Guillermo Sanchez-Delgado

Role of Exercise in the Activation of Brown Adipose Tissue

Background: The energy-burning capacity of brown adipose tissue (BAT) makes it an attractive target for use in anti-obesity therapies. Moreover, due to its ability to oxidize glucose and lipids, BAT activation has been considered a potential therapy to combat type 2 diabetes and atherogenesis. Summary: BAT is mainly regulated by the sympathetic nervous system (SNS); yet, recent findings have shown a group of novel activators that act independently of the stimulation of the SNS such as cardiac natriuretic peptides, irisin, interleukin-6, β-aminoisobutyric acid and fibroblast growth factor 21 that could influence BAT metabolism. Several strategies are being examined to activate and recruit BAT with no side effects. In this review, we postulate that exercise might activate and recruit human BAT through the activation of SNS, heart and skeletal muscle. Key Messages: Epidemiological and well-designed exercise-based randomized controlled studies are needed to clarify if exercise is able to activate BAT in humans.

Prevalence of overweight/obesity and fitness level in preschool children from the north compared with the south of Europe: an exploration with two countries

North–south differences in the prevalence of obesity and fitness levels have been found in European adolescents, yet it is unknown if such differences already exist in very young children.

Activating brown adipose tissue through exercise (ACTIBATE) in young adults: Rationale, design and methodology

AIMS The energy expenditure capacity of brown adipose tissue (BAT) makes it an attractive target as a therapy against obesity and type 2 diabetes. BAT activators namely catecholamines, natriuretic peptides and certain myokines, are secreted in response to exercise. ACTIBATE will determine the effect of exercise on BAT activity and mass measured by positron emission tomography/computed tomography (PET/CT, primary outcome) in young adults. ACTIBATE will also investigate the physiological consequences of activating BAT (secondary outcomes). METHODS ACTIBATE will recruit 150 sedentary, healthy, young adults (50% women) aged 18-25 years. Eligible participants will be randomly assigned to a non-exercise group (n ≈ 50) or one of two exercise groups (n=50 each). Participants in the exercise groups will perform aerobic and strength training 3-4 days/week at a heart rate equivalent to 60% of heart rate reserve (HRres), and at 50% of 1 repetition maximum (RM) for the moderate-intensity group, and at 80% of HRres and 70% RM for the vigorous-intensity group. Laboratory measures completed at baseline and 6 months include BAT activity and mass, resting energy expenditure, meal and cold-induced thermogenesis, body temperature regulation and shivering threshold, body composition and cardiovascular disease risk factors. We will also obtain biopsies from abdominal subcutaneous white adipose tissue and skeletal muscle to analyse the expression of genes encoding proteins involved in the thermogenic machinery. DISCUSSION Findings from ACTIBATE will have significant implications for our understanding of exercise and its protective effects against the development of type 2 diabetes, obesity and related metabolic diseases. ClinicalTrials.gov ID: NCT02365129.

Assessing physical fitness in preschool children: Feasibility, reliability and practical recommendations for the PREFIT battery.

OBJECTIVES In childhood (>6 years-old) and adolescence, fitness testing is feasible, reliable and related to later health. The purpose of this study was to examine the feasibility and reliability of a field-based fitness-test battery in preschool children. DESIGN Repeated measures. METHODS A total of 161 preschoolers aged 3 to 5 years participated in the study. Anthropometry, cardiorespiratory fitness, muscular strength and motor fitness were tested twice (2 weeks apart) using weight, height, waist circumference, PREFIT 20m shuttle run, handgrip strength, standing long jump, 4×10m shuttle run and one-leg stance tests, respectively. RESULTS The main results indicated that all tests are feasible and highly reliable (mean differences, weight=0.04kg, height=0.22cm, waist circumference=-0.08cm, PREFIT 20m shuttle run=2.00 laps, handgrip strength=-0.24kg and 4×10m shuttle run=0.12s), in preschool children, except for the standing long jump test and one-leg stance test (mean differences of -7.31cm and 8.01s). After some methodological adaptations, reliability for standing long jump was improved in a replication study (i.e. from -7 to -2cm). We observed evidence of heteroscedasticity in the 4×10m shuttle run and one-leg stance tests. CONCLUSIONS The PREFIT battery is a feasible and reliable tool to assess physical fitness in preschool children yet standing long jump has shown mixed findings and requires further studies. The one-leg stance test showed poor reliability in our study and if confirmed by future studies, its use in 3 to 5 years-old would not be recommended. Future studies should consider the mean differences provide in this study to explain the changes in test performance.

Reliability and Validity of Different Models of TKK Hand Dynamometers

OBJECTIVE We examined the reliability and validity of the analog and digital models of TKK handgrip dynamometers using calibrated known weights. METHOD A total of 6 dynamometers (3 digital and 3 analog; 2 new and 1 old for each model) were used in this study. RESULTS Intrainstrument reliability was very high; systematic error for test-retest reliability was ≤|0.3 kg|. The systematic error among different instruments (same model) and between different models (digital vs. analog) ranged between |0.4 kg| and |0.6 kg|. The systematic error between new and old dynamometers ranged from |0.8 kg| to |1 kg|. All dynamometers provided lower values for the same known weights than a SECA scale, with a systematic error ranging from -0.94 to -2.64 kg. CONCLUSION This study indicates that clinicians and investigators who provide treatment to address handgrip strength should use the same instrument and model for repeated measures. Distinguishing meaningful change from dynamometer variability is discussed.

Assessment of handgrip strength in preschool children aged 3 to 5 years

We investigated whether there is an optimal grip span for determining the maximum handgrip strength in preschool children and if it is influenced by gender, age, or hand size. A total of 292 preschool children (3–5 years; 59.2% boys) carried out the handgrip strength test with different grip spans (4.0, 4.5, 5.0, 5.5, and 6.0 cm). The hand size was also measured. We also determined the reliability of the optimal grip span in another group of children (n = 56, 57% boys) who did the test twice, with a 3-hour difference between tests. The results showed that 4.0 cm is the optimal grip span to determine the maximum handgrip strength in preschool children. This result applied to both genders, all age groups, and hand sizes. Paired t-tests showed no significant differences between test and retest. These findings may guide clinicians and researchers in selecting the optimal grip span when measuring handgrip strength in preschool children. Level IV

Differences between the most used equations in BAT-human studies to estimate parameters of skin temperature in young lean men

Cold exposure is necessary to activate human brown adipose tissue (BAT), resulting in heat production. Skin temperature is an indirect measure to monitor the body’s reaction to cold. The aim of this research was to study whether the most used equations to estimate parameters of skin temperature in BAT-human studies measure the same values of temperature in young lean men (n = 11: 23.4 ± 0.5 years, fat mass: 19.9 ± 1.2%). Skin temperature was measured with 26 ibuttons at 1-minute intervals in warm and cold room conditions. We used 12 equations to estimate parameters of mean, proximal, and distal skin temperature as well as skin temperature gradients. Data were analysed with Temperatus software. Significant differences were found across equations to measure the same parameters of skin temperature in warm and cold room conditions, hampering comparison across studies. Based on these findings, we suggest to use a set of 14 ibuttons at anatomical positions reported by ISO STANDARD 9886:2004 plus five ibuttons placed on the right supraclavicular fossa, right middle clavicular bone, right middle upper forearm, right top of forefinger, and right upper chest.

RE: Association between habitual physical activity and brown adipose tissue activity in individuals undergoing PET‐CT scan

Dear Editor, We read with interest the relevant study by Dinas et al. where they showed, for the first time, an association between selfreported habitual physical activity and brown adipose tissue (BAT) activity in a sample of forty (14 females) patients with cancer. Their positive findings are of great importance, and despite their study design does not allow to infer any causal relationship, the results are informative and support evidence from exercise-based intervention studies conducted in animal models. Although contribution by Dinas et al. should be recognized, caution is needed when suggesting that habitual physical activity may have an effect on BAT activity. Firstly, they assessed habitual physical activity with a questionnaire. It is known that the assessment of physical activity by questionnaire has low accuracy. In epidemiologic research, self-reported questionnaires are common tools to assess physical activity level because they are easy to use and inexpensive. However, self-reported physical activity suffers from important reporting bias attributable to a combination of social desirability bias and the cognitive challenge associated with estimating frequency and duration of physical activity. Objective measurement tools such as accelerometers, which measure movement intensity, offer a potential solution to problems with self-reported data. Secondly, they did not show whether the association of habitual physical activity with BAT activity was independent of body mass index (BMI). Moreover, the wide age range of their study participants (i.e. 20–80 years) makes difficult to generalize the findings, specially knowing that BAT activity seems to decrease with age. No interaction analysis was performed between sex, physical activity and BAT activity, so the reader cannot know whether the observed association applies to both male and female cancer patients, or whether the association persist, or not, when the analyses are conducted separately in males and in females. Future studies with larger sample size are needed to analyse these associations in men and women separately, as well as in different age groups. Thirdly, associations between BAT mass and activity and BMI or sex should be interpreted cautiously when an individualized cooling protocol has not been carried out prior to the PET/CT scan. Lower temperatures are needed to induce shivering in males compared to females and in obese compared to lean individuals. Thus, the higher BAT activity obtained in females and in lean individuals could be biased by indoor temperatures, which may be low enough to induce nonshivering thermogenesis in females and in lean individuals, but not in males and obese individuals. Fourthly, it is likely that the observed association between selfreported physical activity and BAT activity might be weakened due to the fact that the participants were a group of patients with tumour cells. Tumour cells as well as brown adipocytes have higher levels of F-fluorodeoxyglucose uptake than normal cells. Hence, both types of cells might be competing for the same energy substrate. Therefore, BAT mass and activity can be confounded by competing tracer uptake (F-fluorodeoxyglucose) in tumour cells. Brown adipose tissue has the ability to oxidize glucose and lipids and dissipate energy in the form of heat. Therefore, the energy burning capacity of BAT makes it an attractive target for antiobesity and type 2 diabetes therapies. A potential clinical implication of activating BAT relates to the higher resting energy expenditure and higher thermogenic response to a meal. Modest estimations suggest that 50 g of activated BAT could amount to approximately 5% of resting energy expenditure. A 5% chronic increase in resting energy expenditure turns to approximately 100 kcal/day over the course of a year, which might translate to a loss of approximately 4 7 kg of fat mass yearly. Activated BAT might influence our propensity to become obese, and thus our risk of developing type 2 diabetes and other related metabolic diseases. The sympathetic nervous system (SNS) is the classical regulator of BAT; however, recent findings have shown a pool of novel BAT activators that sidestep the need for stimulating the SNS, such as the cardiac natriuretic peptides. Of interest is that both SNS and non-SNS BAT activators are sensitive to exercise, which opens new horizons to study the potential effect of exercisebased therapeutic interventions. Whether or not physical activity is able to stimulate BAT activity and to increase BAT mass in humans is currently unknown. In addition, a new set of myokines has been discovered, such as irisin and b-aminoisobutyric acid, both released by exercise-stimulated murine and human skeletal muscle, which may activate the browning programme in white adipose tissue. Currently, there are no simple and nonsurgical treatment strategies for treating obesity or type 2 diabetes. While regular physical activity seems to play a key role in the prevention and treatment of obesity and type 2 diabetes, the mechanisms that mediate these effects are currently unknown. Well design exercise-based randomized controlled trials are warranted to answer the question whether exercise is able to (i) activate BAT, (ii) recruit BAT, (iii) stimulate pre-existing BAT precursors and (iv) induce the specific gene programme to favour white-to-brown adipocyte transformation in humans. Findings from these studies will have significant implications for our understanding of physical activity and its protective effects against the development of type 2 diabetes, obesity and related metabolic diseases. As such, the contribution by Dinas et al. has opened new perspectives and is to be acknowledged.

Regulation of energy balance by brown adipose tissue: at least three potential roles for physical activity

Brown adipose tissue (BAT) has the ability to oxidise glucose and lipids, and dissipate energy in the form of heat.1 Thus, it could provide one method to influence energy balance—and therefore, be a player in the fight against obesity and type 2 diabetes. BAT is highly regulated by the sympathetic nervous system (SNS) to increase body temperature when mammals are exposed to cold. The heat production is mediated by uncoupling protein 1 (UCP-1), an inner-membrane mitochondrial protein exclusively expressed in BAT.1 Dogma was that BAT was only present in newborns. However, radiologists using the radiotracer 18F-fluorodeoxyglucose in positron emission tomography (PET)/computed tomography to detect metabolically active tumours, found competing areas in the supraclavicular, thoracic spine and neck regions with high rates of glucose uptake. The significance of BAT for human physiology was recognised in 2007.2 Recently, another type of cells called brown-in-white (BRITE) or beige cells, in white adipose tissue (WAT) have been found.3 BRITE cells possess a multilocular morphology, enriched mitochondria and express the brown adipocyte-specific UCP-1. A potential clinical implication of activating BAT relates to the stimulation of resting energy expenditure and diet-induced thermogenesis. In humans, the thermogenic response to a meal is higher in those possessing BAT. It has been estimated that 50 g of activated BAT might translate to increase ∼5% of resting …

Activation and quantification of human brown adipose tissue: Methodological considerations for between studies comparisons

Article history: Received 6 February 2017 Accepted 9 February 2017 Available online xxxx that aspectwhen activating humanBAT.However,webelieve that several additional factors beyond the cooling method exist that may help to better understandwhy one study did not find differences in BAT volume between white Caucasians and South Asians [2] while the other study did [3]. We extracted these factors from data of both studies as summarized in Table 1.