Le système circadien muti-oscillant est constitué de l'horloge suprachiasmatique (SCN), l'horloge principale dans l'hypothalamus antérieur, et de nombreuses horloges périphériques. L'horloge SCN synchronise les horloges périphériques situées dans chaque organe. L'horloge SCN est une horloge circadienne auto-entretenue qui maintient les rythmes quotidiens comportementaux, physiologiques et neuroendocriniens. Les donneurs de temps (zeitgebers), tels que lumière et nourriture, sont des synchroniseurs puissants, respectivement pour le SCN et les horloges périphériques. La thèse visait à mieux comprendre les interactions entre les horloges circadiennes et le comportement alimentaire chez les espèces nocturnes. Nous avons montré dans la première et la seconde partie que l'alimentation ultradienne affecte les horloges centrales et périphériques chez la souris et le rat. Dans la première étude, nous avons conclu que l'alimentation ultradienne chez la souris a un impact majeur sur la sortie de l'horloge SCN et sur l'horloge périphérique dans le foie, tandis que dans la seconde étude, l'alimentation ultradienne chez le rat n'a eu pas d'impact sur l'horloge SCN, mais il a modifié les horloges périphériques et le métabolisme des lipides. Dans la troisième partie, nous avons montré des effets différentiels du régime alimentaire et de la restriction alimentaire temporelle sur les horloges périphériques du tissu adipeux brun et du muscle squelettique. Dans la quatrième partie, nous avons démontré un rôle du gène d'horloge Rev-erbα dans le comportement alimentaire et le métabolisme énergétique en comparant des souris porteuses d’une délétion de Rev-erbα, soit globale, soit limitée au système nerveux central. L’ensemble de ces études révèle l'interdépendance des horloges circadiennes et du comportement alimentaire, ainsi que leurs effets sur le métabolisme énergétique. / The muti-oscillatory circadian system consists of the suprachiasmatic clock (SCN) the master clock, located above the optic chiasm of the anterior hypothalamus, and many peripheral clocks. The SCN clock synchronizes the other peripheral oscillators located in each organ. The SCN clock is a self-sustaining circadian oscillator maintaining the daily behavioural, physiological, and neuroendocrine rhythms. The zeitgebers such as light and food are potent synchronizers for the SCN and other peripheral clocks. The thesis was aimed to understand different aspects of the interactions between circadian clocks and feeding behaviour in nocturnal species. We showed in the first and second parts that the ultradian feeding affects the central and peripheral clocks in mice and rats. In the first part, we concluded that the ultradian feeding in mice has major impacts on the SCN clock output and the peripheral clock in the liver, while in the second part ultradian feeding in rats does not have impact on the SCN clock but it affects peripheral clocks and lipid metabolism. In the third part, we showed the differential effects of diet and time restricted feeding in brown adipose tissue and skeletal muscle peripheral clocks. In the fourth part, we showed the role of clock gene Rev-erbα on feeding behaviour and energy metabolism by comparing between global and brain specific knock-out mice. The present studies reveal the interdependency of the circadian clocks and feeding behaviour, and their effects on whole-body metabolism.

The intermittent fasting diet has a historical past, but recently, it has regained popularity as a weight loss strategy for the general public. Athletes have also picked up this specialized diet in search of a competitive edge. There are ample studies testing athletes of all levels, but most do not include females or report sex-specific results. This systematic review aimed to identify current research on the effects of intermittent fasting in the understudied population of female athletes. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a comprehensive search was conducted in three databases, including PubMed, Cochrane, and SPORTDiscus, and a total of six studies with experimental or observational designs testing the various effects of intermittent fasting on physical, physiological, and psychological parameters were included. This systematic review shows that studies found significant changes in calorie and fluid intake, body composition, nutrient utilization, well-being, and athletic performances with no changes in muscle strength, ratings of perceived exertion, blood lactate levels, and cognitive function. Multiple studies in this review found mixed results on changes in heart rate and athletic performance (vertical jump height), and no studies found negative effects on athletic performance except in the survey of athletes’ perceptions. Due to conflicting results of current research, more studies are needed to determine the effects of intermittent fasting combined with continuous exercise on athletic women.

Arterial blood pressure (BP) undergoes a 24-hour oscillation that peaks in the active day and reaches a nadir at night during sleep in humans. Reduced nocturnal BP fall (also known as non-dipper) is the most common disruption of BP circadian rhythm and is associated with increased risk of untoward cardiovascular events and target organ injury. Up to 75% of diabetic patients are non-dippers. However, the mechanisms underlying diabetes associated non-dipping BP are largely unknown. To address this important question, we generated a novel diabetic db/db-mPer2Luc mouse model (db/db-mPer2Luc) that allows quantitatively measuring of mPER2 protein oscillation by real-time mPer2Luc bioluminescence monitoring in vitro and in vivo. Using this model, we demonstrated that the db/db-mPer2Luc mice have a diminished BP daily rhythm. The phase of the mPER2 daily oscillation is advanced to different extents in explanted peripheral tissues from the db/db-mPer2Luc mice relative to that in the control mice. However, no phase shift is found in the central oscillator, the suprachiasmatic nucleus (SCN). The results indicate that the desynchrony of mPER2 daily oscillation in the peripheral tissues contributes to the loss of BP daily oscillation in diabetes. Extensive research over the past decades has been focused on how the components of food (what we eat) and the amount of food (how much we eat) affect metabolic diseases. Only recently has it become appreciated that the timing of food intake (when we eat), independent of total caloric and macronutrient quality, is also critical for metabolic health. To investigate the potential effect of the timing of food intake on the BP circadian rhythm, we simultaneously monitored the BP and food intake profiles in the diabetic db/db and control mice using radiotelemetry and BioDAQ systems. We found the loss of BP daily rhythm is associated with disrupted food intake rhythm in the db/db mice. In addition, the normal BP daily rhythm is altered in the healthy mice with abnormal feeding pattern, in which the food is available only during the inactive-phase. To explore whether imposing a normal food intake pattern is able to prevent and restore the disruption of BP circadian rhythm, we conducted active-time restricted feeding (ATRF) in the db/db mice. Strikingly, ATRF completely prevents and restorers the disrupted BP daily rhythm in the db/db mice. While multiple mechanisms likely contribute to the protection of ATRF on the BP daily rhythm, we found that ATRF improves the rhythms of energy metabolism, sleep-wake cycle, BP-regulatory hormones and autonomic nervous system (ANS) in the db/db mice. To further investigate the molecular mechanism by which ATRF regulates BP circadian rhythm, we determined the effect of ATRF on the mRNA expressions of core clock genes and clock target genes in the db/db mice. Of particular interest is that we found among all the genes we examined, the mRNA oscillation of Bmal1, a key core clock gene, is disrupted by diabetes and selectively restored by the ATRF in multiple peripheral tissues in the db/db mice. More importantly, we demonstrated that Bmal1 is partially required for ATRF to protect the BP circadian rhythm. In summary, our findings indicate that the desynchrony of peripheral clocks contributes to the abnormal BP circadian pattern in diabetes. Moreover, our studies suggest ATRF as a novel and effective chronotherapy against the disruption of BP circadian rhythm in diabetes.

Background: The prevalence of diabetes and obesity has been on the rise for many years and the search for new and effective dietetic solutions aiming at reducing calories, reducing body mass and improving diabetes has been ongoing. Currently, the intermittent fasting diet - the practice of alternating periods of eating and fasting - is gaining popularity. One of them is Time-restricted feeding (TRF), which time-limits energy intake within a defined window of time up to 10 hours per day without necessarily altering diet quality or quantity. A reduction in calorie intake, bodyweight, blood pressure, oxidative stress, inflammation biomarkers and triglycerides are evident with TRF studies conducted so far. Aim: The aim of the thesis is to investigate the effects of time-restricted feeding on glycemic biomarkers in human studies. Methods: A literature study is conducted with six chosen experimental studies which are primarily randomized controlled trials or randomized crossover trials with a TRF window of maximum 10 hours per day and predominantly with participants with overweight/obesity, prediabetes, type 2 diabetes and metabolic syndrome. Results: Compared to either baseline and/or control group, fasting glucose was reduced in 3 out of 6 TRF studies, while fasting insulin was reduced in 3 out of 5 TRF studies and HbA1C was decreased in 1 out of 2 TRF studies. For postprandial response, 1 out of 2 TRF studies found a reduction in glucose and likewise for insulin. Mean glucose levels were reduced in 1 out of 3 TRF studies. Insulin resistance was reduced in 3 out of 4 TRF studies while insulin sensitivity was reduced in the one study measuring this. Beta cell function improved in 2 out of 2 TRF studies compared to the control group or baseline. Conclusion: There are indications that TRF has an effect on glycemic biomarkers and thus potentially being able to reduce the risk and/or improve the treatment of type 2 diabetes. But in order to give a more definite answer more studies need to be conducted. In general, these studies should preferably have more participants and be methodologically stronger when it e.g. comes to the control of the dietary regimen.

Bakgrund: Allt fler individer i välutvecklade länder kan klassificeras som överviktiga. Övervikt och fetma ökar risken för en mängd olika sjukdomar och är en av de främsta orsakerna till sjukdomsbördan och för tidig död i Sverige. Det finns därför behov för att kunna rekommendera effektiva kostinterventioner. Kontinuerlig energirestriktion är den vanligaste kostinterventionen, men det finns behov för att kunna rekommendera alternativa kostinterventioner.Syfte: Syftet med denna litteraturstudie var att sammanställa resultaten från randomiserade kontrollerade studier från de senaste fem åren som undersöker effekten av intermittent fasta och tidsbegränsat energiintag jämfört med kontinuerlig energirestriktion på viktreduktion och kroppskomposition.Metod: Litteratursökningen gjordes i databaserna Web of Science och PubMed. Sökningen resulterade i 612 träffar varav tio inkluderades i studien.Resultat: Tre av tio studier påvisade skillnader mellan kostinterventionerna gällande viktreduktion; en till fördel för intermittent fasta jämfört med kontinuerlig energirestriktion (p<0,01) en till fördel för tidsbegränsat energiintag jämfört med kontinuerlig energirestriktion (p<0,05) och en till fördel för kontinuerlig energirestriktion jämfört med intermittent fasta (p<0,05). Två av tio studier påvisade skillnad mellan kostinterventionerna i mängden tappad fettmassa till fördel för intermittent fasta (p<0,01) och tidsbegränsat energiintag (p<0,05) jämfört med kontinuerlig energirestriktion.Konklusion: Intermittent fasta och tidsbegränsat energiintag har i denna litteraturöversikt visat på likvärdiga resultat på viktreduktion och kroppskomposition jämfört med kontinuerlig energirestriktion. Resultaten i de granskade studierna tyder på att det är följsamheten av kostinterventionen som är avgörande för viktreduktion och inte själva kostinterventionen i sig. / Background: There is an increase in overweight and obese people around the world. Overweight and obesity increases the risk of multiple diseases and comorbidities. Continuous energy restriction is the most used diet method. However, research suggests that adherence to the diet diminishes within a couple of months, therefore research in alternative methods has increased. Objectives: The objectives of this literature review were to review the latest literature since 2017 regarding the effects of intermittent fasting and time-restricted feeding compared to continuous energy restriction on weight loss and body composition.Methods: The literature search was done in Web of Science and PubMed. The search resulted in 612 articles. Ten of the 612 articles were included in the literature review.Results: Three out of ten studies showed significant differences between groups regarding weight loss. One in favor of intermittent fasting compared to continuous energy restriction (p<0,01), one in favor of time-restricted feeding compared to continuous energy restriction (p<0,05) and one in favor of continuous energy restriction compared to intermittent fasting (p=0,03). Two out of ten studies showed a significant difference between groups regarding reduction of fat mass in favor of intermittent fasting (p<0,01) and time-restricted feeding (p<0,05) compared to continuous energy restriction.Conclusion: This literature review suggests that intermittent fasting and time-restricted feeding when compared to continuous energy restriction has similar effects on weight loss and body composition. The results of the studies suggest that it is the adherence of the diet that is vital for successful weight loss and not the diet itself.