Is stimulation of browning of human adipose tissue a relevant therapeutic target?

Brown adipose tissue (BAT) and beige adipose tissues are important contributors to cold-induced whole body thermogenesis in rodents. The documentation in humans of cold- and ß-adrenergic receptor agonist-stimulated BAT glucose uptake using positron emission tomography (PET) and of a decrease of this response in individuals with cardiometabolic disorders led to the suggestion that BAT/beige adipose tissues could be relevant targets for prevention and treatment of these conditions. In this brief review, we will critically assess this question by first describing the basic rationale for this affirmation, second by examining the evidence in human studies, and third by discussing the possible means to activate the thermogenic response of these tissues in humans.

A double-edged sword: risks and benefits of heat for human health.

Extreme heat events will become more frequent and intense across the globe. In this science and society article we summarize how heat affects our body and discuss the associated health threats, but also the potential health benefits of heat exposure. Moreover, we provide practical suggestions for sustainable and health-oriented strategies to cope with heat.

Brown adipose tissue metabolism in women is dependent on ovarian status.

In rodents, loss of estradiol (E2) reduces brown adipose tissue (BAT) metabolic activity. Whether E2 impacts BAT activity in women is not known. BAT oxidative metabolism was measured in premenopausal (n = 27; 35 ± 9 yr; body mass index = 26.0 ± 5.3 kg/m2) and postmenopausal (n = 25; 51 ± 8 yr; body mass index = 28.0 ± 5.0 kg/m2) women at room temperature and during acute cold exposure using [11C]acetate with positron emission tomography coupled with computed tomograph. BAT glucose uptake was also measured during acute cold exposure using 2-deoxy-2-[18F]fluoro-d-glucose. To isolate the effects of ovarian hormones from biological aging, measurements were repeated in a subset of premenopausal women (n = 8; 40 ± 4 yr; BMI = 28.0 ± 7.2 kg/m2) after 6 mo of gonadotropin-releasing hormone agonist therapy to suppress ovarian hormones. At room temperature, there was no difference in BAT oxidative metabolism between premenopausal (0.56 ± 0.31 min-1) and postmenopausal women (0.63 ± 0.28 min-1). During cold exposure, BAT oxidative metabolism (1.28 ± 0.85 vs. 0.91 ± 0.63 min-1, P = 0.03) and net BAT glucose uptake (84.4 ± 82.5 vs. 29.7 ± 31.4 nmol·g-1·min-1, P < 0.01) were higher in premenopausal than postmenopausal women. In premenopausal women who underwent gonadotropin-releasing hormone agonist, cold-stimulated BAT oxidative metabolism was reduced to a similar level (from 1.36 ± 0.66 min-1 to 0.91 ± 0.41 min-1) to that observed in postmenopausal women (0.91 ± 0.63 min-1). These results provide the first evidence in humans that reproductive hormones are associated with BAT oxidative metabolism and suggest that BAT may be a target to attenuate age-related reduction in energy expenditure and maintain metabolic health in postmenopausal women.NEW & NOTEWORTHY In rodents, loss of estrogen reduces brown adipose tissue (BAT) activity. Whether this is true in humans is not known. We found that BAT oxidative metabolism and glucose uptake were lower in postmenopausal compared to premenopausal women. In premenopausal women who underwent ovarian suppression to reduce circulating estrogen, BAT oxidative metabolism was reduced to postmenopausal levels. Thus the loss of ovarian function in women leads to a reduction in BAT metabolic activity independent of age.

The effect of preprandial versus postprandial physical activity on glycaemia: Meta-analysis of human intervention studies.

This meta-analysis aims to investigate the effect of preprandial physical activity (PA) versus postprandial PA on glycaemia in human intervention studies. Medline and Embase.com were searched until February 2023 for intervention studies in adults, directly comparing preprandial PA versus postprandial PA on glycaemia. Studies were screened using ASReview (34,837) and full texts were read by two independent reviewers (42 full text, 28 included). Results were analysed using pooled mean differences in random-effects models. Studies were either acute response studies (n = 21) or Randomized Controlled Trials (RCTs) over multiple weeks (n = 7). In acute response studies, postprandial outcomes followed the expected physiological patterns, and outcomes measured over 24 h showed no significant differences. For the RCTs, glucose area under the curve during a glucose tolerance test was slightly, but not significantly lower in preprandial PA vs postprandial PA (-0.29 [95 %CI:-0.66, 0.08] mmol/L, I2 = 64.36 %). Subgroup analyses (quality, health status, etc.) did not significantly change the outcomes. In conclusion, we found no differences between preprandial PA versus postprandial PA on glycaemia both after one PA bout as well as after multiple weeks of PA. The studies were of low to moderate quality of evidence as assessed by GRADE, showed contradictive results, included no long-term studies and used various designs and populations. We therefore need better RCTs, with more similar designs, in larger populations and longer follow-up periods (≥12 weeks) to have a final answer on the questions eat first, then exercise, or the reverse?

The effects of the ß1-adrenergic receptor antagonist bisoprolol administration on mirabegron-stimulated human brown adipose tissue thermogenesis.

AIM: Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by ineffective activation or undesirable off-target effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a ß3-adrenergic receptor (ß3-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this has been accompanied by undesirable cardiovascular effects. Therefore, we hypothesized that combining mirabegron with a ß1-AR antagonist could suppress these unwanted effects and increase the stimulation of the ß3-AR and ß2-AR in BAT. METHODS: We performed a randomized crossover trial (NCT04823442) in 8 lean men. Mirabegron (200 mg) was administered orally with or without the ß1-AR antagonist bisoprolol (10 mg). Dynamic [11C]-acetate and 2-deoxy-2-[18F]fluoro-d-glucose PET/CT scans were performed sequentially after oral administration of mirabegron ± bisoprolol. RESULTS: Compared to room temperature, mirabegron alone increased BAT oxidative metabolism (0.84 ± 0.46 vs. 1.79 ± 0.91 min-1, p = 0.0433), but not when combined with bisoprolol. The metabolic rate of glucose in BAT, measured using [18F]FDG PET, was significantly higher with mirabegron than mirabegron with bisoprolol (24 ± 10 vs. 16 ± 8 nmol/g/min, p = 0.0284). Bisoprolol inhibited the mirabegron-induced increase in systolic blood pressure and heart rate. CONCLUSION: The administration of bisoprolol decreases the adverse cardiovascular effects of mirabegron. However, the provided dose also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis, and glucose uptake. The attenuation in BAT blood flow induced by the large dose of bisoprolol may have limited BAT thermogenesis.

GDF15 promotes weight loss by enhancing energy expenditure in muscle.

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-ß-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

Human thermogenic adipose tissue.

Human thermogenic adipose tissue has long been touted as a promising therapeutic target for obesity and its associated metabolic diseases. Here, we provide a brief overview of the current knowledge of in vivo human thermogenic adipose tissue metabolism. We explore the evidence provided by retrospective and prospective studies describing the association of brown adipose tissue (BAT) [18F]fluorodeoxyglucose accumulation and various cardiometabolic risk factors. Although these studies have been invaluable in generating hypothesis, it has also raised some questions about the reliability of this method as an indicator of BAT thermogenic capacity. We discuss the evidence in support of human BAT functioning as a local thermogenic organ and energy sink, as an endocrine organ, and as a biomarker of adipose tissue health.

Stimulation of the beta-2-adrenergic receptor with salbutamol activates human brown adipose tissue.

While brown adipose tissue (BAT) is activated by the beta-3-adrenergic receptor (ADRB3) in rodents, in human brown adipocytes, the ADRB2 is dominantly present and responsible for noradrenergic activation. Therefore, we performed a randomized double-blinded crossover trial in young lean men to compare the effects of single intravenous bolus of the ADRB2 agonist salbutamol without and with the ADRB1/2 antagonist propranolol on glucose uptake by BAT, assessed by dynamic 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography scan (i.e., primary outcome). Salbutamol, compared with salbutamol with propranolol, increases glucose uptake by BAT, without affecting the glucose uptake by skeletal muscle and white adipose tissue. The salbutamol-induced glucose uptake by BAT positively associates with the increase in energy expenditure. Notably, participants with high salbutamol-induced glucose uptake by BAT have lower body fat mass, waist-hip ratio, and serum LDL-cholesterol concentration. In conclusion, specific ADRB2 agonism activates human BAT, which warrants investigation of ADRB2 activation in long-term studies (EudraCT: 2020-004059-34).

Brown Adipose Tissue-A Translational Perspective.

Brown adipose tissue (BAT) displays the unique capacity to generate heat through uncoupled oxidative phosphorylation that makes it a very attractive therapeutic target for cardiometabolic diseases. Here, we review BAT cellular metabolism, its regulation by the central nervous and endocrine systems and circulating metabolites, the plausible roles of this tissue in human thermoregulation, energy balance, and cardiometabolic disorders, and the current knowledge on its pharmacological stimulation in humans. The current definition and measurement of BAT in human studies relies almost exclusively on BAT glucose uptake from positron emission tomography with 18F-fluorodeoxiglucose, which can be dissociated from BAT thermogenic activity, as for example in insulin-resistant states. The most important energy substrate for BAT thermogenesis is its intracellular fatty acid content mobilized from sympathetic stimulation of intracellular triglyceride lipolysis. This lipolytic BAT response is intertwined with that of white adipose (WAT) and other metabolic tissues, and cannot be independently stimulated with the drugs tested thus far. BAT is an interesting and biologically plausible target that has yet to be fully and selectively activated to increase the body's thermogenic response and shift energy balance. The field of human BAT research is in need of methods able to directly, specifically, and reliably measure BAT thermogenic capacity while also tracking the related thermogenic responses in WAT and other tissues. Until this is achieved, uncertainty will remain about the role played by this fascinating tissue in human cardiometabolic diseases.

Signs of low energy availability in elite male volleyball athletes but no association with risk of bone stress injury and patellar tendinopathy.

Relative Energy Deficiency in Sport (RED-S) syndrome is associated with undesirable health and performance outcomes. The aetiology of RED-S syndrome is low energy availability (LEA). LEA has been reported in male athletes in various sports, but there is little information in team sports. Therefore, the aims of this study were to assess the point-prevalence of surrogate markers of LEA in elite male volleyball players and examine the association between low and normal total-testosterone (TES) on endocrine markers, resting metabolic rate, bone mineral density (BMD), and history of injury/illness. Using a cross-sectional design, 22 elite male volleyball players underwent anthropometric, dual-energy X-ray absorptiometry (DEXA or DXA) and resting metabolic rate testing, bloodwork, dietary analysis, the three-factor eating questionnaire-R18, injury/illness questionnaire and Victorian Institute of Sport Assessment - patellar tendon questionnaire. The primary finding of this investigation was that 36% of athletes had ≥2 surrogate markers of LEA. Although fasted insulin was lower and cortisol was higher in players with low-total TES, low BMD, low RMR and various other endocrine markers linked to LEA were not observed. More research is required to define surrogate markers of LEA in male athletes.HIGHLIGHTS Thirty-six percent of volleyball players had ≥2 surrogate markers of LEA.The Cunningham, 1991 predictive RMR equation and/or the cut-off point (<0.9) may be unsuitable for detecting energy conservation associated with LEA in large male athletes.There was no association between total-TES and risk of bone stress injury, illness and patellar tendinopathy.

High-fructose feeding suppresses cold-stimulated brown adipose tissue glucose uptake independently of changes in thermogenesis and the gut microbiome.

Diets rich in added sugars are associated with metabolic diseases, and studies have shown a link between these pathologies and changes in the microbiome. Given the reported associations in animal models between the microbiome and brown adipose tissue (BAT) function, and the alterations in the microbiome induced by high-glucose or high-fructose diets, we investigated the potential causal link between high-glucose or -fructose diets and BAT dysfunction in humans. Primary outcomes are changes in BAT cold-induced thermogenesis and the fecal microbiome (clinicaltrials.gov, NCT03188835). We show that BAT glucose uptake, but not thermogenesis, is impaired by a high-fructose but not high-glucose diet, in the absence of changes in the gastrointestinal microbiome. We conclude that decreased BAT glucose metabolism occurs earlier than other pathophysiological abnormalities during fructose overconsumption in humans. This is a potential confounding factor for studies relying on 18F-FDG to assess BAT thermogenesis.

Exercise training enhances muscle mitochondrial metabolism in diet-resistant obesity.

BACKGROUND: Current paradigms for predicting weight loss in response to energy restriction have general validity but a subset of individuals fail to respond adequately despite documented diet adherence. Patients in the bottom 20% for rate of weight loss following a hypocaloric diet (diet-resistant) have been found to have less type I muscle fibres and lower skeletal muscle mitochondrial function, leading to the hypothesis that physical exercise may be an effective treatment when diet alone is inadequate. In this study, we aimed to assess the efficacy of exercise training on mitochondrial function in women with obesity with a documented history of minimal diet-induced weight loss. METHODS: From over 5000 patient records, 228 files were reviewed to identify baseline characteristics of weight loss response from women with obesity who were previously classified in the top or bottom 20% quintiles based on rate of weight loss in the first 6 weeks during which a 900 kcal/day meal replacement was consumed. A subset of 20 women with obesity were identified based on diet-resistance (n=10) and diet sensitivity (n=10) to undergo a 6-week supervised, progressive, combined aerobic and resistance exercise intervention. FINDINGS: Diet-sensitive women had lower baseline adiposity, higher fasting insulin and triglycerides, and a greater number of ATP-III criteria for metabolic syndrome. Conversely in diet-resistant women, the exercise intervention improved body composition, skeletal muscle mitochondrial content and metabolism, with minimal effects in diet-sensitive women. In-depth analyses of muscle metabolomes revealed distinct group- and intervention- differences, including lower serine-associated sphingolipid synthesis in diet-resistant women following exercise training. INTERPRETATION: Exercise preferentially enhances skeletal muscle metabolism and improves body composition in women with a history of minimal diet-induced weight loss. These clinical and metabolic mechanism insights move the field towards better personalised approaches for the treatment of distinct obesity phenotypes. FUNDING: Canadian Institutes of Health Research (CIHR-INMD and FDN-143278; CAN-163902; CIHR PJT-148634).

Thermogenic responses to different clamped skin temperatures in cold-exposed men and women.

Despite many decades of research examining thermoregulatory responses under varying cold stresses in humans, very little is known about the variability in metabolic heat production and shivering activity. Here, we used a novel closed-loop mean skin temperature clamping technique with a liquid-conditioned suit to isolate the effects of mean skin temperature on the subjective evaluation of thermal sensation, heat production, shivering responses, and oxidative fuel selection in young, lean, and healthy men (n = 12) and women (n = 12). Our results showed a skin temperature-dependent increase in metabolic heat production (5.2 ± 1.2 kJ/min, 5.9 ± 1.5 kJ/min, and 7.0 ± 1.8 kJ/min with skin temperature maintained at 31 ± 0.1°C, 29 ± 0.2°C, and 27 ± 0.1°C, respectively; P < 0.0001) and shivering intensity in both men and women [0.6 ± 0.1% maximal voluntary contraction (MVC), 1.1 ± 0.4% MVC, and 2.5 ± 0.7% MVC, respectively; P < 0.0001], including sex-dependent differences in heat production at all three temperatures (P < 0.005). Even when controlling for lean body mass and fat mass, sex differences persisted (P = 0.048 and P = 0.004, respectively), whereas controlling for differences in body surface area eliminated these differences. Interestingly, there were no sex differences in the cold-induced change in thermogenesis. Despite clamping skin temperature, there was tremendous variability in the rate of heat production and shivering intensity. Collectively this data suggests that many of the interindividual differences in thermogenesis and shivering may be explained by differences in morphology and body composition.

Impaired Cold-Stimulated Supraclavicular Brown Adipose Tissue Activity in Young Boys With Obesity.

Childhood obesity is a growing worldwide problem. In adults, lower cold-induced brown adipose tissue (BAT) activity is linked to obesity and metabolic dysfunction; this relationship remains uncertain in children. In this cross-sectional study, we compared cold-induced supraclavicular (SCV) BAT activity (percent change in proton density fat fraction [PDFF]) within the SCV region after 1 h of whole-body cold exposure (18°C), using MRI in 26 boys aged 8-10 years: 13 with normal BMI and 13 with overweight/obesity. Anthropometry, body composition, hepatic fat, visceral adipose tissue (VAT), and pre- and postcold PDFF of the subcutaneous adipose tissue (SAT) in the posterior neck region and the abdomen were measured. Boys with overweight/obesity had lower cold-induced percent decline in SCV PDFF compared with those with normal BMI (1.6 ± 0.8 vs. 4.7 ± 1.2%, P = 0.044). SCV PDFF declined significantly in boys with normal BMI (2.7 ± 0.7%, P = 0.003) but not in boys with overweight/obesity (1.1 ± 0.5%, P = 0.053). No cold-induced changes in the PDFF of either neck SAT (-0.89 ± 0.7%, P = 0.250, vs. 0.37 ± 0.3%, P = 0.230) or abdominal SAT (-0.39 ± 0.5%, P = 0.409, and 0.25 ± 0.2%, P = 0.139, for normal BMI and overweight/obesity groups, respectively) were seen. The cold-induced percent decline in SCV PDFF was inversely related to BMI (r = -0.39, P = 0.047), waist circumference (r = -0.48, P = 0.014), and VAT (r = -0.47, P = 0.014). Thus, in young boys, as in adults, BAT activity is lower in those with overweight/obesity, suggesting that restoring activity may be important for improving metabolic health.

Lower brown adipose tissue activity is associated with non-alcoholic fatty liver disease but not changes in the gut microbiota.

In rodents, lower brown adipose tissue (BAT) activity is associated with greater liver steatosis and changes in the gut microbiome. However, little is known about these relationships in humans. In adults (n = 60), we assessed hepatic fat and cold-stimulated BAT activity using magnetic resonance imaging and the gut microbiota with 16S sequencing. We transplanted gnotobiotic mice with feces from humans to assess the transferability of BAT activity through the microbiota. Individuals with NAFLD (n = 29) have lower BAT activity than those without, and BAT activity is inversely related to hepatic fat content. BAT activity is not related to the characteristics of the fecal microbiota and is not transmissible through fecal transplantation to mice. Thus, low BAT activity is associated with higher hepatic fat accumulation in human adults, but this does not appear to have been mediated through the gut microbiota.

Elite Male Volleyball Players Are at Risk of Insufficient Energy and Carbohydrate Intake.

Elite volleyball athletes experience significant physical and psychological demands during the competitive season. The aim was to compare the dietary intake of male volleyball athletes with recommendations for sport and health, and to examine the association of physique traits and knee health on eating behaviours and of eating behaviours on reported dietary intake. Using a retrospective cross-sectional design, 22 male athletes from a national indoor volleyball program underwent anthropometric, dual-energy X-ray absorptiometry and resting metabolic rate testing, 4-day dietary intake and hematological analysis, and also completed the three-factor eating questionnaire-R18 for eating behaviours and the Victorian Institute of Sport Assessment-patellar tendon (VISA-P) questionnaire for knee health. Most players under-consumed energy compared to reference guidelines, secondary to under-consuming carbohydrate for exercise. The primary eating behaviour was cognitive restraint, which was associated with body mass index and ectomorphy. Emotional eating behaviour was associated with VISA-P. Differences in emotional and cognitive restraint eating behaviours did not impact dietary intake. The findings suggest that players are at risk of an impaired ability to adapt to and recover from training during an important segment of the competitive season. Future work should explore the presence of low energy availability in elite male volleyball players.

Challenges in tackling energy expenditure as obesity therapy: From preclinical models to clinical application.

BACKGROUND: A chronic imbalance of energy intake and energy expenditure results in excess fat storage. The obesity often caused by this overweight is detrimental to the health of millions of people. Understanding both sides of the energy balance equation and their counter-regulatory mechanisms is critical to the development of effective therapies to treat this epidemic. SCOPE OF REVIEW: Behaviors surrounding ingestion have been reviewed extensively. This review focuses more specifically on energy expenditure regarding bodyweight control, with a particular emphasis on the organs and attractive metabolic processes known to reduce bodyweight. Moreover, previous and current attempts at anti-obesity strategies focusing on energy expenditure are highlighted. Precise measurements of energy expenditure, which consist of cellular, animal, and human models, as well as measurements of their translatability, are required to provide the most effective therapies. MAJOR CONCLUSIONS: A precise understanding of the components surrounding energy expenditure, including tailored approaches based on genetic, biomarker, or physical characteristics, must be integrated into future anti-obesity treatments. Further comprehensive investigations are required to define suitable treatments, especially because the complex nature of the human perspective remains poorly understood.

Cardiomyocyte-specific Srsf3 deletion reveals a mitochondrial regulatory role.

Serine-rich splicing factor 3 (SRSF3) was recently reported as being necessary to preserve RNA stability via an mTOR mechanism in a cardiac mouse model in adulthood. Here, we demonstrate the link between Srsf3 and mitochondrial integrity in an embryonic cardiomyocyte-specific Srsf3 conditional knockout (cKO) mouse model. Fifteen-day-old Srsf3 cKO mice showed dramatically reduced (below 50%) survival and reduced the left ventricular systolic performance, and histological analysis of these hearts revealed a significant increase in cardiomyocyte size, confirming the severe remodeling induced by Srsf3 deletion. RNA-seq analysis of the hearts of 5-day-old Srsf3 cKO mice revealed early changes in expression levels and alternative splicing of several transcripts related to mitochondrial integrity and oxidative phosphorylation. Likewise, the levels of several protein complexes of the electron transport chain decreased, and mitochondrial complex I-driven respiration of permeabilized cardiac muscle fibers from the left ventricle was impaired. Furthermore, transmission electron microscopy analysis showed disordered mitochondrial length and cristae structure. Together with its indispensable role in the physiological maintenance of mouse hearts, these results highlight the previously unrecognized function of Srsf3 in regulating the mitochondrial integrity.