflected a significantly lower pre-meal utilization of carbohydrates in LE versus EE (P=0.006). LE also increased glucose area under curve above baseline by 46%, demonstrating decreased glucose tolerance (P=0.002). Changes in the daily profile of cortisol and Twrist were also found with LE blunting the cortisol profile, with lower morning and afternoon values, and suppressing the postprandial Twrist peak (P<0.05). CONCLUSIONS: Eating late is associated with decreased resting-energy expenditure, decreased fasting carbohydrate oxidation, decreased glucose tolerance, blunted daily profile in free cortisol concentrations and decreased thermal effect of food on Twrist. These results may be implicated in the differential effects of meal timing on metabolic health.

Circadian rhythmicity as a predictor of weight-loss effectiveness.

OBJECTIVES: Some of the major challenges associated with successful dietary weight management include the identification of individuals not responsive to specific interventions. The aim was to investigate the potential relationship between weight loss and circadian rhythmicity, using wrist temperature and actimetry measurements, in women undergoing a weight-loss program, in order to assess whether circadian rhythmicity could be a marker of weight-loss effectiveness. METHODS: Participants were 85 overweight and obese women (body mass index, BMI: 30.24±4.95 kg m(-2)) subjected to a weight-reduction program. Efficacy of the treatment was defined as total weight loss, percentage of initial weight and weekly weight loss rates. Circadian rhythmicity in wrist temperature motor activity and position were analyzed using different sensors. RESULTS: Lower weight loss was related with a more flattened pattern measured as amplitude from cosinor (r=0.235, P=0.032), a higher fragmentation of rhythms determined by higher intradaily variability (IV) (r=-0.339, P=0.002), and an impaired wrist temperature circadian rhythm determined by the means of Circadian Function Index (r=0.228, P=0.038). Further analyses showed that low responders displayed lower amplitude (0.71±0.36 versus 1.24±0.62, P=0.036) and higher fragmentation of the circadian rhythm (0.24±0.11 versus 0.15±0.07, P=0.043) than high responders. Whereas we did not find significant differences in total activity rates between high responders and low responders, we found significant differences for the mean values of body position for high responders (39.12±3.79°) as compared with low responder women (35.31±2.53°, P=0.01). CONCLUSIONS: Circadian rhythms at the beginning of the treatment are good predictors of future weight loss. Further treatment should consider chronobiological aspects to diagnose obesity and effectiveness of treatments.

Differences in circadian rhythmicity in CLOCK 3111T/C genetic variants in moderate obese women as assessed by thermometry, actimetry and body position.

INTRODUCTION: Genetics is behind our circadian machinery. CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C single-nucleotide polymorphism (SNP) has been previously related to obesity and weight loss. However, phenotypic association and functionality of CLOCK 3111 locus is still unknown. The aim of this study was to determine, in free-living conditions, if the presence of CLOCK 3111C in overweight women could be related to (a) circadian disorders, and (b) changes in sleep quality, to improve understanding of the previously demonstrated associations with obesity and reduced weight loss of the C carriers. METHODS: Wrist temperature, actimetry and position (TAP) and TAP variables were measured as markers of circadian functionality during 8 consecutive days. A rest-activity and food diary was also completed, whereas sleep quality was determined by domiciliary polysomnography. We recruited 85 women who were overweight with body mass index (BMI) of 28.59±4.30 kg m(-2) and age 43±12 years. From this sample, we found that 43 women were carrying the minor allele (C) for CLOCK 3111T/C SNP and 42 women were TT carriers (major allele carriers). Both groups of patients were matched for number, age, obesity parameters and energy intake. RESULTS: Compared with TT subjects, who showed more robust circadian rhythm profiles, patients with the C allele displayed significant circadian abnormalities: lower amplitude and greater fragmentation of the rhythm, a less stable circadian pattern and a significantly weakened circadian function, as assessed by the circadian function index (CFI). C subjects were also less active, started their activities later in the morning and were sleepier during the day, showing a delayed acrophase that characterizes 'evening-type' subjects. CONCLUSION: C genetic variants in CLOCK 3111T/C display a less robust circadian rhythm than TT and a delayed acrophase that characterizes 'evening-type' subjects. We support the notion that identifying CLOCK genotypes in patients may assist the therapist in characterization of the roots of the metabolic problem.