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Background: Working during the night interferes with the timing of normal daily activities and is associated with an increased risk of chronic diseases. Under controlled experimental conditions, interventions focusing on sleep and nutrition can mitigate the short-term adverse effects of shift work. However, it is unclear how these results translate to real-life, how they can be targeted to individual conditions, and how they relate to long-term health. Therefore, the current study aims to implement a personalized sleep and nutritional intervention among night shift workers in the field., Methods: A non-blinded controlled intervention study is used, consisting of a run-in period, an intervention of 3 months, post-intervention measurements, and a follow-up after 12 months. Three study arms are included: sleep intervention, nutritional intervention, and control group (n = 25 each). Participants are healthy 18-60-year male night shift workers, with at least one year of experience in night shift work. Information from the run-in period will be used to personalize the interventions. The main outcomes are sleep measurements and continuous interstitial glucose levels. Furthermore, general health biomarkers and parameters will be determined to further evaluate effects on long-term health., Discussion: This study aims to mitigate negative health consequences associated with night shift work by introducing two personalized preventive interventions. If proven effective, the personalized interventions may serve as practical solutions that can have a meaningful impact on the sustainable health and employability of night shift workers. This study will thereby contribute to the current need for high-quality data on preventative strategies for night shift work in a real-life context., Trial Registration: This trial has been registered under ClinicalTrials.gov Identifier NCT06147089. Registered 27 November 2023., (© 2024. The Author(s).)

Background and Aims: The gut microbiome exerts important roles in health, e.g., functions in metabolism and immunology. These functions are often exerted via short-chain fatty acid (SCFA) production by gut bacteria. Studies demonstrating causal relationships between interventions targeting the microbiome and clinical outcomes are limited. This study aimed to show a causal relationship between microbiome modulation through fibre intervention and health., Methods and Results: This randomized, double-blind, cross-over study included 65 healthy subjects, aged 45-70 years, with increased metabolic risk (i.e., body mass index [BMI] 25-30 kg/m 2 , low to moderate daily dietary fibre intake, <30g/day). Subjects took daily a fibre mixture of Acacia gum and carrot powder or placebo for 12 weeks, with an 8-week wash-out period. Faecal samples for measurement of SCFAs and microbiome analysis were collected every 4 weeks. Before and after each intervention period subjects underwent the mixed-meal PhenFlex challenge Test (PFT). Health effects were expressed as resilience to the stressors of the PFT and as fasting metabolic and inflammatory state. The fibre mixture exerted microbiome modulation, with an increase in β-diversity (p < 0.001). α-diversity was lower during fibre mixture intake compared to placebo after 4, 8 and 12 weeks (p = 0.002; p = 0.012; p = 0.031). There was no effect observed on faecal SCFA concentrations, nor on any of the primary clinical outcomes (Inflammatory resilience: p = 0.605, Metabolic resilience: p = 0.485)., Conclusion: Although the intervention exerted effects on gut microbiome composition, no effects on SCFA production, on resilience or fasting metabolic and inflammatory state were observed in this cohort. REGISTRATION NUMBER CLINICALTRIALS.GOV: NCT04829396., Competing Interests: Declaration of competing interest All authors declare that they have no relevant financial interests or disclosures to report. This study was part of the collaboration project No Guts No Glory., (Copyright © 2024. Published by Elsevier B.V.)

Although lifestyle interventions can lead to diabetes remission, it is unclear to what extent type 2 diabetes (T2D) remission alters or improves the underlying pathophysiology of the disease. Here, we assess the effects of a lifestyle intervention on T2D reversal or remission and the effects on the underlying pathology. In a Dutch primary care setting, 15 adults with an average T2D duration of 13.4 years who were (pharmacologically) treated for T2D received a diabetes subtyping ("diabetyping") lifestyle intervention (DLI) for six months, aiming for T2D remission. T2D subtype was determined based on an OGTT. Insulin and sulphonylurea (SU) derivative treatment could be terminated for all participants. Body weight, waist/hip ratio, triglyceride levels, HbA1c, fasting, and 2h glucose were significantly improved after three and six months of intervention. Remission and reversal were achieved in two and three participants, respectively. Indices of insulin resistance and beta cell capacity improved, but never reached healthy values, resulting in unchanged T2D subtypes. Our study implies that achieving diabetes remission in individuals with a longer T2D duration is possible, but underlying pathology is only minimally affected, possibly due to an impaired beta cell function. Thus, even when T2D remission is achieved, patients need to continue adhering to lifestyle therapy.

Obesity and type 2 diabetes (T2D) have become a global health concern. The prevalence of obesity and T2D is significantly higher in shift workers compared to people working regular hours. An accepted hypothesis is that the increased risk for metabolic health problems arises from aberrantly timed eating behavior, that is, eating out of synchrony with the biological clock. The biological clock is part of the internal circadian timing system, which controls not only the sleep/wake and feeding/fasting cycle, but also many metabolic processes in the body, including the timing of our eating behavior, and processes involved in glucose homeostasis. Rodent studies have shown that eating out of phase with the endogenous clock results in desynchronization between rhythms of the central and peripheral clock systems and between rhythms of different tissue clocks (eg, liver and muscle clock). Glucose homeostasis is a complex process that involves multiple organs. In the healthiest situation, functional rhythms of these organs are synchronized. We hypothesize that desynchronization between different metabolically active organs contributes to alterations in glucose homeostasis. Here we summarize the most recent information on desynchronization between organs due to shift work and shifted food intake patterns and introduce the concept of phenotypic flexibility, a validated test to assess the contribution of each organ to insulin resistance (IR) in humans. We propose this test as a way to provide further insight into the possible desynchronization between tissue clocks. Because different types of IR benefit from different therapeutic approaches, we also describe different chronotherapeutic strategies to promote synchrony within and between metabolically active organs., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Eating out of phase with the endogenous biological clock alters clock and metabolic gene expression in rodents and can induce obesity and type 2 diabetes mellitus. Diet composition can also affect clock gene expression. This study assessed the combined effect of diet composition and feeding time on (1) body composition, (2) energy balance, and (3) circadian expression of hepatic clock and metabolic genes., Methods: Male Wistar rats were fed a chow or a free-choice high-fat, high-sugar (fcHFHS) diet, either ad libitum or with food access restricted to either the light or dark period. Body weight, adiposity, and hepatic fat accumulation as well as hepatic clock and metabolic mRNA expression were measured after 5 weeks of the diet. Energy expenditure was measured using calorimetric cages., Results: Animals with access to the fcHFHS diet only during the light period showed more hepatic fat accumulation than fcHFHS dark-fed animals despite less calories consumed. In contrast, within the chow-fed groups, light-fed animals showed the lowest hepatic fat content, but they also showed the lowest caloric intake. Locomotor activity and heat production followed feeding times, except in the fcHFHS light-fed group. Hepatic clock and metabolic gene expression rhythms also followed timing of food intake. Yet, in the fcHFHS light-fed animals, clock gene expression appeared 3 hours advanced compared with chow light-fed animals, an effect not observed in the fcHFHS dark-fed animals., Conclusions: An fcHFHS diet consumed in the light period promotes hepatic fat accumulation and advances clock gene expression in male Wistar rats, likely because of a mismatch between energy intake and expenditure., (© 2020 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society (TOS).)

Introduction: With chronotherapy, drug administration is synchronized with daily rhythms in drug clearance and pharmacokinetics. Daily rhythms in gene expression are centrally mastered by the suprachiasmatic nucleus of the hypothalamus as well as by tissue clocks containing similar molecular mechanisms in peripheral organs. The central timing system is sensitive to changes in the external environment such as those of the light-dark cycle, meal timing and meal composition. We investigated how changes in diet composition and meal timing would affect the daily hepatic expression rhythms of the nuclear receptors PXR and CAR and of enzymes involved in P450 mediated drug metabolism, as such changes could have consequences for the practice of chronotherapy., Materials and Methods: Rats were subjected to either a regular chow or a free choice high-fat-high-sugar (fcHFHS) diet. These diets were provided ad libitum, or restricted to either the light phase or the dark phase. In a second experiment, rats had access to chow either ad libitum or in 6 meals equally distributed over 24 hours., Results: Pxr, Alas1 and Por displayed significant day-night rhythms under ad libitum chow fed conditions, which for Pxr was disrupted under fcHFHS diet conditions. Although no daily rhythms were detected in expression of CAR, Cyp2b2 and Cyp3a2, the fcHFHS diet did affect basal expression of these genes. In chow fed rats, dark phase feeding induced a diurnal rhythm in Cyp2b2 expression while light phase feeding induced a diurnal rhythm in Car expression and completely shifted the peak expression of Pxr, Car, Cyp2b2, Alas1 and Por. The 6-meals-a-day feeding only abolished the Pxr rhythm but not the rhythms of the other genes., Conclusion: We conclude that although nuclear receptors and enzymes involved in the regulation of hepatic drug metabolism are sensitive to meal composition, changes in meal timing are mainly effectuated via changes in the molecular clock.

The effects of feeding behavior and diet composition, as well as their possible interactions, on daily (clock) gene expression rhythms have mainly been studied in the liver, and to a lesser degree in white adipose tissue (WAT), but hardly in other metabolic tissues such as skeletal muscle (SM) and brown adipose tissues (BAT). We therefore subjected male Wistar rats to a regular chow or free choice high-fat-high sugar (fcHFHS) diet in combination with time restricted feeding (TRF) to either the light or dark phase. In SM, all tested clock genes lost their rhythmic expression in the chow light fed group. In the fcHFHS light fed group rhythmic expression for some, but not all, clock genes was maintained, but shifted by several hours. In BAT the daily rhythmicity of clock genes was maintained for the light fed groups, but expression patterns were shifted as compared with ad libitum and dark fed groups, whilst the fcHFHS diet made the rhythmicity of clock genes become more pronounced. Most of the metabolic genes in BAT tissue tested did not show any rhythmic expression in either the chow or fcHFHS groups. In SM Pdk4 and Ucp3 were phase-shifted, but remained rhythmically expressed in the chow light fed groups. Rhythmic expression was lost for Ucp3 whilst on the fcHFHS diet during the light phase. In summary, both feeding at the wrong time of day and diet composition disturb the peripheral clocks in SM and BAT, but to different degrees and thereby result in a further desynchronization between metabolically active tissues such as SM, BAT, WAT and liver.

Desynchronization between the master clock in the brain, which is entrained by (day) light, and peripheral organ clocks, which are mainly entrained by food intake, may have negative effects on energy metabolism. Bile acid metabolism follows a clear day/night rhythm. We investigated whether in rats on a normal chow diet the daily rhythm of plasma bile acids and hepatic expression of bile acid metabolic genes is controlled by the light/dark cycle or the feeding/fasting rhythm. In addition, we investigated the effects of high caloric diets and time-restricted feeding on daily rhythms of plasma bile acids and hepatic genes involved in bile acid synthesis. In experiment 1 male Wistar rats were fed according to three different feeding paradigms: food was available ad libitum for 24 h (ad lib) or time-restricted for 10 h during the dark period (dark fed) or 10 h during the light period (light fed). To allow further metabolic phenotyping, we manipulated dietary macronutrient intake by providing rats with a chow diet, a free choice high-fat-high-sugar diet or a free choice high-fat (HF) diet. In experiment 2 rats were fed a normal chow diet, but food was either available in a 6-meals-a-day (6M) scheme or ad lib. During both experiments, we measured plasma bile acid levels and hepatic mRNA expression of genes involved in bile acid metabolism at eight different time points during 24 h. Time-restricted feeding enhanced the daily rhythm in plasma bile acid concentrations. Plasma bile acid concentrations are highest during fasting and dropped during the period of food intake with all diets. An HF-containing diet changed bile acid pool composition, but not the daily rhythmicity of plasma bile acid levels. Daily rhythms of hepatic Cyp7a1 and Cyp8b1 mRNA expression followed the hepatic molecular clock, whereas for Shp expression food intake was leading. Combining an HF diet with feeding in the light/inactive period annulled CYp7a1 and Cyp8b1 gene expression rhythms, whilst keeping that of Shp intact. In conclusion, plasma bile acids and key genes in bile acid biosynthesis are entrained by food intake as well as the hepatic molecular clock. Eating during the inactivity period induced changes in the plasma bile acid pool composition similar to those induced by HF feeding.

Specific neurons in the hypothalamus are regulated by peripheral hormones and nutrients to maintain proper metabolic control. It is unclear if nutrients can directly control clock gene expression. We have therefore utilized the immortalized, hypothalamic cell line mHypoE-37, which exhibits robust circadian rhythms of core clock genes. mHypoE-37 neurons were exposed to 0.5 or 5.5 mM glucose, comparable to physiological levels in the brain. Per2 and Bmal1 mRNAs were assessed every 3 hours over 36 hours. Incubation with 5.5 mM glucose significantly shortened the period and delayed the phase of Per2 mRNA levels, but had no effect on Bmal1. Glucose had no significant effect on phospho-GSK3β, whereas AMPK phosphorylation was altered. Thus, the AMPK inhibitor Compound C was utilized, and mRNA levels of Per2, Bmal1, Cryptochrome1 (Cry1), agouti-related peptide (AgRP), carnitine palmitoyltransferase 1C (Cpt1c), and O-linked N-acetylglucosamine transferase (Ogt) were measured. Remarkably, Compound C dramatically reduced transcript levels of Per2, Bmal1, Cry1, and AgRP, but not Cpt1c or Ogt. Because AMPK was not inhibited at the same time or concentrations as the clock genes, we suggest that the effect of Compound C on gene expression occurs through an AMPK-independent mechanism. The consequences of inhibition of the rhythmic expression of clock genes, and in turn downstream metabolic mediators, such as AgRP, could have detrimental effects on overall metabolic processes. Importantly, the effects of the most commonly used AMPK inhibitor Compound C should be interpreted with caution, considering its role in AMPK-independent repression of specific genes, and especially clock gene rhythm dysregulation.

The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to the environment by light, peripheral clocks are entrained by various factors, of which feeding/fasting is the most important. Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and Type 2 diabetes. Diets high in fat or sugar have been shown to alter circadian clock function. This review discusses the recent findings concerning the influence of nutrients, in particular fatty acids and glucose, on behavioral and molecular circadian rhythms and will summarize critical studies describing putative mechanisms by which these nutrients are able to alter normal circadian rhythmicity, in the SCN, in non-SCN brain areas, as well as in peripheral organs. As the effects of fat and sugar on the clock could be through alterations in energy status, the role of specific nutrient sensors will be outlined, as well as the molecular studies linking these components to metabolism. Understanding the impact of specific macronutrients on the circadian clock will allow for guidance toward the composition and timing of meals optimal for physiological health, as well as putative therapeutic targets to regulate the molecular clock., (Copyright © 2015 the American Physiological Society.)

In addition to the amount of ingested calories, both timing of food intake and meal composition are determinants of body weight gain. However, at present, it is unknown if the inappropriate timing of diet components is responsible for body weight gain. In the present study, we therefore studied a time-dependent effect of the diet composition on energy homeostasis. Male Wistar rats were subjected to chow ad libitum (chow group) or a choice diet with saturated fat, a 30% sugar solution, chow and tap water. The choice diet was provided either with all components ad libitum (AL), with ad libitum access to chow, tap water and a 30% sugar solution, but with access to saturated fat only during the light period (LF), or with ad libitum access to chow, tap water and saturated fat, but access to a 30% sugar solution only during the light period (LS). Caloric intake and body weight gain were monitored during 31 days. Energy expenditure was measured in the third week in calorimetric cages. All rats on a choice diet showed hyperphagia and gained more body weight compared to the chow group. Within the choice diet groups, rats on the LS diet were most food efficient (i.e. gained most body weight per ingested calorie) and showed a lower respiratory exchange ratio (RER) with an anti-phasic pattern, whereas no differences in locomotor activity or heat production were found. Collectively these data indicate that the timing of the diet composition affects food efficiency, most likely due to a shifted oxidation pattern, which can predispose for obesity. Further studies are underway to assess putative mechanisms involved in this dysregulation.

Diets high in saturated fatty acids (SFAs) are associated with the development of circadian dysregulation, obesity, and Type 2 diabetes mellitus. Conversely, polyunsaturated fatty acids (PUFAs) have recently been identified to improve insulin sensitivity, reduce weight gain, and relieve obesity-induced inflammation. While saturated fatty acids, such as the prevalent dietary fatty acid palmitate, have been implicated in circadian disruption, there is a paucity of studies regarding the effects of PUFAs on circadian parameters. Therefore, the immortalized murine neuronal model, mHypoE-37, was utilized to examine the effects of the SFA palmitate and omega-3 PUFA docosahexaenoic acid (DHA) on circadian rhythms. The mHypoE-37 neurons express the core clock genes, Bmal1, Per2, and Rev-erbα, in a circadian manner. 25 μM of palmitate significantly increased the transcriptional expression of Bmal1, without altering the expression of inflammatory markers TLR4, IκBα, and IL-6, nor the orexigenic neuropeptide AgRP, suggesting that the observed disruption of the molecular clock is the result of a mechanism distinct from that of hypothalamic cellular inflammation. Furthermore, treatment with the PUFA DHA resulted in alterations in the circadian expression profile of Bmal1, although differentially from the effects of palmitate. In the presence of DHA, the disruptive effects of palmitate on Bmal1 were less pronounced, suggesting a protective effect of DHA. These studies are the first to identify the potential for omega-3 PUFAs to protect against palmitate-mediated dysregulation of circadian parameters and will ultimately improve the understanding of circadian control mechanisms., (Copyright © 2014 the American Physiological Society.)

Background: The Asthma Control Test (ACT) has been validated in a paper and pencil version but has not been validated for use by telephone., Objective: The purpose of this study was to provide validation data for the ACT administered by interactive telephone calls using speech recognition technology., Methods: The ACT was administered to patients who confirmed a diagnosis of physician-diagnosed asthma, and information regarding race/ethnicity, smoking, and asthma course was also obtained during the call. Asthma emergency department visits, hospitalizations, and oral corticosteroid and beta-agonist canister dispensings were assessed for the 12 months after the date of each patient's call. Internal consistency reliability and predictive validity were assessed., Results: Asthma Control Test scores (higher indicates better control) were completed by 2244 patients and were inversely related to black or Hispanic race/ethnicity and smoking. Reliability was 0.83. ACT scores were significantly related to emergency hospital care and oral corticosteroid and beta-agonist dispensings over the period of the subsequent 6 and 12 months. After adjusting for demographic characteristics, a score < or = 15 was associated significantly with an increased 12-month risk of emergency hospital care (odds ratio [OR], 2.5), oral corticosteroid dispensings (OR, 2.6) and dispensing of more than 6 beta-agonist canisters (OR, 6.8) compared with a score > or = 20., Conclusion: These data support the reliability and predictive validity of the ACT administered by interactive telephone calls using speech recognition technology., Clinical Implications: The ACT can be used for outreach or follow-up by means of interactive telephone calls using speech recognition technology.