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
Clemente-Olivo, P.M.; Habibe, J.J.; Vos, M.; Ottenhoff, R.; Jongejan, A.; Herrema, H.; ... ; Vries, J.C. de 2021
Objective: Four-and-a-Half-LIM-domain-protein 2 (FHL2) modulates multiple signal transduction pathways but has not been implicated in obesity or energy metabolism. In humans, methylation and... Show moreObjective: Four-and-a-Half-LIM-domain-protein 2 (FHL2) modulates multiple signal transduction pathways but has not been implicated in obesity or energy metabolism. In humans, methylation and expression of the FHL2 gene increases with age, and high FHL2 expression is associated with increased body weight in humans and mice. This led us to hypothesize that FHL2 is a determinant of diet-induced obesity. Methods: FHL2-deficient (FHL2 & minus;/& minus;) and wild type male mice were fed a high-fat diet. Metabolic phenotyping of these mice, as well as transcriptional analysis of key metabolic tissues was performed. Correlation of the expression of FHL2 and relevant genes was assessed in datasets from white adipose tissue of individuals with and without obesity. Results: FHL2 Deficiency protects mice from high-fat diet-induced weight gain, whereas glucose handling is normal. We observed enhanced energy expenditure, which may be explained by a combination of changes in multiple tissues; mild activation of brown adipose tissue with increased fatty acid uptake, increased cardiac glucose uptake and browning of white adipose tissue. Corroborating our findings in mice, expression of FHL2 in human white adipose tissue positively correlates with obesity and negatively with expression of browning-associated genes. Conclusion: Our results position FHL2 as a novel regulator of obesity and energy expenditure in mice and human. Given that FHL2 expression increases during aging, we now show that low FHL2 expression associates with a healthy metabolic state. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Background: Insulin and growth hormone (GH) - 2 vital metabolic regulatory hormones - regulate glucose, lipid, and energy metabolism. These 2 hormones determine substrate and energy metabolism... Show moreBackground: Insulin and growth hormone (GH) - 2 vital metabolic regulatory hormones - regulate glucose, lipid, and energy metabolism. These 2 hormones determine substrate and energy metabolism under different living conditions. Shift of day and night affects the clock system and metabolism probably through altered insulin and GH secretion. Methods: Five-week-old male mice were randomly assigned to a rotating light (RL) group (3-day normal light/dark cycle followed by 4-day reversed light/dark cycle per week) and normal light (NL) group. Body weight and food intake were recorded every week. Series of blood samples were collected for pulsatile GH analysis, glucose tolerance test, and insulin tolerance test at 9, 10, and 11 weeks from the start of intervention, respectively. Indirect calorimetric measurement was performed, and body composition was tested at 12 weeks. Expressions of energy and substrate metabolism-related genes were evaluated in pituitary and liver tissues at the end of 12-week intervention. Results: The RL group had an increased number of GH pulsatile bursts and reduced GH mass/burst. RL also disturbed the GH secretion regularity and mode. It suppressed insulin secretion, which led to a disturbed insulin/GH balance. It was accompanied by the reduced metabolic flexibility and modified gene expression involved in energy balance and substrate metabolism. Indirect calorimeter recording revealed that RL decreased the respiratory exchange ratio (RER) and oxygen consumption at the dark phase, which resulted in an increase in fat mass and free fatty acid levels in circulation. Conclusion: RL disturbed pulsatile GH secretion and decreased insulin secretion in male mice with significant impairment in energy, substrate metabolism, and body composition. Show less
Our increasing obesogenic and aging society has resulted in a steeply increasing prevalence of cardiometabolic diseases. The main underlying reason is our modern lifestyle with respect to higher... Show moreOur increasing obesogenic and aging society has resulted in a steeply increasing prevalence of cardiometabolic diseases. The main underlying reason is our modern lifestyle with respect to higher availability and intake of food, which often appears unhealthy, and lower energy expenditure related to a sedentary lifestyle. Although the most efficient ways to slow this high prevalence of obesity are just eating less and more healthy, and moving more, to reduce energy intake and increase energy expenditure, respectively, current strategies to achieve this in the long-term are still both insufficient and ineffective, and novel strategies are still eagerly warranted.This thesis emphasizes dietary butyrate as a promising and feasible therapeutic strategy to combat obesity and related cardiometabolic diseases with respect to not only reducing appetite but also activating brown adipose tissue. In a series of subsequent mechanistic studies, we elucidated the mechanisms underlying these metabolic properties systematically from gut to the brain, showing the involvement of gut microbiota, intestinal GLP-1 secretion, vagal nerve activation, and finally central GLP-1 receptor signaling to inhibit NPY neuronal activation. The findings of this thesis provide valuable information on the development of novel therapeutic strategies for combating obesity and associated cardiometabolic diseases. Show less
Worldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of... Show moreWorldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of preventive and curative strategies for cardiometabolic disease is eagerly warranted. With the studies describes in this thesis, we aimed to disentangle the interwoven physiological, environmental and genetic factors that determine cholesterol and energy metabolism to increase our understanding of their contribution to cardiometabolic disease risk. The first part of this thesis focussed on the cholesteryl ester transfer protein (CETP). The lipid transfer properties of CETP induce a proatherogenic lipoprotein profile. Therefore, CETP inhibitory molecules have been developed and tested in clinical trials for their capability to improve the lipoprotein profile and reduce CVD risk. To fully understand the role of CETP in CVD, its physiology and biological function should be fully unravelled. The focus of the second part of this thesis was on the role of energy metabolism in cardiometabolic health. Specifically, we aimed to study the association of environmental and genetic factors, which were previously described to influence brown adipose tissue (BAT) activity, with energy expenditure and disease outcomes. Show less
Cardiovascular diseases (CVD), which are mainly caused by the development of atherosclerosis, are the leading cause of morbidity and mortality in Western Society. Two main risk factors for the... Show moreCardiovascular diseases (CVD), which are mainly caused by the development of atherosclerosis, are the leading cause of morbidity and mortality in Western Society. Two main risk factors for the development of atherosclerosis are hyperlipidemia and inflammation, that cause accumulation of lipids and immune cells, respectively, in the arterial wall. While activation of brown adipose tissue (BAT) is a promising strategy to alleviate hyperlipidemia, reduction of inflammation is also thought to reduce atherosclerosis progression. In this thesis, we aimed to address two key objectives: 1) to identify genetic targets in mice and men that are involved in BAT activity and evaluate their effects on lipoprotein metabolism and atherosclerosis development, and 2) to identify genetic targets in mice that are involved in modulation of the immune system and evaluate their effects on atherosclerosis development. Chapter 1 serves as a general introduction in which hyperlipidemia and inflammation are introduced as the two main causes for atherosclerosis development. More specifically, firstly the physiology and role of BAT in lipoprotein metabolism and atherosclerosis development are explained. Secondly, the contribution of pro- and anti-inflammatory cytokines as well as specific receptors on immune cells in propelling immune responses are explained in the context of atherosclerosis development. Show less
Bogaard, S.J.A. van den; Dumas, E.M.; Teeuwisse, W.M.; Kan, H.E.; Webb, A.; Roos, R.A.C.; Grond, J. van der 2011
