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

Borja Martinez-Tellez, Guillermo Sanchez-Delgado, Francisco M Acosta, Juan M A Alcantara, Francisco J Amaro-Gahete, Wendy D Martinez-Avila, Elisa Merchan-Ramirez, Victoria Muñoz-Hernandez, Francisco J Osuna-Prieto, Lucas Jurado-Fasoli, Huiwen Xu, Lourdes Ortiz-Alvarez, María J Arias-Tellez, Andrea Mendez-Gutierrez, Idoia Labayen, Francisco B Ortega, Milena Schönke, Patrick C N Rensen, Concepción M Aguilera, José M Llamas-Elvira, Ángel Gil, Jonatan R Ruiz, Borja Martinez-Tellez, Guillermo Sanchez-Delgado, Francisco M Acosta, Juan M A Alcantara, Francisco J Amaro-Gahete, Wendy D Martinez-Avila, Elisa Merchan-Ramirez, Victoria Muñoz-Hernandez, Francisco J Osuna-Prieto, Lucas Jurado-Fasoli, Huiwen Xu, Lourdes Ortiz-Alvarez, María J Arias-Tellez, Andrea Mendez-Gutierrez, Idoia Labayen, Francisco B Ortega, Milena Schönke, Patrick C N Rensen, Concepción M Aguilera, José M Llamas-Elvira, Ángel Gil, Jonatan R Ruiz

Abstract

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.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Participant enrollment in the ACTIBATE…
Fig. 1. Participant enrollment in the ACTIBATE study.
BMI body mass index, CON control group, MOD-EX moderate-intensity exercise group, VIG-EX vigorous-intensity exercise group, ECG electrocardiogram.
Fig. 2. Effect of the 24-week supervised…
Fig. 2. Effect of the 24-week supervised exercise intervention on brown adipose tissue (BAT) volume, 18F-fluorodeoxyglucose (18F-FDG) uptake (Standardized uptake Value [SUV] mean and peak), and mean radiodensity.
a Total BAT volume. b Total BAT SUVmean. c Total BAT SUVpeak. d Total BAT mean radiodensity (CON n = 25; MOD-EX n = 17; VIG-EX n = 16). E Regional BAT volume, SUVmean, and SUVpeak. SUV values are shown relative to lean mass. Δ was calculated as post-intervention minus baseline values for every outcome. P values are from analyses of covariance adjusting for baseline values (n = 97). In panel e, all P values ≥0.1. CON control group, HU Hounsfield Units, MOD-EX Moderate-intensity exercise group, VIG-EX Vigorous-intensity exercise group. Bars represent mean and standard deviation. Source data are provided as a Source Data file.
Fig. 3. Associations between the Δ outdoor…
Fig. 3. Associations between the Δ outdoor ambient temperature and Δ (post-intervention minus baseline value) brown adipose tissue (BAT)-related outcomes.
a Total BAT volume. b Total BAT standardized uptake value (SUV) mean. c Total BAT SUVpeak. d Total BAT mean radiodensity (CON n = 25; MOD-EX n = 17; VIG-EX n = 16). e Regional BAT volume, SUVmean, and SUVpeak. SUV values are shown relative to lean mass. P and β values are obtained from linear regression analyses. β non-standardized coefficients, BAT brown adipose tissue, CON Control group, HU Hounsfield units, MOD-EX moderate-intensity exercise group, R2 explained variance, SUV standardized uptake value, VIG-EX vigorous-intensity exercise group, WAT white adipose tissue.
Fig. 4. Effect of the 24-week supervised…
Fig. 4. Effect of the 24-week supervised exercise intervention on secondary endpoints.
a Body weight and composition parameters, b cardiometabolic risk factors, and c physical fitness parameters. Δ was calculated as post-intervention minus baseline value for every outcome. Serum concentrations were log10 transformed. P values are from analyses of covariance (ANCOVAs), adjusting for baseline values. * and † indicate significant differences between pairs after Bonferroni correction. BP Blood pressure, CON Control group, HDL-C high-density lipoprotein cholesterol, MOD-EX Moderate-intensity exercise group, RM repetition maximum, VAT visceral adipose tissue, VO2 oxygen consumption, VIG-EX vigorous-intensity exercise group. Bars represent the mean and standard deviation. Source data are provided as a Source Data file.

References

    1. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 2007;293:E444–E452. doi: 10.1152/ajpendo.00691.2006.
    1. Orava J, et al. Brown adipose tissue function is accompanied by cerebral activation in lean but not in obese humans. J. Cereb. Blood Flow. Metab. 2014;34:1018–1023. doi: 10.1038/jcbfm.2014.50.
    1. Din MU, et al. Human brown adipose tissue [(15)O]O2 PET imaging in the presence and absence of cold stimulus. Eur. J. Nucl. Med. Mol. imaging. 2016;43:1878–1886. doi: 10.1007/s00259-016-3364-y.
    1. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiological Rev. 2004;84:277–359. doi: 10.1152/physrev.00015.2003.
    1. van Marken Lichtenbelt WD, et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 2009;360:1500–1508. doi: 10.1056/NEJMoa0808718.
    1. Cypess AM, et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 2009;360:1509–1517. doi: 10.1056/NEJMoa0810780.
    1. Virtanen KA, et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 2009;360:1518–1525. doi: 10.1056/NEJMoa0808949.
    1. Saito M, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009;58:1526–1531. doi: 10.2337/db09-0530.
    1. Zingaretti MC, et al. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J. 2009;23:3113–3120. doi: 10.1096/fj.09-133546.
    1. Petrovic N, et al. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocyt. J. Biol. Chem. 2010;285:7153–7164. doi: 10.1074/jbc.M109.053942.
    1. Wu J, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150:366–376. doi: 10.1016/j.cell.2012.05.016.
    1. Montanari, T., Pošćić, N. & Colitti, M. Factors involved in white-to-brown adipose tissue conversion and in thermogenesis: a review. Obes. Rev. 495–513. 10.1111/obr.12520 (2017).
    1. Ruiz JR, et al. Role of human brown fat in obesity, metabolism and cardiovascular disease: strategies to turn up the heat. Prog. Cardiovasc. Dis. 2018;61:232–245. doi: 10.1016/j.pcad.2018.07.002.
    1. Hanssen MJW, et al. Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes. 2016;65:1179–1189. doi: 10.2337/db15-1372.
    1. Hanssen, M. J. et al. Short-term cold acclimation recruits brown adipose tissue in obese humans. Diabetes65, 1179–89 (2016).
    1. van der Lans AAJJ, et al. Cold-activated brown adipose tissue in human adults: methodological issues. AJP Regul. Integr. Comp. Physiol. 2014;307:R103–R113. doi: 10.1152/ajpregu.00021.2014.
    1. Luna F, Roca P, Oliver J, Antenucci CD. Maximal thermogenic capacity and non-shivering thermogenesis in the South American subterranean rodent Ctenomys talarum. J. Comp. Physiol. B. 2012;182:971–983. doi: 10.1007/s00360-012-0675-6.
    1. Berbée JFP, et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat. Commun. 2015;6:6356. doi: 10.1038/ncomms7356.
    1. Din, M. U. et al. Postprandial oxidative metabolism of human brown fat indicates thermogenesis. Cell Metab. 1–10 10.1016/j.cmet.2018.05.020 (2018).
    1. Deshmukh AS, et al. Proteomics-based comparative mapping of the secretomes of human brown and white adipocytes reveals EPDR1 as a novel batokine. Cell Metab. 2019;30:963–975.e7. doi: 10.1016/j.cmet.2019.10.001.
    1. Scheele C, Wolfrum C. Brown adipose crosstalk in tissue plasticity and human metabolism. Endocr. Rev. 2020;41:53–65. doi: 10.1210/endrev/bnz007.
    1. Villarroya F, Cereijo R, Villarroya J, Giralt M. Brown adipose tissue as a secretory organ. Nat. Rev. Endocrinol. 2017;13:26–35. doi: 10.1038/nrendo.2016.136.
    1. Lehnig AC, et al. Exercise training induces depot-specific adaptations to white and brown adipose tissue. iScience. 2019;11:425–439. doi: 10.1016/j.isci.2018.12.033.
    1. De Matteis R, et al. Exercise as a new physiological stimulus for brown adipose tissue activity. Nutr., Metab., cardiovascular Dis. 2013;23:582–590. doi: 10.1016/j.numecd.2012.01.013.
    1. Ruiz, J. R., Martinez-Tellez, B., Sanchez-Delgado, G., Aguilera, C. M. & Gil, A. Regulation of energy balance by brown adipose tissue: at least three potential roles for physical activity. Br. J. Sports Med.10.1136/bjsports-2014-094537 (2015).
    1. Mendez-Gutierrez A, Osuna-Prieto FJ, Aguilera CM, Ruiz JR, Sanchez-Delgado G. Endocrine mechanisms connecting exercise to brown adipose tissue metabolism: a human perspective. Curr. Diabetes Rep. 2020;20:40. doi: 10.1007/s11892-020-01319-7.
    1. Sanford JA, et al. Molecular Transducers of Physical Activity Consortium (MoTrPAC): mapping the dynamic responses to exercise. Cell. 2020;181:1464–1474. doi: 10.1016/j.cell.2020.06.004.
    1. Motiani P, et al. Decreased insulin-stimulated brown adipose tissue glucose uptake after short-term exercise training in healthy middle-aged men. Diabetes Obes. Metab. 2017;19:1379–1388. doi: 10.1111/dom.12947.
    1. Motiani P, et al. Exercise training alters lipoprotein particles independent of brown adipose tissue metabolic activity. Obes. Sci. Pract. 2019;5:258–272. doi: 10.1002/osp4.330.
    1. Din UM, et al. Human brown fat radiodensity indicates underlying tissue composition and systemic metabolic health. J. Clin. Endocrinol. Metab. 2017;102:2258–2267. doi: 10.1210/jc.2016-2698.
    1. Pfannenberg C, et al. Impact of age on the relationships of brown adipose tissue with sex and adiposity in humans. Diabetes. 2010;59:1789–1793. doi: 10.2337/db10-0004.
    1. Fletcher LA, et al. Sexual dimorphisms in adult human brown adipose tissue. Obesity. 2020;28:241–246. doi: 10.1002/oby.22698.
    1. Martinez-Tellez, B. et al. A new personalized cooling protocol to activate brown adipose tissue in young adults. Front. Physiol.8, 863 (2017).
    1. Chen KY, et al. Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): recommendations for standardized FDG-PET/CT experiments in humans. Cell Metab. 2016;24:210–222. doi: 10.1016/j.cmet.2016.07.014.
    1. Martinez-Tellez B, et al. The impact of using BARCIST 1.0 criteria on quantification of BAT volume and activity in three independent cohorts of adults. Sci. Rep. 2018;8:8567. doi: 10.1038/s41598-018-26878-4.
    1. Martinez-Tellez, B. et al. Distribution of brown adipose tissue radiodensity in young adults: implications for cold [18F]FDG-PET/CT analyses. Mol. Imaging Biol.10.1007/s11307-019-01381-y (2019).
    1. Fraum TJ, et al. Repeatability of quantitative brown adipose tissue imaging metrics on positron emission tomography with 18F-fluorodeoxyglucose in humans. Cell Metab. 2019;30:212–224.e4. doi: 10.1016/j.cmet.2019.05.019.
    1. Ouellet V, et al. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J. Clin. Endocrinol. Metab. 2011;96:192–199. doi: 10.1210/jc.2010-0989.
    1. Martinez-Tellez, B. et al. Association of wrist and ambient temperature with cold-induced brown adipose tissue and skeletal muscle 18F-FDG uptake in young adults. Am. J. Physiol. Regul. Integr. Comp. Physiol.10.1152/ajpregu.00238.2018 (2018).
    1. Kim S, Krynyckyi BR, Machac J, Kim CK. Temporal relation between temperature change and FDG uptake in brown adipose tissue. Eur. J. Nucl. Med. Mol. Imaging. 2008;35:984–989. doi: 10.1007/s00259-007-0670-4.
    1. Senn JR, et al. Outdoor temperature influences cold induced thermogenesis in humans. Front. Physiol. 2018;9:1–9. doi: 10.3389/fphys.2018.01184.
    1. Persichetti A, et al. Prevalence, mass, and glucose-uptake activity of 18F-FDG-detected brown adipose tissue in humans living in a temperate zone of Italy. PLoS ONE. 2013;8:1–8. doi: 10.1371/journal.pone.0063391.
    1. Pace L, et al. Determinants of physiologic 18F-FDG uptake in brown adipose tissue in sequential PET/CT examinations. Mol. Imaging Biol. 2011;13:1029–1035. doi: 10.1007/s11307-010-0431-9.
    1. Bahler L, Deelen JW, Hoekstra JB, Holleman F, Verberne HJ. Seasonal influence on stimulated BAT activity in prospective trials: a retrospective analysis of BAT visualized on 18F-FDG PET-CTs and 123I-mIBG SPECT-CTs. J. Appl. Physiol. 2016;120:1418–1423. doi: 10.1152/japplphysiol.00008.2016.
    1. Lee P, et al. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes. 2014;177:1–59.
    1. Becher, T. et al. Brown adipose tissue is associated with cardiometabolic health. Nat. Med.27 58–65 (2021).
    1. Acosta, F. M. et al. Relationship between the daily rhythm of distal skin temperature and brown adipose tissue 18 F-FDG uptake in young sedentary adults. J. Biol. Rhythms 074873041986540. 10.1177/0748730419865400 (2019).
    1. Blondin, D. P. et al. Dietary fatty acid metabolism of brown adipose tissue in cold-acclimated men. Nat. Commun.8, 14146 (2017).
    1. Hohtola E, González-Alonso J. Motor unit function during cold induced thermogenesis in muscle—new perspectives on old concepts. Acta Physiol. 2020;228:1–2. doi: 10.1111/apha.13408.
    1. Behm DG, Carter TB. Effect of exercise-related factors on the perception of time. Front. Physiol. 2020;11:1–11. doi: 10.3389/fphys.2020.00770.
    1. Acosta, F. M. et al. Association of objectively measured physical activity with brown adipose tissue volume and activity in young adults. J. Clin. Endocrinol. Metab.10.1210/jc.2018-01312 (2018).
    1. Martinez-Tellez B, Sanchez-Delgado G, Amaro-Gahete FJ, Acosta FM, Ruiz JR. Relationships between cardiorespiratory fitness/muscular strength and 18F-fluorodeoxyglucose uptake in brown adipose tissue after exposure to cold in young, sedentary adults. Sci. Rep. 2019;9:11314. doi: 10.1038/s41598-019-47918-7.
    1. Vosselman, M. J. et al. Low brown adipose tissue activity in endurance trained compared to lean sedentary men. Int. J. Obes. 1–7. 10.1038/ijo.2015.130 (2015).
    1. Singhal V, et al. Effect of chronic athletic activity on brown fat in young women. PLoS One. 2016;11:e0156353. doi: 10.1371/journal.pone.0156353.
    1. Sanchez-Delgado, G., Martinez-Tellez, B., Gil, A. & Ruiz, J. R. Is brown adipose tissue-mediated adaptive thermogenesis the missing component of the constrained total energy expenditure model? Ann. Nutr. Metab.69, 51–53 (2016).
    1. Pontzer H. Energy constraint as a novel mechanism linking exercise and health. Physiology. 2018;33:384–393. doi: 10.1152/physiol.00027.2018.
    1. Pontzer, H. et al. Constrained total energy expenditure and metabolic adaptation to physical activity in adult humans. Curr. Biol. 1–8. 10.1016/j.cub.2015.12.046 (2016).
    1. Carpentier AC, et al. Brown adipose tissue energy metabolism in humans. Front. Endocrinol. 2018;9:1–21. doi: 10.3389/fendo.2018.00447.
    1. Blondin, D. P. et al. Increased brown adipose tissue oxidative capacity in cold-acclimated humans. J Clin Endocrinol Metab.10.1210/jc.2013-3901 (2014).
    1. Abu-Farha M, et al. Brown adipose tissue energy metabolism in humans. Front. Endocrinol. 2018;1:447.
    1. Orava J, et al. Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab. 2011;14:272–279. doi: 10.1016/j.cmet.2011.06.012.
    1. Hoeke G, Kooijman S, Boon MR, Rensen PCN, Berbeé JFP. Role of brown fat in lipoprotein metabolism and atherosclerosis. Circulation Res. 2016;118:173–182. doi: 10.1161/CIRCRESAHA.115.306647.
    1. Schilperoort M, Hoeke G, Kooijman S, Rensen PCN. Relevance of lipid metabolism for brown fat visualization and quantification. Curr. Opin. Lipidol. 2016;27:242–248. doi: 10.1097/MOL.0000000000000296.
    1. Cartee GD, et al. Prolonged increase in insulin-stimulated glucose transport in muscle after exercise. Am. J. Physiol. Endocrinol. Metab. 1989;256:494–499. doi: 10.1152/ajpendo.1989.256.4.E494.
    1. Fiorenza M, et al. High-intensity exercise training enhances mitochondrial oxidative phosphorylation efficiency in a temperature-dependent manner in human skeletal muscle: implications for exercise performance. FASEB J. 2019;33:8976–8989. doi: 10.1096/fj.201900106RRR.
    1. Richard MA, et al. Determination of a pharmacokinetic model for [11c]-acetate in brown adipose tissue. EJNMMI Res. 2019;9:1–16. doi: 10.1186/s13550-019-0497-6.
    1. Blondin DP, et al. Inhibition of intracellular triglyceride lipolysis suppresses cold-induced brown adipose tissue metabolism and increases shivering in humans. Cell Metab. 2017;25:438–447. doi: 10.1016/j.cmet.2016.12.005.
    1. Din UM, et al. Human brown adipose tissue [15O]O2 PET imaging in the presence and absence of cold stimulu. Eur. J. Nucl. Med. Mol. Imaging. 2016;43:1878–1886. doi: 10.1007/s00259-016-3364-y.
    1. Cypess AM, et al. Anatomical localization, gene expression profiling and functional characterization of adult human neck brown fat. Nat. Med. 2013;19:635–639. doi: 10.1038/nm.3112.
    1. de Jong JMA, et al. Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice. Nat. Metab. 2019;1:830–843. doi: 10.1038/s42255-019-0101-4.
    1. Kajimura S, Spiegelman BM. Confounding issues in the “humanized” BAT of mice. Nat. Metab. 2020;2:303–304. doi: 10.1038/s42255-020-0192-y.
    1. Kellman GM, et al. MR imaging of the supraclavicular region: normal anatomy. Am. J. Roentgenol. 1987;148:77–82. doi: 10.2214/ajr.148.1.77.
    1. Sun W, et al. snRNA-seq reveals a subpopulation of adipocytes that regulates thermogenesis. Nature. 2020;587:98–102. doi: 10.1038/s41586-020-2856-x.
    1. Aldiss P, et al. Exercise training in obese rats does not induce browning at thermoneutrality and induces a muscle-like signature in brown adipose tissue. Front. Endocrinol. 2020;11:1–14. doi: 10.3389/fendo.2020.00097.
    1. McKie GL, et al. Housing temperature affects the acute and chronic metabolic adaptations to exercise in mice. J. Physiol. 2019;597:4581–4600. doi: 10.1113/JP278221.
    1. Williams MA, et al. Resistance exercise in individuals with and without cardiovascular disease: 2007 update: a scientific statement from the American Heart Association Council on Clinical Cardiology and Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2007;116:572–584. doi: 10.1161/CIRCULATIONAHA.107.185214.
    1. Rossato M. Aging and brown adipose tissue activity decline in human: does the brain extinguish the fire? Aging Clin. Exp. Res. 2016;28:579–581. doi: 10.1007/s40520-016-0572-z.
    1. Heaton JM. The distribution of brown adipose tissue in the human. J. Anat. 1972;112:35–39.
    1. Enerbäck S. Human brown adipose tissue. Cell Metab. 2010;11:248–252. doi: 10.1016/j.cmet.2010.03.008.
    1. Harrington DM, et al. Cardiometabolic risk factor response to a lifestyle intervention: a randomized trial. Metab. Syndr. Relat. Disord. 2015;13:125–131. doi: 10.1089/met.2014.0112.
    1. Mikus CR, et al. The effects of exercise on the lipoprotein subclass profile: a meta-analysis of 10 interventions. Atherosclerosis. 2015;243:364–372. doi: 10.1016/j.atherosclerosis.2015.10.018.
    1. Lynes MD, et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat. Med. 2017;23:631–637. doi: 10.1038/nm.4297.
    1. Stanford KI, et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 2018;27:1111–1120.e3. doi: 10.1016/j.cmet.2018.03.020.
    1. Kong X, et al. Brown adipose tissue controls skeletal muscle function via the secretion of myostatin. Cell Metab. 2018;0:1–13.
    1. Sanchez-Delgado G, et al. Activating brown adipose tissue through exercise (ACTIBATE) in young adults: Rationale, design and methodology. Contemp. Clin. Trials. 2015;45:416–425. doi: 10.1016/j.cct.2015.11.004.
    1. Schulz KF, Grimes DA. Generation of allocation sequences in randomised trials: chance, not choice. Lancet. 2002;359:515–519. doi: 10.1016/S0140-6736(02)07683-3.
    1. World Health Organization. WHO global recommendations on physical activity for health (World Health Organization, Geneva, Switzerland, 2010).
    1. Schindelin J, et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods. 2012;9:676–682. doi: 10.1038/nmeth.2019.
    1. Leitner BP, et al. Mapping of human brown adipose tissue in lean and obese young men. Proc. Natl Acad. Sci. USA. 2017;114:8649–8654. doi: 10.1073/pnas.1705287114.
    1. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin. Chem. 1972;18:499–502. doi: 10.1093/clinchem/18.6.499.
    1. Ruiz-Ruiz J, Mesa JLM, Gutiérrez A, Castillo MJ. Hand size influences optimal grip span in women but not in men. J. Hand Surg. 2002;27:897–901. doi: 10.1053/jhsu.2002.34315.
    1. Wathen, D. Load assignment. In: Essentials of Strength Training and Conditioning. (ed. Baechle, T. R.). pp. 435–439, (Champaign, Human Kinetics, 1994).
    1. Balke B, Ware RW. An experimental study of physical fitness of Air Force personnel. U. S. Armed Forces Med. J. 1959;10:675–688.
    1. Benjamini, Y., Krieger, A. M. & Yekutieli, D. Adaptive linear step-up procedures that control the false discovery rate. Biometrika93, 491–507(2006).

Source: PubMed

3
Prenumerera