Background: Harnessing cold-induced thermogenesis (CIT) and brown adipose tissue (BAT) activity has been proposed as a means of counteracting a positive energy balance, and thus of combating... Show moreBackground: Harnessing cold-induced thermogenesis (CIT) and brown adipose tissue (BAT) activity has been proposed as a means of counteracting a positive energy balance, and thus of combating obesity and its related comorbidities. However, it has remained unclear whether CIT and BAT activity show diurnal variation in humans -knowledge that might allow treatments based on these factors to be time-optimized.Methods: A randomized crossover experiment was designed to examine whether CIT shows morning/evening variation in young, healthy adults (n = 14, 5 women). On the first experimental day, subjects' shivering thresholds were determined following a cooling protocol. After z96 h had elapsed, the sub-jects then returned on two further days (approx. 48 h apart) at 08:00 h or 18:00 in random order. On both the latter days, the resting energy expenditure (REE) was measured before the subjects underwent personalized cold exposure (i.e., according to their shivering threshold). CIT was then assessed for 60 min by indirect calorimetry. In an independent cross-sectional study (n = 133, 88 women), subjects came to the laboratory between 8:00 and 18:00 h and their BAT F-18-fluordeoxyglucose (F-18-FDG) uptake was assessed after personalized cold stimulation.Results: Both the REE and CIT were similar in the morning and evening (all P > 0.05). Indeed, 60 min of personalized-mild cold exposure in the morning or evening elicited a similar change in energy expen-diture (16.8 +/- 12.8 vs. 15.7 +/- 15.1% increase above REE, P = 0.72). BAT F-18-FDG uptake was also similar in the morning, evening and afternoon (all P > 0.05).Conclusion: CIT does not appear to show morning/evening variation in young healthy adults, with the current study design and methodology. BAT F-18-FDG uptake appears not to change across the day either, although experiments with a within-subject study design are needed to confirm these findings. (C) 2021 The Author(s). Published by Elsevier Ltd. Show less
Throughout evolution, humans have lived in synchrony with the natural light-dark cycle. Our bodies were used to going to sleep a few hours after dark, and waking up just before dawn. However, in... Show moreThroughout evolution, humans have lived in synchrony with the natural light-dark cycle. Our bodies were used to going to sleep a few hours after dark, and waking up just before dawn. However, in modern society the unambiguous availability of artificial light has desynchronized our biological clock from the naturally occurring day and night, with large consequences for metabolic health. This thesis sheds light on the negative health consequences of a disturbed biological clock, and elucidates novel approaches to prevent disease associated with chronic rhythm disruption, as occurs in shift work. We have identified important mechanisms through which rhythm disruption contributes to (cardio)metabolic disease, namely by exacerbating vascular inflammation and by deregulating rhythm in glucocorticoid hormone, thereby affecting the metabolic activity of tissues such as brown fat and bone. We continued by investigating two main approaches to prevent diseases associated with circadian disturbances: (1) by limiting disruption of the circadian timing system, and (2) by directly targeting the affected tissues. We found that timed feeding (1) and stimulation of the metabolic activity of brown fat (2) are both promising strategies to prevent and/or reduce (cardio)metabolic disease risk in the ever-increasing population of individuals who suffer from circadian disturbances. Show less
Cardiovascular diseases (CVD) are the leading cause of death worldwide, and disturbances in day-night rhythms have recently been implicated as a novel risk factor for CVD. We investigated the... Show moreCardiovascular diseases (CVD) are the leading cause of death worldwide, and disturbances in day-night rhythms have recently been implicated as a novel risk factor for CVD. We investigated the effects of modulating circadian rhythms on energy metabolism using animal models and by studying plasma metaoblites and lipids in humans. Using animal studies we observed that brown adipose tissue (BAT) is strongly regulated by the biological clock, possibly via circadian glucocorticoid rhythms, and attenuated BAT activity through prolonged light exposure increases adiposity. Research focusing on the rhythm in human BAT, and regulation thereof, is necessary to confirm the translational value of our findings. We also observed that mistimed light exposure enhances atherosclerosis development, which may provide a mechanistic link between the known association between shift work and CVD. We anticipate that living according to the natural circadian rhythms presumably contributes to cardiometabolic health. Since disturbances in day-night rhythms are inevitable in modern society, in the future we may advise individuals at risk for development of CVD refrain from shift work and short sleep duration. In addition, data in this thesis may be useful to design strategies to avoid the disadvantageous metabolic effects of shift work. Show less
In order to cope with and to predict 24-hour rhythms in the environment, most, if not all, organisms have a circadian timing system. The most important mammalian circadian pacemaker is located in... Show moreIn order to cope with and to predict 24-hour rhythms in the environment, most, if not all, organisms have a circadian timing system. The most important mammalian circadian pacemaker is located in the suprachiasmatic nucleus at the base of the hypothalamus in the brain. Over the years, it has become clear that the circadian system is complex and that additional oscillators exist, both within and outside the central nervous system. The aim of this thesis was to obtain insight in the hierarchical organization of the circadian timing system and to determine whether certain attributes arise at the tissue level. The data reveal that interactions between the SCN and the periphery, as well as interactions between subregions within the SCN, contribute significantly to the functioning of the circadian system. Another important finding is that the multiple components of the circadian system can, under certain circumstances, dissociate. The hierarchical organization of the circadian timing system, the interactions between and within organizational levels, and importantly, the ability of several components to dissociate, may provide the circadian system the required plasticity to adjust to biologically relevant changes in the environment. Show less
