The influence of bright and dim light on substrate metabolism, energy expenditure and thermoregulation in insulin-resistant individuals depends on time of day.

AIMS/HYPOTHESIS: In our modern society, artificial light is available around the clock and most people expose themselves to electrical light and light-emissive screens during the dark period of the natural light/dark cycle. Such suboptimal lighting conditions have been associated with adverse metabolic effects, and redesigning indoor lighting conditions to mimic the natural light/dark cycle more closely holds promise to improve metabolic health. Our objective was to compare metabolic responses to lighting conditions that resemble the natural light/dark cycle in contrast to suboptimal lighting in individuals at risk of developing metabolic diseases. METHODS: Therefore, we here performed a non-blinded, randomised, controlled, crossover trial in which overweight insulin-resistant volunteers (n = 14) were exposed to two 40 h laboratory sessions with different 24 h lighting protocols while staying in a metabolic chamber under real-life conditions. In the Bright day-Dim evening condition, volunteers were exposed to electric bright light (~1250 lx) during the daytime (08:00-18:00 h) and to dim light (~5 lx) during the evening (18:00-23:00 h). Vice versa, in the Dim day-Bright evening condition, volunteers were exposed to dim light during the daytime and bright light during the evening. Randomisation and allocation to light conditions were carried out by sequential numbering. During both lighting protocols, we performed 24 h indirect calorimetry, and continuous core body and skin temperature measurements, and took frequent blood samples. The primary outcome was plasma glucose focusing on the pre- and postprandial periods of the intervention. RESULTS: Spending the day in bright light resulted in a greater increase in postprandial triacylglycerol levels following breakfast, but lower glucose levels preceding the dinner meal at 18:00 h, compared with dim light (5.0 ± 0.2 vs 5.2 ± 0.2 mmol/l, n = 13, p=0.02). Dim day-Bright evening reduced the increase in postprandial glucose after dinner compared with Bright day-Dim evening (incremental AUC: 307 ± 55 vs 394 ± 66 mmol/l × min, n = 13, p=0.009). After the Bright day-Dim evening condition the sleeping metabolic rate was identical compared with the baseline night, whereas it dropped after Dim day-Bright evening. Melatonin secretion in the evening was strongly suppressed for Dim day-Bright evening but not for Bright day-Dim evening. Distal skin temperature for Bright day-Dim evening was lower at 18:00 h (28.8 ± 0.3°C vs 29.9 ± 0.4°C, n = 13, p=0.039) and higher at 23:00 h compared with Dim day-Bright evening (30.1 ± 0.3°C vs 28.8 ± 0.3°C, n = 13, p=0.006). Fasting and postprandial plasma insulin levels and the respiratory exchange ratio were not different between the two lighting protocols at any time. CONCLUSIONS/INTERPRETATION: Together, these findings suggest that the indoor light environment modulates postprandial substrate handling, energy expenditure and thermoregulation of insulin-resistant volunteers in a time-of-day-dependent manner. TRIAL REGISTRATION: ClinicalTrials.gov NCT03829982. FUNDING: We acknowledge the financial support from the Netherlands Cardiovascular Research Initiative: an initiative with support from the Dutch Heart Foundation (CVON2014-02 ENERGISE).

Brown adipose tissue activation is not related to hypermetabolism in emphysematous chronic obstructive pulmonary disease patients.

BACKGROUND: Brown adipose tissue (BAT) has been primarily researched as a potential target for mitigating obesity. However, the physiological significance of BAT in relation to cachexia remains poorly understood. The objective of this study was to investigate the putative contribution of BAT on different components of energy metabolism in emphysematous chronic obstructive pulmonary disease (COPD) patients. METHODS: Twenty COPD patients (mean ± SD age 62 ± 6, 50% female, median [range] BMI 22.4 [15.1-32.5] kg/m2 and 85% low FFMI) were studied. Basal metabolic rate (BMR) was assessed by ventilated hood, total daily energy expenditure (TDEE) by doubly labelled water and physical activity by triaxial accelerometry. BMR was adjusted for fat-free mass (FFM) as assessed by deuterium dilution. Analysis of BAT and WAT was conducted in a subset of ten patients and six age-matched, gender-matched and BMI-matched healthy controls. BAT glucose uptake was assessed by means of cold-stimulated integrated [18F]FDG positron-emission tomography and magnetic resonance imaging. WAT was collected from subcutaneous abdominal biopsies to analyse metabolic and inflammatory gene expression levels. Lung function was assessed by spirometry and body plethysmography and systemic inflammation by high sensitivity C-reactive protein. RESULTS: Mean TDEE was 2209 ± 394 kcal/day, and mean BMR was 1449 ± 214 kcal/day corresponding to 120% of predicted. FFM-adjusted BMR did not correlate with lung function or C-reactive protein. Upon cooling, energy expenditure increased, resulting in a non-shivering thermogenesis of (median [range]) 20.1% [3.3-41.3] in patients and controls. Mean BAT glucose uptake was comparable between COPD and controls (1.5 [0.1-6.2] vs. 1.1 [0.7-3.9]). In addition, no correlation was found between BMR adjusted for FFM and BAT activity or between cold-induced non-shivering energy expenditure and BAT activity. Gene expression levels of the brown adipocyte or beige markers were also comparable between the groups. No (serious) adverse events were reported. CONCLUSIONS: Although COPD patients were hypermetabolic at rest, no correlation was found between BMR or TDEE and BAT activity. Furthermore, both BAT activity and gene expression levels of the brown adipocyte or beige markers were comparable between COPD patients and controls.

Resveratrol treatment does not reduce arterial inflammation in males at risk of type 2 diabetes: a randomized crossover trial.

PURPOSE: Resveratrol has shown promising anti-inflammatory effects in in vitro and animal studies. We aimed to investigate this effect on arterial inflammation in vivo. METHODS: This was an additional analysis of a double-blind randomized crossover trial which included eight male subjects with decreased insulin sensitivity who underwent an 18F-fluoroxyglucose (18F-FDG) PET/CT after 34 days of placebo and resveratrol treatment (150 mg/day). 18F-FDG uptake was analyzed in the carotid arteries and the aorta, adipose tissue regions, spleen, and bone marrow as measures for arterial and systemic inflammation. Maximum target-to-background ratios (TBRmax) were compared between resveratrol and placebo treatment with the non-parametric Wilcoxon signed-rank test. Median values are shown with their interquartile range. RESULTS: Arterial 18F-FDG uptake was non-significantly higher after resveratrol treatment (TBRmax all vessels 1.7 (1.6-1.7)) in comparison to placebo treatment (1.5 (1.4-1.6); p=0.050). Only in visceral adipose tissue, the increase in 18F-FDG uptake after resveratrol reached statistical significance (p=0.024). Furthermore, CRP-levels were not significantly affected by resveratrol treatment (p=0.091). CONCLUSIONS: Resveratrol failed to attenuate arterial or systemic inflammation as measured with 18F-FDG PET in subjects at risk of developing type 2 diabetes. However, validation of these findings in larger human studies is needed.

Nicotinamide Riboside Enhances In Vitro Beta-adrenergic Brown Adipose Tissue Activity in Humans.

CONTEXT: Elevating nicotinamide adenine dinucleotide (NAD+) levels systemically improves metabolic health, which can be accomplished via nicotinamide riboside (NR). Previously, it was demonstrated that NR supplementation in high-fat-diet (HFD)-fed mice decreased weight gain, normalized glucose metabolism, and enhanced cold tolerance. OBJECTIVE: Because brown adipose tissue (BAT) is a major source of thermogenesis, we hypothesize that NR stimulates BAT in mice and humans. DESIGN AND INTERVENTION: HFD-fed C56BL/6J mice were supplemented with 400 mg/kg/day NR for 4 weeks and subsequently exposed to cold. In vitro primary adipocytes derived from human BAT biopsies were pretreated with 50 µM or 500 µM NR before measuring mitochondrial uncoupling. Human volunteers (45-65 years; body mass index, 27-35 kg/m2) were supplemented with 1000 mg/day NR for 6 weeks to determine whether BAT activity increased, as measured by [18F]FDG uptake via positron emission tomography-computed tomography (randomized, double blinded, placebo-controlled, crossover study with NR supplementation). RESULTS: NR supplementation in HFD-fed mice decreased adipocyte cell size in BAT. Cold exposure further decreased adipocyte cell size on top of that achieved by NR alone independent of ex vivo lipolysis. In adipocytes derived from human BAT, NR enhanced in vitro norepinephrine-stimulated mitochondrial uncoupling. However, NR supplementation in human volunteers did not alter BAT activity or cold-induced thermogenesis. CONCLUSIONS: NR stimulates in vitro human BAT but not in vivo BAT in humans. Our research demonstrates the need for further translational research to better understand the differences in NAD+ metabolism in mouse and human.

No evidence for brown adipose tissue activation after creatine supplementation in adult vegetarians.

Creatine availability in adipose tissue has been shown to have profound effects on thermogenesis and energy balance in mice. However, whether dietary creatine supplementation affects brown adipose tissue (BAT) activation in humans is unclear. In the present study, we report the results of a double-blind, randomized, placebo-controlled, cross-over trial (NCT04086381) in which 14 young, healthy, vegetarian adults, who are characterized by low creatine levels, received 20 g of creatine monohydrate per day or placebo. Participants were eligible if they met the following criteria: male or female, white, aged 18-30 years, consuming a vegetarian diet (≥6 months) and body mass index 20-25 kg m-2. BAT activation after acute cold exposure was determined by calculating standard uptake values (SUVs) acquired by [18F]fluorodeoxyglucose positron emission tomography-magnetic resonance imaging. BAT volume (-31.32 (19.32) SUV (95% confidence interval (CI) -73.06, 10.42; P = 0.129)), SUVmean (-0.34 (0.29) SUV (95% CI -0.97, 0.28; P = 0.254)) and SUVmax (-2.49 (2.64) SUV (95% CI -8.20, 3.21; P = 0.362)) following acute cold exposure were similar between placebo and creatine supplementation. No side effects of creatine supplementation were reported; one participant experienced bowel complaints during placebo, which resolved without intervention. Our data show that creatine monohydrate supplementation in young, healthy, lean, vegetarian adults does not enhance BAT activation after acute cold exposure.

The effect of cold exposure with shivering on glucose tolerance in healthy men.

Muscle glycogen use and glucose uptake during cold exposure increases with shivering intensity. We hypothesized that cold exposure, with shivering, would subsequently increase glucose tolerance. Fifteen healthy men (age = 26 ± 5 yr, body mass index = 23.9 ± 2.5 kg·m-2 ) completed two experimental trials after an overnight fast. Cold exposure (10°C) was applied during the first trial, via a water-perfused suit, to induce at least 1 h of shivering in each participant. For comparison, a thermoneutral (32°C) condition was applied during the second trial, under identical conditions, for the same duration as determined during the cold exposure. After the thermal exposures, participants rested under a duvet for 90 min, which was followed by a 3-h oral glucose tolerance test. Skin temperature (means ± SE) decreased at the end of the cold exposure compared with that before (26.9 ± 0.3 vs. 33.7 ± 0.1°C, P < 0.001). Total energy expenditure during the 1 h of shivering was greater than that during the time-matched thermoneutral condition (619 ± 23 vs. 309 ± 7 kJ, P < 0.001). Cold exposure increased the areas under the glucose and insulin curves by 4.8% (P = 0.066) and 24% (P = 0.112), respectively. The Matsuda and insulin-glucose indices changed after cold exposure by -21% (P = 0.125) and 30% (P = 0.100), respectively. Cold exposure did not subsequently increase glucose tolerance. Instead, the Matsuda and insulin-glucose indices suggest insulin resistance post shivering.NEW & NOTEWORTHY This is the first study to examine the effect of cold-induced shivering on subsequent glucose tolerance determined under thermoneutral conditions. Plasma glucose and insulin concentrations increased during the oral glucose tolerance test post shivering. Additionally, insulin sensitivity indices suggest insulin resistance following cold exposure. These results provide evidence for an acute post-shivering response, whereby glucose metabolism has deteriorated, contrary to the results from earlier studies on cold acclimation.

Comparative transcriptome analysis of human skeletal muscle in response to cold acclimation and exercise training in human volunteers.

BACKGROUND: Cold acclimation and exercise training were previously shown to increase peripheral insulin sensitivity in human volunteers with type 2 diabetes. Although cold is a potent activator of brown adipose tissue, the increase in peripheral insulin sensitivity by cold is largely mediated by events occurring in skeletal muscle and at least partly involves GLUT4 translocation, as is also observed for exercise training. METHODS: To investigate if cold acclimation and exercise training overlap in the molecular adaptive response in skeletal muscle, we performed transcriptomics analysis on vastus lateralis muscle collected from human subjects before and after 10 days of cold acclimation, as well as before and after a 12-week exercise training intervention. RESULTS: Cold acclimation altered the expression of 756 genes (422 up, 334 down, P < 0.01), while exercise training altered the expression of 665 genes (444 up, 221 down, P < 0.01). Principal Component Analysis, Venn diagram, similarity analysis and Rank-rank Hypergeometric Overlap all indicated significant overlap between cold acclimation and exercise training in upregulated genes, but not in downregulated genes. Overlapping gene regulation was especially evident for genes and pathways associated with extracellular matrix remodeling. Interestingly, the genes most highly induced by cold acclimation were involved in contraction and in signal transduction between nerve and muscle cells, while no significant changes were observed in genes and pathways related to insulin signaling or glucose metabolism. CONCLUSIONS: Overall, our results indicate that cold acclimation and exercise training have overlapping effects on gene expression in human skeletal muscle, but strikingly these overlapping genes are designated to pathways related to tissue remodeling rather than metabolic pathways.

Passive exposure to heat improves glucose metabolism in overweight humans.

AIM: Heat exposure has been indicated to positively affect glucose metabolism. An involvement of heat shock protein 72 (HSP72) in the enhancement of insulin sensitivity upon heat exposure has been previously suggested. Here, we performed an intervention study exploring the effect of passive heat acclimation (PHA) on glucose metabolism and intracellular (a) HSP72 concentrations in overweight humans. METHODS: Eleven non-diabetic overweight (BMI 27-35 kg/m2 ) participants underwent 10 consecutive days of PHA (4-6 h/day, 34.4 ± 0.2°C, 22.8 ± 2.7%RH). Before and after PHA, whole-body insulin sensitivity was assessed using a one-step hyperinsulinaemic-euglycaemic clamp, skeletal muscle biopsies were taken to measure intracellular iHSP72, energy expenditure and substrate oxidation were measured using indirect calorimetry and blood samples were drawn to assess markers of metabolic health. Thermophysiological adaptations were measured during a temperature ramp protocol before and after PHA. RESULTS: Despite a lack of change in iHSP72, 10 days of PHA reduced basal (9.7 ± 1.4 pre- vs 8.4 ± 2.1 µmol · kg-1 · min-1 post-PHA, P = .038) and insulin-stimulated (2.1 ± 0.9 pre- vs 1.5 ± 0.8 µmol · kg-1 · min-1 post-PHA, P = .005) endogenous glucose production (EGP) and increased insulin suppression of EGP (78.5 ± 9.7% pre- vs 83.0 ± 7.9% post-PHA, P = .028). Consistently, fasting plasma glucose (6.0 ± 0.5 pre- vs 5.8 ± 0.4 mmol/L post-PHA, P = .013) and insulin concentrations (97 ± 55 pre- vs 84 ± 49 pmol/L post-PHA, P = .026) decreased significantly. Moreover, fat oxidation increased, and free fatty acids as well as cholesterol concentrations and mean arterial pressure decreased after PHA. CONCLUSION: Our results show that PHA for 10 days improves glucose metabolism and enhances fat metabolism, without changes in iHSP72. Further exploration of the therapeutic role of heat in cardio-metabolic disorders should be considered.

Hot-water immersion does not increase postprandial muscle protein synthesis rates during recovery from resistance-type exercise in healthy, young males.

The purpose of this study was to assess the impact of postexercise hot-water immersion on postprandial myofibrillar protein synthesis rates during recovery from a single bout of resistance-type exercise in healthy, young men. Twelve healthy, adult men (age: 23 ± 1 y) performed a single bout of resistance-type exercise followed by 20 min of water immersion of both legs. One leg was immersed in hot water [46°C: hot-water immersion (HWI)], while the other leg was immersed in thermoneutral water (30°C: CON). After water immersion, a beverage was ingested containing 20 g intrinsically L-[1-13C]-phenylalanine and L-[1-13C]-leucine labeled milk protein with 45 g of carbohydrates. In addition, primed continuous L-[ring-2H5]-phenylalanine and L-[1-13C]-leucine infusions were applied, with frequent collection of blood and muscle samples to assess myofibrillar protein synthesis rates in vivo over a 5-h recovery period. Muscle temperature immediately after water immersion was higher in the HWI compared with the CON leg (37.5 ± 0.1 vs. 35.2 ± 0.2°C; P < 0.001). Incorporation of dietary protein-derived L-[1-13C]-phenylalanine into myofibrillar protein did not differ between the HWI and CON leg during the 5-h recovery period (0.025 ± 0.003 vs. 0.024 ± 0.002 MPE; P = 0.953). Postexercise myofibrillar protein synthesis rates did not differ between the HWI and CON leg based upon L-[1-13C]-leucine (0.050 ± 0.005 vs. 0.049 ± 0.002%/h; P = 0.815) and L-[ring-2H5]-phenylalanine (0.048 ± 0.002 vs. 0.047 ± 0.003%/h; P = 0.877), respectively. Hot-water immersion during recovery from resistance-type exercise does not increase the postprandial rise in myofibrillar protein synthesis rates. In addition, postexercise hot-water immersion does not increase the capacity of the muscle to incorporate dietary protein-derived amino acids in muscle tissue protein during subsequent recovery.NEW & NOTEWORTHY This is the first study to assess the effect of postexercise hot-water immersion on postprandial myofibrillar protein synthesis rates and the incorporation of dietary protein-derived amino acids into muscle protein. We observed that hot-water immersion during recovery from a single bout of resistance-type exercise does not further increase myofibrillar protein synthesis rates or augment the postprandial incorporation of dietary protein-derived amino acids in muscle throughout 5 h of postexercise recovery.

In vitro effects of sitosterol and sitostanol on mitochondrial respiration in human brown adipocytes, myotubes and hepatocytes.

PURPOSE: Lowering of LDL cholesterol levels by plant sterols and stanols is associated with decreased risk of cardiovascular disease in humans. Plant sterols and stanols also lower triacylglycerol (TG). However, it is not fully understood how reduction in TG is achieved and what the full potential of plant sterols and stanols is on whole-body metabolism. We here hypothesize that high levels of plant sterols and stanols stimulate whole-body energy expenditure, which can be attributed to changes in mitochondrial function of brown adipose tissue (BAT), skeletal muscle and liver. METHODS: Phytosterolemic mice were fed chow diets for 32 weeks to examine whole-body weight gain. In vitro, 24-h incubation were performed in adipocytes derived from human BAT, human myotubes or HepG2 human hepatocytes using sitosterol or sitostanol. Following mitochondrial function was assessed using seahorse bioanalyzer. RESULTS: Chow feeding in phytosterolemic mice resulted in diminished increase in body weight compared to control mice. In vitro, sitosterol or sitostanol did not change mitochondrial function in adipocytes derived from human BAT or in cultured human myotubes. Interestingly, maximal mitochondrial function in HepG2 human hepatocytes was decreased following sitosterol or sitostanol incubation, however, only when mitochondrial function was assessed in low glucose-containing medium. CONCLUSIONS: Beneficial in vivo effects of plant sterols and stanols on lipid and lipoprotein metabolism are well recognized. Our results indicate that alterations in human mitochondrial function are apparently not involved to explain these beneficial effects.

Higher Plasma Sclerostin and Lower Wnt Signaling Gene Expression in White Adipose Tissue of Prediabetic South Asian Men Compared with White Caucasian Men.

BACKGROUND: South Asians generally have an unfavourable metabolic phenotype compared with white Caucasians, including central obesity and insulin resistance. The Wnt protein family interacts with insulin signaling, and impaired Wnt signaling is associated with adiposity and type 2 diabetes mellitus. We aimed to investigate Wnt signaling in relation to insulin signaling in South Asians compared with white Caucasians. METHODS: Ten Dutch South Asian men with prediabetes and overweight or obesity and 10 matched Dutch white Caucasians were included. Blood samples were assayed for the Wnt inhibitor sclerostin. Subcutaneous white adipose tissue (WAT) and skeletal muscle biopsies were assayed for Wnt and insulin signaling gene expression with quantitative reverse transcription polymerase chain reaction (Clinicaltrials.gov NCT02291458). RESULTS: Plasma sclerostin was markedly higher in South Asians compared with white Caucasians (+65%, P<0.01). Additionally, expression of multiple Wnt signaling genes and key insulin signaling genes were lower in WAT in South Asians compared with white Caucasians. Moreover, in WAT in both ethnicities, Wnt signaling gene expression strongly positively correlated with insulin signaling gene expression. In skeletal muscle, WNT10B expression in South Asians was lower, but expression of other Wnt signaling and insulin signaling genes was comparable between ethnicities. Wnt and insulin signaling gene expression also positively correlated in skeletal muscle, albeit less pronounced. CONCLUSION: South Asian men with overweight or obesity and prediabetes have higher plasma sclerostin and lower Wnt signaling gene expression in WAT compared with white Caucasians. We interpret that reduced Wnt signaling could contribute to impaired insulin signaling in South Asians.

Short-term discontinuation of vagal nerve stimulation alters 18F-FDG blood pool activity: an exploratory interventional study in epilepsy patients.

BACKGROUND: Vagus nerve activation impacts inflammation. Therefore, we hypothesized that vagal nerve stimulation (VNS) influenced arterial wall inflammation as measured by 18F-FDG uptake. RESULTS: Ten patients with left-sided VNS for refractory epilepsy were studied during stimulation (VNS-on) and in the hours after stimulation was switched off (VNS-off). In nine patients, 18F-FDG uptake was measured in the right carotid artery, aorta, bone marrow, spleen, and adipose tissue. Target-to-background ratios (TBRs) were calculated to normalize the respective standardized uptake values (SUVs) for venous blood pool activity. Median values are shown with interquartile range and compared using the Wilcoxon signed-rank test. Arterial SUVs tended to be higher during VNS-off than VNS-on [SUVmax all vessels 1.8 (1.5-2.2) vs. 1.7 (1.2-2.0), p = 0.051]. However, a larger difference was found for the venous blood pool at this time point, reaching statistical significance in the vena cava superior [meanSUVmean 1.3 (1.1-1.4) vs. 1.0 (0.8-1.1); p = 0.011], resulting in non-significant lower arterial TBRs during VNS-off than VNS-on. Differences in the remaining tissues were not significant. Insulin levels increased after VNS was switched off [55.0 pmol/L (45.9-96.8) vs. 48.1 pmol/L (36.9-61.8); p = 0.047]. The concurrent increase in glucose levels was not statistically significant [4.8 mmol/L (4.7-5.3) vs. 4.6 mmol/L (4.5-5.2); p = 0.075]. CONCLUSIONS: Short-term discontinuation of VNS did not show a consistent change in arterial wall 18F-FDG-uptake. However, VNS did alter insulin and 18F-FDG blood levels, possibly as a result of sympathetic activation.

Early evening light mitigates sleep compromising physiological and alerting responses to subsequent late evening light.

The widespread use of electric light and electronic devices has resulted in an excessive exposure to light during the late-evening and at night. This late light exposure acutely suppresses melatonin and sleepiness and delays the circadian clock. Here we investigate whether the acute effects of late-evening light exposure on our physiology and sleepiness are reduced when this light exposure is preceded by early evening bright light. Twelve healthy young females were included in a randomised crossover study. All participants underwent three evening (18:30-00:30) sessions during which melatonin, subjective sleepiness, body temperature and skin blood flow were measured under different light conditions: (A) dim light, (B) dim light with a late-evening (22:30-23:30) light exposure of 750 lx, 4000 K, and (C) the same late-evening light exposure, but now preceded by early-evening bright light exposure (18.30-21.00; 1200 lx, 4000 K). Late-evening light exposure reduced melatonin levels and subjective sleepiness and resulted in larger skin temperature gradients as compared to dim. Interestingly, these effects were reduced when the late-evening light was preceded by an early evening 2.5-hour bright light exposure. Thus daytime and early-evening exposure to bright light can mitigate some of the sleep-disruptive consequences of light exposure in the later evening.

Effect of local skin blood flow during light and medium activities on local skin temperature predictions.

The quality of local skin temperature prediction by thermophysiological models depends on the local skin blood flow (SBF) control functions. These equations were derived for low activity levels (0.8-1met) and mostly in sitting or supine position. This study validates and discusses the prediction of foot SBF during activities of 1-3met in male and females, and the effect on the foot skin temperature prediction (ΔTskin,foot) using the thermophysiological simulation model ThermoSEM. The SBF at the foot was measured for ten male and ten female human subjects at baseline and during three activities (sitting, walking at 1km/h, preferred walking around 3km/h). Additional measurements included the energy expenditure, local skin temperatures (Tskin,loc), environmental conditions and body composition. Measured, normalized foot SBF is 2-8 times higher than the simulated SBF during walking sessions. Also, SBF increases are significantly higher in females vs. males (preferred walking: 4.8±1.5 versus 2.7±1.4, P < 0.05). The quality of ΔTskin,foot using the simulated foot SBF is poor (median deviation is -4.8°C, maximumumdeviationis-6°C). Using the measured SBF in ThermoSEM results in an improved local skin temperature prediction (new maximum deviation is -3.3°C). From these data a new SBF model was developed that includes the walking activity level and gender, and improves SBF prediction and ΔTskin,foot of the thermophysiological model. Accurate SBF and local skin temperature predictions are beneficial in optimizing thermal comfort simulations in the built environment, and might also be applied in sport science or patient's temperature management.

Absence of 18 F-fluorodeoxyglucose uptake using Positron Emission Tomography/Computed Tomography in Madelung's disease: A case report.

Madelung's disease is characterized by the manifestation of multiple ectopic lipomas, usually found in the cervical-thoracic region, however, clinical manifestation may vary among patients. It has been postulated that lipomas associated with Madelung's disease are linked to brown adipose tissue (BAT) due to the presence of uncoupling protein 1 (UCP1). Therefore, we here investigated whether BAT activity is present in a patient with Madelung's disease. 18 F-fluorodeoxyglucose (18 F-FDG) uptake using PET/CT after a cooling procedure was measured together with body temperature and energy expenditure. Finally, adipose tissue biopsies were taken from the lipomas for gene expression analysis and histology. 18 F-FDG uptake was not detected after the cooling procedure in the lipomas. Furthermore, adipose tissue biopsies derived from the lipomas did not express UCP1. We thus conclude that cold-stimulated BAT activity was not detected in lipomas associated with Madelung's disease. Additional research in other patients is needed to unravel the role of dysfunctional BAT in Madelung's disease.

TSH suppression aggravates arterial inflammation - an 18F-FDG PET study in thyroid carcinoma patients.

PURPOSE: We aimed to investigate the influence of both hypothyroidism and thyroid-stimulating hormone (TSH) suppression on vascular inflammation, as assessed with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT). METHODS: Ten thyroid carcinoma patients underwent an 18F-FDG PET/CT during post-thyroidectomy hypothyroidism and during thyrotropin (TSH) suppression after 131I (radioiodine) ablation therapy. We analysed the 18F-FDG uptake in the carotids, aortic arch, ascending, descending, and abdominal aorta to investigate the effects of thyroid hormone status on arterial inflammation. Target-to-background ratios (TBRs) corrected for blood pool activity were established for all arterial territories. Results were further compared to euthyroid historic control subjects. RESULTS: In general, there was a trend towards higher vascular TBRs during TSH suppression than during hypothyroidism (TBRmax all vessels = 1.6 and 1.8, respectively, p = 0.058), suggesting a higher degree of arterial inflammation. In concurrence with this, we found increased C-reactive protein (CRP) levels after levothyroxine treatment (CRP = 2.9 mg/l and 4.8 mg/l, p = 0.005). An exploratory comparison with euthyroid controls showed significant higher TBRs during TSH suppression for the carotids, aortic arch, thoracic descending aorta, and when all vascular territories were combined (TBRmaxp = 0.013, p = 0.016, p = 0.030 and p = 0.018 respectively). CONCLUSIONS: Arterial inflammation is increased during TSH suppression. This finding sheds new light on the underlying mechanism of the suspected increased risk of cardiovascular disease in patients with TSH suppression.

[18F]BODIPY-triglyceride-containing chylomicron-like particles as an imaging agent for brown adipose tissue in vivo.

Brown adipose tissue (BAT) is present in human adults and the current gold standard to visualize and quantify BAT is [18F]FDG PET-CT. However, this method fails to detect BAT under insulin-resistant conditions associated with ageing and weight gain, such as type 2 diabetes. The aim of this study was to develop a novel triglyceride-based tracer for BAT. For this purpose we designed a dual-modal fluorescent/PET fatty acid tracer based on commercially available BODIPY-FL-C16, which can be esterified to its correspondent triglyceride, radiolabeled and incorporated into pre-synthesized chylomicron-like particles. BODIPY-FL-C16 was coupled to 1,2-diolein with a subsequent radiolabeling step resulting in [18F]BODIPY-C16-triglyceride that was incorporated into chylomicron-like particles. Various quality control steps using fluorescent and radioactive methods were conducted before BAT visualization was tested in mice. Triglyceride synthesis, radiolabeling and subsequent incorporation into chylomicron-like particles was carried out in decent yields. This radiotracer appeared able to visualize BAT in vivo, and the uptake of the radiotracer was stimulated by cold exposure. The here reported method can be used to incorporate radiolabeled triglycerides into pre-synthesized chylomicron-like particles. Our approach is feasible to visualize and quantify the uptake of triglyceride-derived fatty acids by BAT.

In Vivo Detection of Human Brown Adipose Tissue During Cold and Exercise by PET/CT.

The role of brown adipose tissue (BAT) in non-shivering thermogenesis is well established in animals. BAT is activated following cold exposure, resulting in non-shivering thermogenesis, to ensure a constant body temperature. In mitochondria of brown adipocytes, glucose and fatty acids are used as substrate for uncoupling resulting in heat production. Activated BAT functions as a sink for glucose and fatty acids and this hallmark has designated BAT a target in the fight against metabolic diseases like type 2 diabetes mellitus and obesity. In order to make valid claims regarding BAT activity in humans, BAT activity needs to be quantified. The combination of positron emission tomography (PET) and computer tomography (CT) analysis is currently the most frequently used imaging technique to determine BAT activity in humans. Here, we will discuss the history of PET/CT and radioisotopes used to determine BAT activity in humans. Moreover, we will assess how PET/CT is used to determine BAT activity following cold and exercise.

Human brown adipose tissue: Underestimated target in metabolic disease?

Active brown adipose tissue (BAT) has, since it rediscovery in adult humans in 2009, received much attention for its ability to increase energy expenditure when activated. By means of mitochondrial uncoupling activity BAT's main function is to produce heat instead of storing energy such as in white adipose tissue (WAT). Therefore, BAT is considered a new potential target to treat obesity and the metabolic syndrome. However, the contribution of this thermogenic tissue is still a matter of debate among researchers. The aim of this review is to give an overview of the differences between classical brown adipocytes and inducible beige adipocytes in humans, and the potential activators of BAT in humans. Furthermore newly described genetic markers for identification of these two types of brown adipocytes are examined. Finally, the potential of the current measurement techniques, and the contribution of BAT activity to whole body energy expenditure are discussed.