Objective:To identify the best quantitative fat-water MRI biomarker for disease progression of leg muscles in Becker muscular dystrophy (BMD) by applying a stepwise approach based on standardized response mean (SRM) over 24 months, correlations with baseline ambulatory tests and reproducibility.Methods:Dixon fat-water imaging was performed at baseline (n=24) and 24 months (n=20). Fat fractions (FF) were calculated for three center slices and the whole muscles for 19 muscles and six muscle groups. Contractile cross sectional area (cCSA) was obtained from the center slice. Functional assessments included knee extension and flexion force, and three ambulatory tests (North Star Ambulatory Assessment (NSAA), 10-meter run, six-minute walking test). MR parameters were selected using SRM (≥0.8) and correlation with all ambulatory tests (rho≤-0.8). Parameters were evaluated based on intraclass correlation coefficient (ICC) and standard deviation (SD) of the difference. Sample sizes (SS) were calculated assuming 50% reduction in disease progression over 24 months in a clinical trial with 1:1 randomization.Results:Median whole muscle FF increased between 0.2-2.6% without consistent cCSA changes. High SRMs and strong functional correlations were found for eight FF but no cCSA parameters. All parameters showed excellent ICC (≥0.999) and similar SD of the inter-rater difference. Whole thigh three center slices FF was the best biomarker (SRM=1.04, correlations rho≤-0.81, ICC=1.00, SD=0.23%, SS=59) based on low SD and acquisition and analysis time.Conclusion:In BMD, median FF of all muscles increased over 24 months. Whole thigh three center slices FF reduced the SS by approximately 40% compared to NSAA.

Abreu-Vieira et al. Heterogeneous Cold-Induced Changes in BAT Voxel-wise analysis showed that while cold exposure changed the fat fraction across nearly all thermoneutral fat fractions, decreases were most pronounced at high thermoneutral fat fractions. Conclusion: Cold-induced changes in fat fraction occurred over the entire range of thermoneutral fat fractions, and were especially found in lipid-rich regions of the supraclavicular adipose depot. Due to the variability in response between lipid-rich and lipid-poor regions, care should be taken when applying fat fraction thresholds for MRI BAT analysis.

Aim: To compare the effects of cold exposure and the β3-adrenergic receptor agonist mirabegron on plasma lipids, energy expenditure and brown adipose tissue (BAT) activity in South Asians versus Europids. Materials and Methods: Ten lean Dutch South Asian (aged 18-30 years; body mass index [BMI] 18-25 kg/m 2) and 10 age-and BMI-matched Europid men participated in a randomized, double-blinded, cross-over study consisting of three interventions: short-term (~2 hours) cold exposure, mirabegron (200 mg one dose p.o.) and placebo. Before and after each intervention, we performed lipidomic analysis in serum, assessed resting energy expenditure (REE) and skin temperature, and measured BAT fat fraction by magnetic resonance imaging. Results: In both ethnicities, cold exposure increased the levels of several serum lipid species, whereas mirabegron only increased free fatty acids. Cold exposure increased lipid oxidation in both ethnicities, while mirabegron increased lipid oxidation in Europids only. Cold exposure and mirabegron enhanced supraclavicular skin

Brown adipose tissue (BAT) improves energy metabolism by combusting glucose and lipids into heat. Agonism of the glucagon-like peptide-1 receptor (GLP-1R) within the central nervous system activates BAT in mice. Moreover, in patients with type 2 diabetes, GLP-1R agonism lowers body weight and improves glucose and lipid levels, possibly involving BAT activation. Interestingly, people from South Asian descent are prone to develop cardiometabolic disease. We studied the effect of GLP-1R agonism on BAT in humans, specifically in South Asians and Europids without obesity or type 2 diabetes. Methods: Twelve Dutch South Asian and 12 age-and BMI-matched Europid nondiabetic men received 12 weeks extended-release exenatide (Bydureon) in this single-arm prospective study. Before and after treatment, BAT was visualized by a cold-induced [ 18 F]FDG-PET/CT scan and a thermoneutral MRI scan, and resting energy expenditure (REE), substrate oxidation, body composition and fasting plasma glucose and serum lipids were determined. Appetite was rated using a visual analogue scale. Results: Since the effect of exenatide on metabolic parameters did not evidently differ between ethnicities, data of all participants were pooled. Exenatide decreased body weight (−1.5 ± 0.4 kg, p b 0.01), without affecting REE or substrate oxidation, and transiently decreased appetite ratings during the first weeks. Exenatide also lowered triglycerides (−15%, p b 0.05) and total cholesterol (−5%, p b 0.05), and tended to lower glucose levels. Notably, exenatide increased BAT metabolic volume (+28%, p b 0.05) and mean standardized uptake value (+11%, p b 0.05) ([ 18 F]FDG-PET/CT), without affecting supraclavicular adipose tissue fat fraction (MRI). Conclusions/interpretation: We show for the first time that GLP-1R agonism increases [ 18 F]FDG uptake by BAT in South Asian and Europid men without obesity or type 2 diabetes. Trial registry: Clinicaltrials.gov NCT03002675.

Context Cold exposure mobilizes lipids to feed thermogenic processes in organs, including brown adipose tissue (BAT). In rodents, BAT metabolic activity exhibits a diurnal rhythm, which is highest at the start of the wakeful period. Objective To investigate whether cold-induced thermogenesis displays diurnal variation in humans, and differs between males and females. Design Randomized crossover study. Participants Twenty-four young and lean males (n=12) and females (n=12). Intervention 2.5-hour personalized cooling using water-perfused mattresses in the morning (7:45 AM) and evening (7:45 PM), with one day in between. Main outcome measures Energy expenditure (EE) and supraclavicular skin temperature in response to cold exposure. Results In males, cold-induced EE was higher in the morning than in the evening (+54±10% vs. +30±7%, P=0.05). By contrast, cold-induced EE did not differ between the morning and the evening in females (+37±9% vs. +30±10%, P=0.42). Additionally, only in males, supraclavicular skin temperature upon cold increased more in the morning than in the evening (+0.2±0.1°C vs. -0.2±0.2°C, P=0.05). In males, circulating free fatty acid (FFA) levels were increased after cold in the morning, but not in the evening (+90±18% vs. +9±8%, P<0.001). In females, circulating FFA (+94±21% vs. +20±5%, P=0.006), but also triglycerides (+42±5% vs. +29±4%, P=0.01) and cholesterol levels (+17±2% vs. 11±2%, P=0.05) were more increased after cold exposure in the morning, than in the evening. Conclusions Cold-induced thermogenesis is higher in the morning than in the evening in males, however, lipid metabolism is more modulated in the morning than in the evening in females.