Adropin is a peptide hormone encoded by the Energy Homeostasis Associated (ENHO) gene whose physiological role in humans remains incompletely defined. Here we investigated the impact of dietary interventions that affect systemic glucose and lipid metabolism on plasma adropin concentrations in humans. Consumption of glucose or fructose as 25% of daily energy requirements (E) differentially affected plasma adropin concentrations (P < 0.005) irrespective of duration, sex or age. Glucose consumption reduced plasma adropin from 3.55 ± 0.26 to 3.28 ± 0.23 ng/ml (N = 42). Fructose consumption increased plasma adropin from 3.63 ± 0.29 to 3.93 ± 0.34 ng/ml (N = 45). Consumption of high fructose corn syrup (HFCS) as 25% E had no effect (3.43 ± 0.32 versus 3.39 ± 0.24 ng/ml, N = 26). Overall, the effect of glucose, HFCS and fructose on circulating adropin concentrations were similar to those observed on postprandial plasma triglyceride concentrations. Furthermore, increases in plasma adropin levels with fructose intake were most robust in individuals exhibiting hypertriglyceridemia. Individuals with low plasma adropin concentrations also exhibited rapid increases in plasma levels following consumption of breakfasts supplemented with lipids. These are the first results linking plasma adropin levels with dietary sugar intake in humans, with the impact of fructose consumption linked to systemic triglyceride metabolism. In addition, dietary fat intake may also increase circulating adropin concentrations.

Chrononutrition is a rapidly evolving field of nutritional epidemiology that addresses the complex relationship between temporal eating patterns, circadian rhythms, and metabolic health, but most prior research has focused on the cardiometabolic consequences of time-restricted feeding and intermittent fasting. The purpose of this topical review is to summarize epidemiological evidence from observational and intervention studies regarding the role of chrononutrition metrics related to eating timing and regularity in cardiometabolic health preservation and cardiovascular disease prevention. Observational studies are limited due to the lack of time-stamped diet data in most population-based studies. Findings from cohort studies generally indicate that breakfast skipping or the later timing of the first eating occasion, a later lunch and dinner, and a greater proportion of caloric intake consumed in the evening are associated with adverse cardiometabolic outcomes, including higher risk for coronary heart disease, hypertension, type 2 diabetes, obesity, dyslipidemia, and systemic inflammation. Randomized controlled trials are also limited, as most in the field of chrononutrition focus on the cardiometabolic consequences of time-restricted feeding. Overall, interventions that shift eating timing patterns to earlier in the day and that restrict evening caloric intake tend to have protective effects on cardiometabolic health, but small sample sizes and short follow-up are notable limitations. Innovation in dietary assessment approaches, to develop low-cost validated tools with acceptable participant burden that reliably capture chrononutrition metrics, is needed for advancing observational evidence. Culturally responsive pragmatic intervention studies with sufficiently large and representative samples are needed to understand the impact of fixed and earlier eating timing schedules on cardiometabolic health. Additional research is warranted to understand the modifiable determinants of temporal eating patterns, to investigate the role of chrononutrition in the context of other dimensions of diet (quantity, quality, and food and nutrition security) in achieving cardiometabolic health equity, and to elucidate underlying physiological mechanisms.

Background

The timing and regularity of eating patterns could play a role in systemic inflammation, as circadian clocks responsible for daily rhythms of inflammatory signaling are entrained by food intake.

Purpose

To evaluate associations of intra-weekly and weekday-weekend differences in eating timing patterns with high-sensitivity C-reactive protein (hsCRP).

Methods

A community-based sample of 103 U.S. women from the American Heart Association Go Red for Women Strategically Focused Research Network completed a meal-timing questionnaire and provided a blood sample for measurement of hsCRP. Differences in weekday versus weekend eating start time, eating end time, and nightly fasting duration were calculated as eating jetlag metrics. Intra-weekly variability in eating timing patterns was defined by the standard deviation (SD) of these variables. Multivariable linear regression models were used to evaluate cross-sectional associations of eating timing variability metrics with hsCRP.

Results

Each additional 30-min difference in weekday-weekend eating end time was related to 13% higher hsCRP (p = .023). Similarly, every 30-min increase in eating end time SD, reflecting greater variability in timing of last eating occasion, was associated with 29% higher hsCRP. Per 1-hr weekday-weekend difference in nightly fasting duration, there was a 45% elevation in hsCRP (p = .003). Every 30-min increase in nightly fasting duration SD, representing greater variability in span of the daily fasting/eating periods, was associated with 46% higher hsCRP.

Conclusions

Variable eating timing patterns were associated with higher hsCRP. Intervention studies are needed to determine whether stabilizing the timing of eating occasions may represent a novel strategy to reduce chronic inflammation.

Context

Mouse studies suggest that adropin, a peptide hormone, is required for metabolic homeostasis and prevention of obesity-associated insulin resistance. Whether obesity and insulin resistance are associated with low plasma adropin levels in humans is not known.

Objectives

Our objective was to investigate the hypothesis that obesity and indicators of insulin resistance are associated with low adropin levels and determine whether weight loss regulates adropin levels.

Design and participants

Plasma was obtained from 85 female [age 21-67 yr, body mass index (BMI) 19.4-71.5 kg/m2] and 45 male (age 18-70 yr, BMI 19.1-62.6 kg/m2) volunteers for other clinical studies. The impact of Roux-en-Y gastric bypass was investigated in 19 obese females (BMI 37-65 kg/m2) using samples collected at baseline and 1-12 months after surgery.

Results

Adropin levels correlate negatively with BMI (r=-0.335, P<0.001) and age (r=-0.263, P=0.003). Age-adjusted adropin levels are higher in males [4.1 ng/ml; 95% confidence interval (CI)=3.6-4.6 ng/ml] than females (3.0 ng/ml; 95% CI=2.6-3.4 ng/ml) (P=0.001). In all subjects, lower age-adjusted adropin levels were observed in overweight (3.3 ng/ml; 95% CI=2.8-3.8 ng/ml, P=0.033) and obese (2.7 ng/ml; 95% CI=2.1-3.3 ng/ml, P=0.001) compared with healthy-weight subjects (4.1 ng/ml; 95% CI=3.6-4.5 ng/ml). This effect was gender specific (weight category×gender, P<0.001) and was observed in males only. Aging and diagnosis with two or more metabolic syndrome risk factors was associated with low adropin levels, irrespective of sex. Adropin concentrations increased after Roux-en-Y gastric bypass, peaking 3 months after surgery (P<0.01).

Conclusions

Although males exhibit higher adropin levels that are reduced by obesity, aging and markers of insulin resistance are associated with low plasma adropin irrespective of sex.

Nightly fasting duration (NFD) and eating timing and frequency may influence cardiometabolic health via their impact on circadian rhythms, which are entrained by food intake, but observational studies are limited. This 1-year prospective study of 116 US women (33 ± 12y, 45% Hispanic) investigated associations of habitual NFD and eating timing and frequency with cardiovascular health (CVH; American Heart Association Life's Simple 7 score) and cardiometabolic risk factors. NFD, eating timing and frequency, and nighttime eating levels were evaluated from 1-week electronic food records completed at baseline and 1 y. In multivariable-adjusted linear regression models, longer NFD was associated with poorer CVH (β = -0.22, p = 0.016 and β = -0.22, p = 0.050) and higher diastolic blood pressure (DBP) (β = 1.08, p < 0.01 and β = 1.74, p < 0.01) in cross-sectional and prospective analyses, respectively. Later timing of the first eating occasion at baseline was associated with poorer CVH (β = -0.20, p = 0.013) and higher DBP (β = 1.18, p < 0.01) and fasting glucose (β = 1.43, p = 0.045) at 1 y. After adjustment for baseline outcomes, longer NFD and later eating times were also associated with higher waist circumference (β = 0.35, p = 0.021 and β = 0.27, p < 0.01, respectively). Eating frequency was inversely related to DBP in cross-sectional (β = -1.94, p = 0.033) and prospective analyses (β = -3.37, p < 0.01). In cross-sectional analyses of baseline data and prospective analyses, a higher percentage of daily calories consumed at the largest evening meal was associated with higher DBP (β = 1.69, p = 0.046 and β = 2.32, p = 0.029, respectively). Findings suggest that frequent and earlier eating may lower cardiometabolic risk, while longer NFD may have adverse effects. Results warrant confirmation in larger multi-ethnic cohort studies with longer follow-up periods.

Objective

The role of metabolic condition and diet in regulating circulating levels of adropin, a peptide hormone linked to cardiometabolic control, is not well understood. In this study, weight loss and diet effects on plasma adropin concentrations were examined.

Methods

This report includes data from (1) a weight loss trial, (2) an evaluation of acute exercise effects on mixed-meal (60% kcal from carbohydrates) tolerance test responses, and (3) a meta-analysis to determine normal fasting adropin concentrations.

Results

Distribution of plasma adropin concentrations exhibited positive skew and kurtosis. The effect of weight loss on plasma adropin concentrations was dependent on baseline plasma adropin concentrations, with an inverse association between baseline and a decline in concentrations after weight loss (Spearman's ρ = -0.575; P < 0.001). When ranked by baseline plasma adropin concentrations, only values in the upper quartile declined with weight loss. Plasma adropin concentrations under the main area of the bell curve correlated negatively with habitual carbohydrate intake and plasma lipids. There was a negative correlation between baseline values and a transient decline in plasma adropin during the mixed-meal tolerance test.

Conclusions

Plasma adropin concentrations in humans are sensitive to dietary macronutrients, perhaps due to habitual consumption of carbohydrate-rich diets suppressing circulating levels. Very high adropin levels may indicate cardiometabolic conditions sensitive to weight loss.

Background Sleep variability and social jetlag are associated with adverse cardiometabolic outcomes via circadian disruption. Variable eating patterns also lead to circadian disruption, but associations with cardiometabolic health are unknown. Methods and Results Women (n=115, mean age: 33±12 years) completed a 1-week food record using the Automated Self-Administered 24-Hour Dietary Assessment Tool at baseline and 1 year. Timing of first and last eating occasions, nightly fasting duration, and %kcal consumed after 5 pm (%kcal 5 pm) and 8 pm (%kcal 8 pm) were estimated. Day-to-day eating variability was assessed from the SD of these variables. Eating jetlag was defined as weekday-weekend differences in these metrics. Multivariable-adjusted linear models examined cross-sectional and longitudinal associations of day-to-day variability and eating jetlag metrics with cardiometabolic risk. Greater jetlag in eating start time, nightly fasting duration, and %kcal 8 pm related to higher body mass index and waist circumference at baseline (P<0.05). In longitudinal analyses, a 10% increase in %kcal 8 pm SD predicted increased body mass index (β, 0.52; 95% CI, 0.23-0.81) and waist circumference (β, 1.73; 95% CI, 0.58-2.87); greater %kcal 8 pm weekday-weekend differences predicted higher body mass index (β, 0.25; 95% CI, 0.07-0.43). Every 30-minute increase in nightly fasting duration SD predicted increased diastolic blood pressure (β, 0.95; 95% CI, 0.40-1.50); an equivalent increase in nightly fasting duration weekday-weekend differences predicted higher systolic blood pressure (β, 0.58; 95% CI, 0.11-1.05) and diastolic blood pressure (β, 0.45; 95% CI, 0.10-0.80). Per 10% increase in %kcal 5 pm SD, there were 2.98 mm Hg (95% CI, 0.04-5.92) and 2.37mm Hg (95% CI, 0.19-4.55) increases in systolic blood pressure and diastolic blood pressure; greater %kcal 5 pm weekday-weekend differences predicted increased systolic blood pressure (β, 1.83; 95% CI, 0.30-3.36). For hemoglobin A1c, every 30-minute increase in eating start and end time SD and 10% increase in %kcal 5 pm SD predicted 0.09% (95% CI, 0.03-0.15), 0.06% (95% CI, 0.001-0.12), and 0.23% (95% CI, 0.07-0.39) increases, respectively. Conclusions Variable eating patterns predicted increased blood pressure and adiposity and worse glycemic control. Findings warrant confirmation in population-based cohorts and intervention studies.

Background

Previous studies have shown mixed results on the association between carbohydrate intake and insomnia. However, any influence that refined carbohydrates have on risk of insomnia is likely commensurate with their relative contribution to the overall diet, so studies are needed that measure overall dietary glycemic index (GI), glycemic load, and intakes of specific types of carbohydrates.

Objective

We hypothesized that higher GI and glycemic load would be associated with greater odds of insomnia prevalence and incidence.

Methods

This was a prospective cohort study with postmenopausal women who participated in the Women's Health Initiative Observational Study, investigating the relations of GI, glycemic load, other carbohydrate measures (added sugars, starch, total carbohydrate), dietary fiber, and specific carbohydrate-containing foods (whole grains, nonwhole/refined grains, nonjuice fruits, vegetables, dairy products) with odds of insomnia at baseline (between 1994 and 1998; n = 77,860) and after 3 y of follow-up (between 1997 and 2001; n = 53,069).

Results

In cross-sectional and longitudinal analyses, higher dietary GI was associated with increasing odds of prevalent (fifth compared with first quintile OR: 1.11; CI: 1.05, 1.16; P-trend = 0.0014) and incident (fifth compared with first quintile OR: 1.16; CI: 1.08, 1.25; P-trend < 0.0001) insomnia in fully adjusted models. Higher intakes of dietary added sugars, starch, and nonwhole/refined grains were each associated with higher odds of incident insomnia. By contrast, higher nonjuice fruit and vegetable intakes were significantly associated with lower odds of incident insomnia. Also, higher intakes of dietary fiber, whole grains, nonjuice fruit, and vegetables were significantly associated with lower odds of prevalent insomnia.

Conclusions

The results suggest that high-GI diets could be a risk factor for insomnia in postmenopausal women. Substitution of high-GI foods with minimally processed, whole, fiber-rich carbohydrates should be evaluated as potential treatments of, and primary preventive measures for, insomnia in postmenopausal women.

The Go Red for Women movement was initiated by the American Heart Association (AHA) in the early 2000s to raise awareness concerning cardiovascular disease (CVD) risk in women. In 2016, the AHA funded 5 research centers across the United States to advance our knowledge of the risks and presentation of CVD that are specific to women. This report highlights the findings of the centers, showing how insufficient sleep, sedentariness, and pregnancy-related complications may increase CVD risk in women, as well as presentation and factors associated with myocardial infarction with nonobstructive coronary arteries and heart failure with preserved ejection fraction in women. These projects were augmented by collaborative ancillary studies assessing the relationships between various lifestyle behaviors, including nightly fasting duration, mindfulness, and behavioral and anthropometric risk factors and CVD risk, as well as metabolomic profiling of heart failure with preserved ejection fraction in women. The Go Red for Women Strategically Focused Research Network enhanced the evidence base related to heart disease in women, promoting awareness of the female-specific factors that influence CVD.

Patients with primary mitochondrial oxidative phosphorylation (OxPhos) defects present with fatigue and multi-system disorders, are often lean, and die prematurely, but the mechanistic basis for this clinical picture remains unclear. By integrating data from 17 cohorts of patients with mitochondrial diseases (n = 690) we find evidence that these disorders increase resting energy expenditure, a state termed hypermetabolism. We examine this phenomenon longitudinally in patient-derived fibroblasts from multiple donors. Genetically or pharmacologically disrupting OxPhos approximately doubles cellular energy expenditure. This cell-autonomous state of hypermetabolism occurs despite near-normal OxPhos coupling efficiency, excluding uncoupling as a general mechanism. Instead, hypermetabolism is associated with mitochondrial DNA instability, activation of the integrated stress response (ISR), and increased extracellular secretion of age-related cytokines and metabokines including GDF15. In parallel, OxPhos defects accelerate telomere erosion and epigenetic aging per cell division, consistent with evidence that excess energy expenditure accelerates biological aging. To explore potential mechanisms for these effects, we generate a longitudinal RNASeq and DNA methylation resource dataset, which reveals conserved, energetically demanding, genome-wide recalibrations. Taken together, these findings highlight the need to understand how OxPhos defects influence the energetic cost of living, and the link between hypermetabolism and aging in cells and patients with mitochondrial diseases.