Cold-induced changes in plasma signaling lipids are associated with a healthier cardiometabolic profile independently of brown adipose tissue.

Cold exposure activates brown adipose tissue (BAT) and potentially improves cardiometabolic health through the secretion of signaling lipids by BAT. Here, we show that 2 h of cold exposure in young adults increases the levels of omega-6 and omega-3 oxylipins, the endocannabinoids (eCBs) anandamide and docosahexaenoylethanolamine, and lysophospholipids containing polyunsaturated fatty acids. Contrarily, it decreases the levels of the eCBs 1-LG and 2-LG and 1-OG and 2-OG, lysophosphatidic acids, and lysophosphatidylethanolamines. Participants overweight or obese show smaller increases in omega-6 and omega-3 oxylipins levels compared to normal weight. We observe that only a small proportion (∼4% on average) of the cold-induced changes in the plasma signaling lipids are slightly correlated with BAT volume. However, cold-induced changes in omega-6 and omega-3 oxylipins are negatively correlated with adiposity, glucose homeostasis, lipid profile, and liver parameters. Lastly, a 24-week exercise-based randomized controlled trial does not modify plasma signaling lipid response to cold exposure.

Cold exposure modulates potential brown adipokines in humans, but only FGF21 is associated with brown adipose tissue volume.

OBJECTIVE: The study objective was to investigate the effect of cold exposure on the plasma levels of five potential human brown adipokines (chemokine ligand 14 [CXCL14], growth differentiation factor 15 [GDF15], fibroblast growth factor 21 [FGF21], interleukin 6 [IL6], and bone morphogenic protein 8b [BMP8b]) and to study whether such cold-induced effects are related to brown adipose tissue (BAT) volume, activity, or radiodensity in young humans. METHODS: Plasma levels of brown adipokines were measured before and 1 h and 2 h after starting an individualized cold exposure in 30 young adults (60% women, 21.9 ± 2.3 y; 24.9 ± 5.1 kg/m2 ). BAT volume, 18 F-fluorodeoxyglucose uptake, and radiodensity were assessed by a static positron emission tomography-computerized tomography scan after cold exposure. RESULTS: Cold exposure increased the concentration of CXCL14 (Δ2h = 0.58 ± 0.98 ng/mL; p = 0.007), GDF15 (Δ2h = 19.63 ± 46.2 pg/mL; p = 0.013), FGF21 (Δ2h = 33.72 ± 55.13 pg/mL; p = 0.003), and IL6 (Δ1h = 1.98 ± 3.56 pg/mL; p = 0.048) and reduced BMP8b (Δ2h = -37.12 ± 83.53 pg/mL; p = 0.022). The cold-induced increase in plasma FGF21 was positively associated with BAT volume (Δ2h: ß = 0.456; R2 = 0.307; p = 0.001), but not with 18 F-fluorodeoxyglucose uptake or radiodensity. None of the changes in the other studied brown adipokines was related to BAT volume, activity, or radiodensity. CONCLUSIONS: Cold exposure modulates plasma levels of several potential brown adipokines in humans, whereas only cold-induced changes in FGF21 levels are associated with BAT volume. These findings suggest that human BAT might contribute to the circulatory pool of FGF21.

Adults with metabolically healthy overweight or obesity present more brown adipose tissue and higher thermogenesis than their metabolically unhealthy counterparts.

BACKGROUND: There is a subset of individuals with overweight/obesity characterized by a lower risk of cardiometabolic complications, the so-called metabolically healthy overweight/obesity (MHOO) phenotype. Despite the relatively higher levels of subcutaneous adipose tissue and lower visceral adipose tissue observed in individuals with MHOO than individuals with metabolically unhealthy overweight/obesity (MUOO), little is known about the differences in brown adipose tissue (BAT). METHODS: This study included 53 young adults (28 women) with a body mass index (BMI) ≥25 kg/m2 which were classified as MHOO (n = 34) or MUOO (n = 19). BAT was assessed through a static 18F-FDG positron emission tomography/computed tomography scan after a 2-h personalized cooling protocol. Energy expenditure, skin temperature, and thermal perception were assessed during a standardized mixed meal test (3.5 h) and a 1-h personalized cold exposure. Body composition was assessed by dual-energy x-ray absorptiometry, energy intake was determined during an ad libitum meal test and dietary recalls, and physical activity levels were determined by a wrist-worn accelerometer. FINDINGS: Participants with MHOO presented higher BAT volume (+124%, P = 0.008), SUVmean (+63%, P = 0.001), and SUVpeak (+133%, P = 0.003) than MUOO, despite having similar BAT mean radiodensity (P = 0.354). In addition, individuals with MHOO exhibited marginally higher meal-induced thermogenesis (P = 0.096) and cold-induced thermogenesis (+158%, P = 0.050). Moreover, MHOO participants showed higher supraclavicular skin temperature than MUOO during the first hour of the postprandial period and during the cold exposure, while no statistically significant differences were observed in other skin temperature parameters. We observed no statistically significant differences between MHOO and MUOO in thermal perception, body composition, outdoor ambient temperature exposure, resting metabolic rate, energy intake, or physical activity levels. INTERPRETATION: Adults with MHOO present higher BAT volume and activity than MUOO. The higher meal- and cold-induced thermogenesis and cold-induced supraclavicular skin temperature are compatible with a higher BAT activity. Overall, these results suggest that BAT presence and activity might be linked to a healthier phenotype in young adults with overweight or obesity. FUNDING: See acknowledgments section.

Effect of Moderate Versus Vigorous Exercise Intensity on Body Composition in Young Untrained Adults: The Activating Brown Adipose Tissue Through Exercise (ACTIBATE) Randomized Controlled Trial.

The present study aimed to investigate the effect of a 24-week aerobic + resistance training programs at moderate versus vigorous intensity on body composition, and the persistence of the changes after a 10-month free-living period, in young untrained adults. This report is based on a secondary analysis from the activating brown adipose tissue through exercise (ACTIBATE) single-center unblinded randomized controlled trial. A total of 144 young adults (65.6% women) aged 18-25 years were randomly allocated to three different groups: (a) aerobic + resistance exercise training program based on the international physical activity recommendations at vigorous intensity (Ex-Vigorous group), (b) at moderate intensity (Ex-Moderate group), and (c) control group (no exercise). Body composition outcomes were determined by a dual-energy X-ray absorptiometry scanner. Both Ex-Vigorous and Ex-Moderate decreased body weight, fat mass, and visceral adipose tissue mass in a similar manner (all p < .04). After a 10-month free-living period, these parameters returned to baseline levels in both exercise groups (all ps < .03). No differences between the exercise groups and the control group were noted in lean mass changes (all ps > .1). A 24-week aerobic + resistance training intervention based on the international physical activity recommendations was enough to improve body weight, fat mass, and visceral adipose tissue mass in untrained young adults, independently of the exercise intensity (moderate vs. vigorous).

A bout of endurance and resistance exercise transiently decreases plasma levels of bile acids in young, sedentary adults.

Circulating bile acids (BA) are signaling molecules that control glucose and lipid metabolism. However, the effects of acute exercise on plasma levels of BA in humans remain poorly understood. Here, we evaluate the effects of a bout of maximal endurance exercise (EE) and resistance exercise (RE) on plasma levels of BA in young, sedentary adults. Concentration of eight plasma BA was measured by liquid chromatography-tandem mass spectrometry before and 3, 30, 60, and 120 min after each exercise bout. Cardiorespiratory fitness (CRF) was assessed in 14 young adults (21.8 ± 2.5 yo, 12 women); muscle strength was assessed in 17 young adults (22.4 ± 2.5 yo, 11 women). EE transiently decreased plasma levels of total, primary, and secondary BA at 3 and 30 min after exercise. RE exerted a prolonged reduction in plasma levels of secondary BA (p < 0.001) that lasted until 120 min. Primary BA levels of cholic acid (CA) and chenodeoxycholic acid (CDCA) were different across individuals with low/high CRF levels after EE (p ≤ 0.044); CA levels were different across individuals with low/high handgrip strength levels. High CRF individuals presented higher levels of CA and CDCA 120 min after exercise vs baseline (+77% and +65%) vs the low CRF group (-5% and -39%). High handgrip strength levels individuals presented higher levels of CA 120 min after exercise versus baseline (+63%) versus the low handgrip strength group (+6%). The study findings indicate that an individual's level of physical fitness can influence how circulating BA respond to both endurance and resistance exercise. Additionally, the study suggests that changes in plasma BA levels after exercising could be related to the control of glucose homeostasis in humans.

Association of meal timing with body composition and cardiometabolic risk factors in young adults.

PURPOSE: To investigate the association of meal timing with body composition and cardiometabolic risk factors in young adults. METHODS: In this cross-sectional study participated 118 young adults (82 women; 22 ± 2 years old; BMI: 25.1 ± 4.6 kg/m2). Meal timing was determined via three non-consecutive 24-h dietary recalls. Sleep outcomes were objectively assessed using accelerometry. The eating window (time between first and last caloric intake), caloric midpoint (local time at which ≥ 50% of daily calories are consumed), eating jetlag (variability of the eating midpoint between non-working and working days), time from the midsleep point to first food intake, and time from last food intake to midsleep point were calculated. Body composition was determined by DXA. Blood pressure and fasting cardiometabolic risk factors (i.e., triglycerides, total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, and insulin resistance) were measured. RESULTS: Meal timing was not associated with body composition (p > 0.05). The eating window was negatively related to HOMA-IR and cardiometabolic risk score in men (R2 = 0.348, ß = - 0.605; R2 = 0.234, ß = - 0.508; all p ≤ 0.003). The time from midsleep point to first food intake was positively related to HOMA-IR and cardiometabolic risk score in men (R2 = 0.212, ß = 0.485; R2 = 0.228, ß = 0.502; all p = 0.003). These associations remained after adjusting for confounders and multiplicity (all p ≤ 0.011). CONCLUSIONS: Meal timing seems unrelated to body composition in young adults. However, a longer daily eating window and a shorter time from midsleep point to first food intake (i.e., earlier first food intake in a 24 h cycle) are associated with better cardiometabolic health in young men. CLINICAL TRIAL REGISTRATION: NCT02365129 ( https://www. CLINICALTRIALS: gov/ct2/show/NCT02365129?term=ACTIBATE&draw=2&rank=1 ).

Exercise-induced changes on exerkines that might influence brown adipose tissue metabolism in young sedentary adults.

ABSTRACTIn rodents, exercise alters the plasma concentration of exerkines that regulate white adipose tissue (WAT) browning or brown adipose tissue (BAT) metabolism. This study aims to analyse the acute and chronic effect of exercise on the circulating concentrations of 16 of these exerkines in humans. Ten young sedentary adults (6 female) performed a maximum walking effort test and a resistance exercise session. The plasma concentration of 16 exerkines was assessed before, and 3, 30, 60, and 120 min after exercise. Those exerkines modified by exercise were additionally measured in another 28 subjects (22 women). We also measured the plasma concentrations of the exerkines before and after a 24-week exercise programme (endurance + resistance; 3-groups: control, moderate-intensity and vigorous-intensity) in 110 subjects (75 women). Endurance exercise acutely increased the plasma concentration of lactate, norepinephrine, brain-derived neurotrophic factor, interleukin 6, and follistatin-like protein 1 (3 min after exercise), and musclin and fibroblast growth factor 21 (30 and 60 min after exercise), decreasing the plasma concentration of leptin (30 min after exercise). Adiponectin, atrial natriuretic peptide (ANP), ß-aminoisobutyric acid, meteorin-like, follistatin, pro-ANP, irisin and myostatin were not modified or not detectable. The resistance exercise session increased the plasma concentration of lactate 3 min after exercise. Chronic exercise did not alter the plasma concentration of these exerkines. In sedentary young adults, acute endurance exercise releases to the bloodstream exerkines that regulate BAT metabolism and WAT browning. In contrast, neither a low-volume resistance exercise session nor a 24-week training programme modified plasma levels of these molecules.HighlightsAcute endurance exercise increases the plasma concentration of lactate, norepinephrine, brain-derived neurotrophic factor, interleukin 6, follistatin-like protein 1, musclin, and fibroblast growth factor 21, and decrease the plasma concentration of leptin.The exercise-induced change in lactate plasma concentration is positively associated with brown adipose tissue volume, glucose uptake and radiodensity.Neither acute resistance exercise nor chronic exercise significantly alter the plasma concentration of these exerkines.Trial registration: ClinicalTrials.gov identifier: NCT02365129.

Reproducibility of the energy metabolism response to an oral glucose tolerance test: influence of a postcalorimetric correction procedure.

PURPOSE: Metabolic flexibility (MetF), which is a surrogate of metabolic health, can be assessed by the change in the respiratory exchange ratio (RER) in response to an oral glucose tolerance test (OGTT). We aimed to determine the day-to-day reproducibility of the energy expenditure (EE) and RER response to an OGTT, and whether a simulation-based postcalorimetric correction of metabolic cart readouts improves day-to-day reproducibility. METHODS: The EE was assessed (12 young adults, 6 women, 27 ± 2 years old) using an Omnical metabolic cart (Maastricht Instruments, Maastricht, The Netherlands) after an overnight fast (12 h) and after a 75-g oral glucose dose on 2 separate days (48 h). On both days, we assessed EE in 7 periods (one 30-min baseline and six 15-min postprandial). The ICcE was performed immediately after each recording period, and capillary glucose concentration (using a digital glucometer) was determined. RESULTS: We observed a high day-to-day reproducibility for the assessed RER (coefficients of variation [CV] < 4%) and EE (CVs < 9%) in the 7 different periods. In contrast, the RER and EE areas under the curve showed a low day-to-day reproducibility (CV = 22% and 56%, respectively). Contrary to our expectations, the postcalorimetric correction procedure did not influence the day-to-day reproducibility of the energy metabolism response, possibly because the Omnical's accuracy was ~ 100%. CONCLUSION: Our study demonstrates that the energy metabolism response to an OGTT is poorly reproducible (CVs > 20%) even using a very accurate metabolic cart. Furthermore, the postcalorimetric correction procedure did not influence the day-to-day reproducibility. Trial registration NCT04320433; March 25, 2020.

Acute and long-term exercise differently modulate plasma levels of oxylipins, endocannabinoids, and their analogues in young sedentary adults: A sub-study and secondary analyses from the ACTIBATE randomized controlled-trial.

BACKGROUND: Fatty acid-derived lipid mediators including oxylipins, endocannabinoids (eCBs), and their analogues, have emerged as key metabolites in the inflammatory and immune response to physiological stressors. METHODS: This report was based on a sub-study and secondary analyses the ACTIBATE single-center unblinded randomized controlled trial (ClinicalTrials.gov ID: NCT02365129). The study was performed in the Sport and Health University Research Institute and the Virgen de las Nieves University Hospital of the University of Granada. Eligible participants were young, sedentary adults with no chronic diseases. Here, we performed both an acute endurance and resistance exercise sub-studies (n.ß=.ß14 and 17 respectively), and a 24-week supervised exercise intervention, combining endurance and resistance exercise training at moderate-intensity (MOD-EX) or vigorous-intensity (VIG-EX) exercise groups, in young sedentary adults. Randomization was performed by unrestricted randomization. Plasma levels of oxylipins, eCBs, and their analogues were measured using liquid chromatography-tandem mass spectrometry. FINDINGS: Both endurance and resistance exercise increased by.ß+50% the plasma levels of dihomo-..-linolenic acid and arachidonic acid (AA) omega-6 derived oxylipins, as well as eicosapentaenoic acid and docosahexaenoic acid omega-3 derived after 3 and 120.ßmin of the bout of exercise (all ..2.ß....ß0.219 and P.ß..±.ß0.039). These exercise modalities also increased the levels of anandamide and eCBs analogues (+25%). 145 young sedentary adults were assigned to a control (CON, n.ß=.ß54), a MOD-EX (n.ß=.ß48) or a VIG-EX (n.ß=.ß43). 102 participants were included in the final long-term analyses (CON, n.ß=.ß36; MOD-EX, n.ß=.ß33; and VIG-EX, n.ß=.ß33) of the trial. After 24-week of supervised exercise, MOD-EX decreased plasma levels of omega-6 oxylipins, concretely linoleic acid (LA) and adrenic acid derived oxylipins, and the eCBs analogues OEA and LEA in comparison to the CON (all P.ß..±.ß0.021). VIG-EX decreased LA-derived oxylipins and LEA compared to CON. No relevant adverse events were recorded. INTERPRETATION: Endurance and resistance exercises acutely increased plasma levels of oxylipins, eCBs, and their analogues, whereas 24 weeks of exercise training decreased fasting plasma levels of omega-6 oxylipins, and eCBs analogues in young, sedentary adults. FUNDING: See Acknowledgments section.

A larger brown fat volume and lower radiodensity are related to a greater cardiometabolic risk, especially in young men.

Objectives: Brown adipose tissue (BAT) is important in the maintenance of cardiometabolic health in rodents. Recent reports appear to suggest the same in humans, although if this is true remains elusive partly because of the methodological bias that affected previous research. This cross-sectional work reports the relationships of cold-induced BAT volume, activity (peak standardized uptake, SUVpeak), and mean radiodensity (an inverse proxy of the triacylglycerols content) with the cardiometabolic and inflammatory profile of 131 young adults, and how these relationships are influenced by sex and body weight. Design: This is a cross-sectional study. Methods: Subjects underwent personalized cold exposure for 2 h to activate BAT, followed by static 18F-fluorodeoxyglucose PET-CT scanning to determine BAT variables. Information on cardiometabolic risk (CMR) and inflammatory markers was gathered, and a CMR score and fatty liver index (FLI) were calculated. Results: In men, BAT volume was positively related to homocysteine and liver damage markers concentrations (independently of BMI and seasonality) and the FLI (all P ≤ 0.05). In men, BAT mean radiodensity was negatively related to the glucose and insulin concentrations, alanine aminotransferase activity, insulin resistance, total cholesterol/HDL-C, LDL-C/HDL-C, the CMR score, and the FLI (all P ≤ 0.02). In women, it was only negatively related to the FLI (P < 0.001). These associations were driven by the results for the overweight and obese subjects. No relationship was seen between BAT and inflammatory markers (P > 0.05). Conclusions: A larger BAT volume and a lower BAT mean radiodensity are related to a higher CMR, especially in young men, which may support that BAT acts as a compensatory organ in states of metabolic disruption.

No evidence of brown adipose tissue activation after 24 weeks of supervised exercise training in young sedentary adults in the ACTIBATE randomized controlled trial.

Exercise modulates both brown adipose tissue (BAT) metabolism and white adipose tissue (WAT) browning in murine models. Whether this is true in humans, however, has remained unknown. An unblinded randomized controlled trial (ClinicalTrials.gov ID: NCT02365129) was therefore conducted to study the effects of a 24-week supervised exercise intervention, combining endurance and resistance training, on BAT volume and activity (primary outcome). The study was carried out in the Sport and Health University Research Institute and the Virgen de las Nieves University Hospital of the University of Granada (Spain). One hundred and forty-five young sedentary adults were assigned to either (i) a control group (no exercise, n = 54), (ii) a moderate intensity exercise group (MOD-EX, n = 48), or (iii) a vigorous intensity exercise group (VIG-EX n = 43) by unrestricted randomization. No relevant adverse events were recorded. 97 participants (34 men, 63 women) were included in the final analysis (Control; n = 35, MOD-EX; n = 31, and VIG-EX; n = 31). We observed no changes in BAT volume (Δ Control: -22.2 ± 52.6 ml; Δ MOD-EX: -15.5 ± 62.1 ml, Δ VIG-EX: -6.8 ± 66.4 ml; P = 0.771) or 18F-fluorodeoxyglucose uptake (SUVpeak Δ Control: -2.6 ± 3.1 ml; Δ MOD-EX: -1.2 ± 4.8, Δ VIG-EX: -2.2 ± 5.1; p = 0.476) in either the control or the exercise groups. Thus, we did not find any evidence of an exercise-induced change on BAT volume or activity in young sedentary adults.

Acute Effects of Whole-Body Electromyostimulation on Energy Expenditure at Resting and during Uphill Walking in Healthy Young Men.

The effects of the different electrical frequencies of whole-body electrical stimulation (WB-EMS) on energy expenditure (EE) and the respiratory exchange ratio (RER) remain poorly understood. This study aimed to determine the effects of different WB-EMS electrical frequencies on EE and the RER during supine resting and uphill walking. A total of 10 healthy and recreationally active men (21.6 ± 3.3 years old) participated in the present study. Participants completed two testing sessions in a randomized order. In each session, a variety of impulse frequencies (1 hertz (Hz), 2 Hz, 4 Hz, 6 Hz, 8 Hz, and 10 Hz) were applied in a randomized order, allowing a 10 min passive recovery between them. Oxygen consumption and carbon dioxide production were measured to calculate EE and the RER. All frequencies increased EE at rest (all p ≤ 0.001), with 4 Hz being the frequency producing the highest increase (Δ = 8.89 ± 1.49 kcal/min), as did 6 Hz (Δ = 8.05 ± 1.52 kcal/min) and 8 Hz (Δ = 7.04 ± 2.16 kcal/min). An increment in the RER at rest was observed with 4 Hz, 6 Hz, 8 Hz and 10 Hz (all p ≤ 0.016), but not with 1 Hz and 2 Hz (p ≥ 0.923). During uphill walking, the frequency that elicited the highest increase in EE was 6 Hz (Δ = 4.87 ± 0.84 kcal/min) compared to the unstimulated condition. None of the impulse frequencies altered the RER during uphill walking. WB-EMS increases EE in healthy young men both during resting and uphill walking.

Association of shivering threshold time with body composition and brown adipose tissue in young adults.

PURPOSE: Brown adipose tissue (BAT) increases metabolic heat production in response to cold exposure. Body size and composition are involved in the human cold response, yet the influence of BAT herein have not fully been explored. Here, we aimed to study the association of the cold-induced shivering threshold time with body composition, BAT, the perception of shivering and skin temperature in young adults. METHODS: 110 young healthy adults (81 females; age = 21.7 ± 2.1 years, BMI = 24.2 ± 4.3 kg/m2) underwent 2 h of individualized cooling, followed by the quantification of BAT using a18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography-computed tomography (PET-CT) scan. Body mass index (BMI), lean mass, fat mass and body surface area (BSA) were also measured. Shivering threshold time was defined as the time until shivering occurred using an individualized cooling protocol. RESULTS: The shivering threshold time was on average 116.1 min for males and 125.8 min for females, and was positively associated to BMI (ß = 3.106; R2 = 0.141; p = 0.001), lean mass (ß = 2.295; R2 = 0.128; p = 0.001) and fat mass (ß = 1.492; R2 = 0.121; p = 0.001) in females, but not in males (all p ≥ 0.409). The shivering threshold time was positively associated with BSA in males (p = 0.047) and females (p = 0.001), but it was not associated with BAT volume or [18F]FDG uptake nor with the perception of shivering and skin temperature perception in both sexes. CONCLUSION: The shivering threshold time is positively associated with whole-body adiposity and lean mass in females, but not in males. The shivering threshold time was positively associated with BSA, but no association was observed with BAT nor with the perception of shivering or skin temperature. Future research should consider the influence of body composition when applying cooling protocols among individuals with different phenotypical features.

Circulating concentrations of free triiodothyronine are associated with central adiposity and cardiometabolic risk factors in young euthyroid adults

Thyroid dysfunction is associated with classic cardiometabolic risk factors in humans. However, this relationship remains unclear in young euthyroid adults. The present work examines the associations of circulating thyroid hormones (THs) and thyroid-stimulating hormone (TSH) concentrations with body composition and cardiometabolic risk factors in young euthyroid adults. A total of 106 sedentary, euthyroid adults (72 women; 22 ± 2 years old) participated in this cross-sectional study. THs and TSH serum concentrations were determined in fasting conditions (6 h). Body composition (fat mass (FM), lean mass (LM), and visceral adipose tissue (VAT)) was determined by dual-energy X-ray absorptiometry, anthropometric parameters (weight, height, and waist circumference) were measured, and neck adipose tissue mass was quantified through computed tomography (CT) scanning. Cardiometabolic risk factors including fasting glucose and lipid metabolism markers, hepatic phosphatase and transaminases, and blood pressure were also assessed. Free triiodothyronine (FT3) concentration was positively associated with body mass index, LM, VAT, and waist circumference (all P ≤ 0.038). FT3 was also associated with glucose, insulin, HOMA-IR, fatty liver index, and blood pressure (all P < 0.024). All the associations were attenuated when adjusting for sex. In contrast, we found no associations of TSH or free thyroxine with any body composition parameter or cardiometabolic risk factors. In conclusion, FT3 is associated with central adiposity and cardiometabolic risk factors including insulin resistance, fatty liver index, and mean, systolic and diastolic blood pressure in young euthyroid adults. ClinicalTrials.gov identifier: NCT02365129. (AU)

Circulating concentrations of free triiodothyronine are associated with central adiposity and cardiometabolic risk factors in young euthyroid adults.

Thyroid dysfunction is associated with classic cardiometabolic risk factors in humans. However, this relationship remains unclear in young euthyroid adults. The present work examines the associations of circulating thyroid hormones (THs) and thyroid-stimulating hormone (TSH) concentrations with body composition and cardiometabolic risk factors in young euthyroid adults. A total of 106 sedentary, euthyroid adults (72 women; 22 ± 2 years old) participated in this cross-sectional study. THs and TSH serum concentrations were determined in fasting conditions (6 h). Body composition (fat mass (FM), lean mass (LM), and visceral adipose tissue (VAT)) was determined by dual-energy X-ray absorptiometry, anthropometric parameters (weight, height, and waist circumference) were measured, and neck adipose tissue mass was quantified through computed tomography (CT) scanning. Cardiometabolic risk factors including fasting glucose and lipid metabolism markers, hepatic phosphatase and transaminases, and blood pressure were also assessed. Free triiodothyronine (FT3) concentration was positively associated with body mass index, LM, VAT, and waist circumference (all P ≤ 0.038). FT3 was also associated with glucose, insulin, HOMA-IR, fatty liver index, and blood pressure (all P < 0.024). All the associations were attenuated when adjusting for sex. In contrast, we found no associations of TSH or free thyroxine with any body composition parameter or cardiometabolic risk factors. In conclusion, FT3 is associated with central adiposity and cardiometabolic risk factors including insulin resistance, fatty liver index, and mean, systolic and diastolic blood pressure in young euthyroid adults. ClinicalTrials.gov identifier: NCT02365129.

Beyond appetite regulation: Targeting energy expenditure, fat oxidation, and lean mass preservation for sustainable weight loss.

New appetite-regulating antiobesity treatments such as semaglutide and agents under investigation such as tirzepatide show promise in achieving weight loss of 15% or more. Energy expenditure, fat oxidation, and lean mass preservation are important determinants of weight loss and weight-loss maintenance beyond appetite regulation. This review discusses prior failures in clinical development of weight-loss drugs targeting energy expenditure and explores novel strategies for targeting energy expenditure: mitochondrial proton leak, uncoupling, dynamics, and biogenesis; futile calcium and substrate cycling; leptin for weight maintenance; increased sympathetic nervous system activity; and browning of white fat. Relevant targets for preserving lean mass are also reviewed: growth hormone, activin type II receptor inhibition, and urocortin 2 and 3. We endorse moderate modulation of energy expenditure and preservation of lean mass in combination with efficient appetite reduction as a means of obtaining a significant, safe, and long-lasting weight loss. Furthermore, we suggest that the regulatory guidelines should be revisited to focus more on the quality of weight loss and its maintenance rather than the absolute weight loss. Commitment to this research focus both from a scientific and from a regulatory point of view could signal the beginning of the next era in obesity therapies.

Effects of Intermittent Fasting on Cardiometabolic Health: An Energy Metabolism Perspective.

This review summarizes the effects of different types of intermittent fasting (IF) on human cardiometabolic health, with a focus on energy metabolism. First, we discuss the coordinated metabolic adaptations (energy expenditure, hormonal changes and macronutrient oxidation) occurring during a 72 h fast. We then discuss studies investigating the effects of IF on cardiometabolic health, energy expenditure and substrate oxidation. Finally, we discuss how IF may be optimized by combining it with exercise. In general, IF regimens improve body composition, ectopic fat, and classic cardiometabolic risk factors, as compared to unrestricted eating, especially in metabolically unhealthy participants. However, it is still unclear whether IF provides additional cardiometabolic benefits as compared to continuous daily caloric restriction (CR). Most studies found no additional benefits, yet some preliminary data suggest that IF regimens may provide cardiometabolic benefits in the absence of weight loss. Finally, although IF and continuous daily CR appear to induce similar changes in energy expenditure, IF regimens may differentially affect substrate oxidation, increasing protein and fat oxidation. Future tightly controlled studies are needed to unravel the underlying mechanisms of IF and its role in cardiometabolic health and energy metabolism.

Uncertain association between maximal fat oxidation during exercise and cardiometabolic risk factors in healthy sedentary adults.

The present work examines the relationships between maximal fat oxidation during a graded exercise test (MFO), the intensity of exercise that elicits MFO (Fatmax), and traditional cardiometabolic risk factors in healthy, sedentary adults. A total of 119 (81 women) young, sedentary adults (22.1 ± 2.2 years old), and 71 (37 women) middle-aged, sedentary adults (53.4 ± 4.9 years old) participated in the current study. Systolic and diastolic blood pressures were determined following standard procedures. Plasma glucose, insulin, total cholesterol, high-density lipoprotein cholesterol and triglycerides were determined in a fasted state and the homeostatic model assessment of insulin resistance index and low-density lipoprotein cholesterol levels subsequently calculated. A sex and age group-specific cardiometabolic risk Z-score was also calculated for each subject based on waist circumference, systolic and diastolic blood pressure, plasma glucose, high-density lipoprotein cholesterol and triglycerides. MFO and Fatmax were determined using a walking graded exercise test using indirect calorimetry. No clear association was seen of MFO and Fatmax with any cardiometabolic risk factor (all P≥0.05), except for a weak, inverse association between Fatmax and the fatty liver index (P=0.027). Similarly, neither MFO nor Fatmax was apparently associated with the cardiometabolic risk Z-score (all P≥0.05). The current findings suggest an uncertain association of MFO and Fatmax during a graded exercise test with the cardiometabolic profile of healthy, sedentary adults.HighlightsThe study of the physiological mechanisms that trigger the onset of metabolic disorders has received considerable attention in recent years, with changes in MFO and Fatmax being highlighted as a potential key factor.This work shows that MFO and Fatmax during a graded exercise test are not associated with the cardiometabolic profile in sedentary, healthy adults.Further studies are needed to elucidate which other physiological disorders are related to cardiometabolic risk.

Diurnal variations of cold-induced thermogenesis in young, healthy adults: A randomized crossover trial.

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 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 ≈96 h had elapsed, the subjects 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 18F-fluordeoxyglucose (18F-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 expenditure (16.8 ± 12.8 vs. 15.7 ± 15.1% increase above REE, P = 0.72). BAT 18F-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 18F-FDG uptake appears not to change across the day either, although experiments with a within-subject study design are needed to confirm these findings. Registered under ClinicalTrials.gov Identifier no. NCT02365129.