- Email: [email protected]
A New Connection between Muscle and Brown Fat
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Laura L. Hayman, PhD, RN, FAAN Associate Dean for Research & Professor of Nursing University of Massachusetts Boston College of Nursing & Health Sciences Director of Research GoKids Boston Boston, Massachusetts Reprint requests: Laura L. Hayman, PhD, RN, FAAN, Associate Dean for Research & Professor of Nursing, University of Massachusetts Boston, College of Nursing & Health Sciences, Director of Research, GoKids Boston, 100 Morrissey Blvd, Boston, MA 02123-3393. E-mail: [email protected]
References 1. Ogden CL, Carroll MD, Flegal KM. High body mass index for age among US children and adolescents, 2003-2006. JAMA 2008;299:2401-5. 2. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents and adults, 1999-2002. JAMA 2004;291:2847-50. 3. Freedman DS, Mei Z, Srinivasan SR, Berenson GS, Dietz WH. Cardiovascular risk factors and excess adiposity among overweight children and adolescents: the Bogalusa Heart Study. J Pediatr 2007;150:12-7. 4. Daniels SR. The consequences of childhood overweight and obesity. Future Child 2006;16:47-67. 5. Weiss R, Dziura J, Bergent TS, Tamborlane WV, Taksali SE, Yeckel CW, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004;350:2362-74.
Vol. 158, No. 5 6. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P. Increased incidence of non-insulin dependent diabetes mellitus among adolescents. J Pediatr 1996;128(pt 1):608-15. 7. Urbina EM, Gidding SS, Bao W, Pickoff AS, Berdusis K, Berenson GS. Effect of body size, ponderosity, and blood pressure on left ventricular growth in children and young adults in the Bogalusa Heart Study. Circulation 1995;91:2400-6. 8. Li X, Li S, Ulusoy E, Chen W, Srinivasan SR, Berenson GS. Childhood adiposity as a predictor of cardiac mass in adulthood: the Bogalusa Heart Study. Circulation 2004;110:3488-92. 9. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345-52. 10. Levy D, Garrison RJ, Savage DD, Kannel WB, Casteli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561-6. 11. Crowley DI, Khoury PR, Urbina EM, Ippisch HM, Kimball TR. Cardiovascular impact of pediatric obesity epidemic: higher left ventricular mass related to higher body mass index. J Pediatr 2011;158:709-14. 12. deSimone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol 1995;25:1056-62. 13. Verdecchia P, Carini G, Circo A, Dovellini E, Giovannini E, Lombardo M, et al. Left ventricular mass and cardiovascular morbidity in essential hypertension: the MAVI study. J Am Coll Cardiol 2001;38:1829-35. 14. Hayman LL, Meininger JC, Daniels SR, McCrindle BW, Helden L, Ross J, et al. Primary prevention of cardiovascular disease in nursing practice: focus on children and youth. Circulation 2007;116:344-57.
A New Connection between Muscle and Brown Fat
T
he obesity pandemic has been particularly devastating two revolutions in the past 20 years. In the 1990s, it was to children. Along with the increased fat, we are also found that WAT is an endocrine organ, releasing hormones seeing increased rates of type 2 diabetes, a syndrome and other mediators that inform the rest of the body of its nuformerly rare but now all too common in the pediatric poptritional status and, in excess, help trigger the low-grade inulation worldwide.1 At one level, the problem is simply flammation associated with insulin resistance. It has also excessive energy intake compared with become clear that there are at least two difSee related article, p 722 energy expenditure. At the center of this ferent types of WAT, subcutaneous and vismetabolic crisis is the adipose tissue depot. ceral, the former being metabolically neutral or positive and There are two types of fat: the better-known white adipose the latter conferring increased risk for the metabolic syntissue (WAT), which stores energy, and the more obscure drome.3 BAT was once considered even less relevant. It was thought brown adipose tissue (BAT), which consumes calories via therto be functional only in neonates who required it for thermomogenesis in response to environmental and dietary stimuli.2 Thermogenesis occurs in the tissue’s numerous mitochondria genesis; but was believed to disappear after the first few years that contain the specific inner membrane protein uncoupling of life, when muscle-based shivering could take over. Part of protein 1, which responds to sympathetic nervous system stimthe reason for this misunderstanding is that BAT is very ulation by uncoupling aerobic respiration and dissipating the difficult to find, and even more challenging to measure. In intermembrane proton-motive force to generate heat. contrast to rodents, which have a prominent interscapular Human fat was once thought to be a neutral repository for BAT depot that is rather pure in brown adipocytes, human calories. Our understanding of its function has undergone BAT is distributed throughout the body in multiple locations. Moreover, within those sites, there are wide differences in the amount of brown adipocytes among individuals. Going deeper, even within the depots themselves, the distribution BAT Brown adipose tissue BMI Body mass index of brown adipocytes is heterogeneous, with the mature brown CT PET WAT
Computed tomography Positron emission tomography White adipose tissue
0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2011.01.001
696
May 2011 and white adipocytes present in varying ratios, with an apparent randomness reminiscent of a fractal distribution.4-6 The BAT revolution began in the early 2000s with the publication of several studies showing the detection of 18F-fluorodeoxyglucose—avid adipose tissue via positron emission tomography (PET)/computed tomography (CT).2 Then in 2009, adult human BAT was reported to be quantifiable using noninvasive PET/CT, and its activity was found to be higher in women and in younger adults with a lower body mass index (BMI) and percentage of body fat.5-9 In parallel with the breakthroughs in imaging BAT came molecular studies describing intriguing paradoxes related to the origin of the mature human brown adipocytes. Although brown adipocytes are derived from multipotent mesenchymal stem cells, different anatomic locations of BAT might have distinct pedigrees. In the mouse, some BAT depots share an origin with muscle cells,10 whereas others share a lineage with white adipocytes. So, in the space of one decade, we have gone from thinking that there were no human brown adipocytes to recognizing at least two different types with possibly different functions. Anatomic studies have shown that the distribution of BAT in children is similar to that in adults, but more extensive. It is found adjacent to the cervical and supraclavicular muscles and vasculature and in thorax near the great vessels, esophagus, and trachea. In the abdomen, discrete masses of BAT follow the aorta and lie near posterior structures, such as the pancreas, autonomic ganglia, kidneys, and adrenal glands. There also is an interscapular depot, corresponding to the major depot in rodents, but this disappears in early childhood.11 As in adults, 18F-fluorodeoxyglucose—PET studies are revealing more information about the functional characteristics of pediatric BAT. Metabolically active BAT is seen predominantly in the cervical and supraclavicular depots and at times in the paraspinal, but not the interscapular, region.12 Thus, BAT in children occurs in essentially the same depots identified histologically decades before.4,11 What is most striking about pediatric BAT is that its basal activity is much higher than that of adult BAT—in the 30%-40% range, based on retrospective studies12,13—suggesting an even more prominent role in pediatric metabolism.14 It is in this context that Gilsanz et al15 add important new facets to our understanding of pediatric BAT in this issue of The Journal. In one of the largest studies of brown fat in children done to date, the authors examined BAT activity in a cohort of 71 children and adolescents who underwent PET/CT scanning for clinical indications. Their findings reinforce several epidemiologic features of pediatric BAT. Most notably, the frequency of detection of BAT was considerably higher than that seen in free-living adults scanned for cancer surveillance—nearly 40%. In addition, the prevalence of detection was the same in boys and girls, suggesting that BAT plays a more central role in pediatric metabolism. The particularly novel finding in this study—something that had not yet been shown in either children or adults—is a correlation between BAT activity and the size of certain regions of body musculature. Specifically, the authors found
EDITORIALS significantly greater muscle mass in the neck and gluteal regions in both boys and girls who had detectable brown fat. This correlation was independent of age, BMI, or subcutaneous fat content. The reason that this finding was even possible is that the authors cleverly took advantage of their powerful imaging methodology. PET/CT is currently the only modality that provides both functional and precise structural information at a whole-body level. We should now expect an increased number of studies examining the relationship between BAT activity and the structure and function of other body tissues. A principal limitation of this study is that as good as PET/ CT is in measuring BAT activity, its accuracy is both limited and unknown. This is particularly challenging in retrospective studies, in which the experimental conditions are not explicitly controlled. The authors relied on two independent radiologists to identify BAT, which necessarily will differ from the criteria used in other studies. This difference is to be expected given that the field has not yet identified a common standard for defining BAT based on PET/CT findings. In part this is because we do not know how much of the total BAT mass is present but not sufficiently stimulated to allow detection. We also do not know whether there are multiple sites in which the density of brown adipocytes is too low for detection but nonetheless could affect metabolism in aggregate. For example, histological studies have revealed BAT depots surrounding the great vessels and viscera, but these are rarely detectable via PET/CT. Unfortunately, the entire field is suffering from this limitation, and there is no obvious resolution in the study of human BAT, although there is the hope that magnetic resonance imaging can improve on our current methodologies. Retrospective studies such as the one published in this issue of The Journal are particularly valuable, because prospective experiments involving healthy children using PET/ CT are virtually impossible to carry out given the radiation exposure. Thus the work of Gilsanz et al is important not only for the new information it provides, but also for emphasizing what future studies should address. For example, the lineages of the adipocytes in the different human BAT depots remain unknown. Which ones have a muscle-based origin, and which ones are fat-based? The link between BAT and muscle mass could suggest a common progenitor. Alternatively, it could indicate that muscle and brown fat are two separate, complementary arms of a response to cold exposure and the need for thermogenesis. An even larger, more fundamental physiological question arising from this study and the limited previous studies involves the purpose of brown fat in children. Compared with adults, children have a quite high rate of detectable basal BAT activity, and there appears to be no difference between boys and girls and no association with BMI. Perhaps brown fat plays a significant role in regulating energy expenditure in children, involved in the response to both cold and nutritional status. At what stage of development does the rate of basal BAT activity begin to decline to adult levels? When does the difference between males and females begin? 697
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Are there hormones or cytokines that maintain BAT activity and increased energy expenditure in children that can be used to treat obesity? Although there are far more questions than answers, it is exciting to see that our understanding of pediatric BAT is now coming of age. n Aaron M. Cypess, MD, PhD, MMSc Joslin Diabetes Center Boston, Massachusetts
Vol. 158, No. 5
7. 8. 9.
Reprint requests: Aaron M. Cypess, MD, PhD, MMSc, Joslin Diabetes Center, One Joslin Place, Boston, MA, 02215. E-mail: [email protected]
10.
References
11.
1. Crocker MK, Yanovski JA. Pediatric obesity: etiology and treatment. Endocrinol Metab Clin North Am 2009;38:525-48. 2. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007;293:E444-52. 3. Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006;444:847-53. 4. Heaton JM. The distribution of brown adipose tissue in the human. J Anat 1972;112:35-9. 5. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509-17. 6. Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, et al. The presence of UCP1 demonstrates that metabolically active adi-
12. 13.
14. 15.
pose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 2009;23:3113-20. Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009;360:1500-8. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360:1518-25. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009;58:1526-31. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 2008; 454:961-7. Aherne W, Hull D. Brown adipose tissue and heat production in the newborn infant. J Pathol Bacteriol 1966;91:223-34. Gelfand MJ, O’Hara SM, Curtwright LA, Maclean JR. Pre-medication to block [(18)F]FDG uptake in the brown adipose tissue of pediatric and adolescent patients. Pediatr Radiol 2005;35:984-90. Zukotynski KA, Fahey FH, Laffin S, Davis R, Treves ST, Grant FD, et al. Constant ambient temperature of 24 degrees C significantly reduces FDG uptake by brown adipose tissue in children scanned during the winter. Eur J Nucl Med Mol Imaging 2009;36:602-6. Cypess AM, Kahn CR. The role and importance of brown adipose tissue in energy homeostasis. Curr Opin Pediatr 2010;22: 478-84. Gilsanz V, Chung SA, Jackson H, Dorey F, Hu HH. Functional brown adipose tissue is related to muscle volume in children and teenagers. J Pediatr 2011;158:722-6.
Adiposity and Bone: The Influence of Subcutaneous versus Visceral Fat and Insulin Resistance
I
s obesity bad for bones? Does the presence of comorbidities the same research group showing that insulin resistance was of obesity, particularly insulin resistance, make it even associated with lower adjusted whole-body BMC.5 Thus obesity or its complications may result in low BMC. worse? The literature on the impact of adiposity on bone The term ‘‘adjusted’’ when describing whole body BMC health in children and adolescents has been confusing. results warrants careful consideration. Studies, including this Some studies conclude that overweight children and adolesone,4 show that whole-body BMC increases cents, compared with healthy-weight peers, See related article, p 727 in proportion to body weight.2,3 At first have a lower bone mineral content 1 glance, bone health appears to be better among children and (BMC), whereas other studies found a higher BMC or no difadolescents who are overweight or obese compared with their ference.2,3 Data presented by Pollock et al 4 in this issue of The Journal provide an additional twist. They found that overlean counterparts. Recognizing that children of similar age weight adolescents with at least one cardiometabolic risk facmay differ in stature and body composition, the International tor (high waist circumference, blood pressure, fasting glucose, Society of Clinical Densitometry recommended that the and triglycerides or low high-density lipoprotein cholesterol) assessment of bone health should account for the size of the had lower adjusted BMC than overweight adolescents withchild.6 However, guidelines for size adjustment have not been established and have proved challenging. Clearly accounting out cardiometabolic risk factors. Adjusted BMC in adolesfor stature is important because tall individuals have a larger cents with $2 cardiometabolic risk factors was even lower. skeleton than short individuals. Less clear is whether to account Notably, the degree of adiposity was higher in adolescents for differences in fat-free soft tissue (FFST) mass between indiwith cardiovascular risk factors. These findings are similar viduals of similar stature. Muscles place large forces on bone, to those in overweight prepubertal children published by and bones adapt (in size and in mineral content) to forces BMC FFST
Bone mineral content Fat-free soft tissue
0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2011.01.021
698
www.jpeds.com
Laura L. Hayman, PhD, RN, FAAN Associate Dean for Research & Professor of Nursing University of Massachusetts Boston College of Nursing & Health Sciences Director of Research GoKids Boston Boston, Massachusetts Reprint requests: Laura L. Hayman, PhD, RN, FAAN, Associate Dean for Research & Professor of Nursing, University of Massachusetts Boston, College of Nursing & Health Sciences, Director of Research, GoKids Boston, 100 Morrissey Blvd, Boston, MA 02123-3393. E-mail: [email protected]
References 1. Ogden CL, Carroll MD, Flegal KM. High body mass index for age among US children and adolescents, 2003-2006. JAMA 2008;299:2401-5. 2. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents and adults, 1999-2002. JAMA 2004;291:2847-50. 3. Freedman DS, Mei Z, Srinivasan SR, Berenson GS, Dietz WH. Cardiovascular risk factors and excess adiposity among overweight children and adolescents: the Bogalusa Heart Study. J Pediatr 2007;150:12-7. 4. Daniels SR. The consequences of childhood overweight and obesity. Future Child 2006;16:47-67. 5. Weiss R, Dziura J, Bergent TS, Tamborlane WV, Taksali SE, Yeckel CW, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 2004;350:2362-74.
Vol. 158, No. 5 6. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P. Increased incidence of non-insulin dependent diabetes mellitus among adolescents. J Pediatr 1996;128(pt 1):608-15. 7. Urbina EM, Gidding SS, Bao W, Pickoff AS, Berdusis K, Berenson GS. Effect of body size, ponderosity, and blood pressure on left ventricular growth in children and young adults in the Bogalusa Heart Study. Circulation 1995;91:2400-6. 8. Li X, Li S, Ulusoy E, Chen W, Srinivasan SR, Berenson GS. Childhood adiposity as a predictor of cardiac mass in adulthood: the Bogalusa Heart Study. Circulation 2004;110:3488-92. 9. Koren MJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension. Ann Intern Med 1991;114:345-52. 10. Levy D, Garrison RJ, Savage DD, Kannel WB, Casteli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561-6. 11. Crowley DI, Khoury PR, Urbina EM, Ippisch HM, Kimball TR. Cardiovascular impact of pediatric obesity epidemic: higher left ventricular mass related to higher body mass index. J Pediatr 2011;158:709-14. 12. deSimone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol 1995;25:1056-62. 13. Verdecchia P, Carini G, Circo A, Dovellini E, Giovannini E, Lombardo M, et al. Left ventricular mass and cardiovascular morbidity in essential hypertension: the MAVI study. J Am Coll Cardiol 2001;38:1829-35. 14. Hayman LL, Meininger JC, Daniels SR, McCrindle BW, Helden L, Ross J, et al. Primary prevention of cardiovascular disease in nursing practice: focus on children and youth. Circulation 2007;116:344-57.
A New Connection between Muscle and Brown Fat
T
he obesity pandemic has been particularly devastating two revolutions in the past 20 years. In the 1990s, it was to children. Along with the increased fat, we are also found that WAT is an endocrine organ, releasing hormones seeing increased rates of type 2 diabetes, a syndrome and other mediators that inform the rest of the body of its nuformerly rare but now all too common in the pediatric poptritional status and, in excess, help trigger the low-grade inulation worldwide.1 At one level, the problem is simply flammation associated with insulin resistance. It has also excessive energy intake compared with become clear that there are at least two difSee related article, p 722 energy expenditure. At the center of this ferent types of WAT, subcutaneous and vismetabolic crisis is the adipose tissue depot. ceral, the former being metabolically neutral or positive and There are two types of fat: the better-known white adipose the latter conferring increased risk for the metabolic syntissue (WAT), which stores energy, and the more obscure drome.3 BAT was once considered even less relevant. It was thought brown adipose tissue (BAT), which consumes calories via therto be functional only in neonates who required it for thermomogenesis in response to environmental and dietary stimuli.2 Thermogenesis occurs in the tissue’s numerous mitochondria genesis; but was believed to disappear after the first few years that contain the specific inner membrane protein uncoupling of life, when muscle-based shivering could take over. Part of protein 1, which responds to sympathetic nervous system stimthe reason for this misunderstanding is that BAT is very ulation by uncoupling aerobic respiration and dissipating the difficult to find, and even more challenging to measure. In intermembrane proton-motive force to generate heat. contrast to rodents, which have a prominent interscapular Human fat was once thought to be a neutral repository for BAT depot that is rather pure in brown adipocytes, human calories. Our understanding of its function has undergone BAT is distributed throughout the body in multiple locations. Moreover, within those sites, there are wide differences in the amount of brown adipocytes among individuals. Going deeper, even within the depots themselves, the distribution BAT Brown adipose tissue BMI Body mass index of brown adipocytes is heterogeneous, with the mature brown CT PET WAT
Computed tomography Positron emission tomography White adipose tissue
0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2011.01.001
696
May 2011 and white adipocytes present in varying ratios, with an apparent randomness reminiscent of a fractal distribution.4-6 The BAT revolution began in the early 2000s with the publication of several studies showing the detection of 18F-fluorodeoxyglucose—avid adipose tissue via positron emission tomography (PET)/computed tomography (CT).2 Then in 2009, adult human BAT was reported to be quantifiable using noninvasive PET/CT, and its activity was found to be higher in women and in younger adults with a lower body mass index (BMI) and percentage of body fat.5-9 In parallel with the breakthroughs in imaging BAT came molecular studies describing intriguing paradoxes related to the origin of the mature human brown adipocytes. Although brown adipocytes are derived from multipotent mesenchymal stem cells, different anatomic locations of BAT might have distinct pedigrees. In the mouse, some BAT depots share an origin with muscle cells,10 whereas others share a lineage with white adipocytes. So, in the space of one decade, we have gone from thinking that there were no human brown adipocytes to recognizing at least two different types with possibly different functions. Anatomic studies have shown that the distribution of BAT in children is similar to that in adults, but more extensive. It is found adjacent to the cervical and supraclavicular muscles and vasculature and in thorax near the great vessels, esophagus, and trachea. In the abdomen, discrete masses of BAT follow the aorta and lie near posterior structures, such as the pancreas, autonomic ganglia, kidneys, and adrenal glands. There also is an interscapular depot, corresponding to the major depot in rodents, but this disappears in early childhood.11 As in adults, 18F-fluorodeoxyglucose—PET studies are revealing more information about the functional characteristics of pediatric BAT. Metabolically active BAT is seen predominantly in the cervical and supraclavicular depots and at times in the paraspinal, but not the interscapular, region.12 Thus, BAT in children occurs in essentially the same depots identified histologically decades before.4,11 What is most striking about pediatric BAT is that its basal activity is much higher than that of adult BAT—in the 30%-40% range, based on retrospective studies12,13—suggesting an even more prominent role in pediatric metabolism.14 It is in this context that Gilsanz et al15 add important new facets to our understanding of pediatric BAT in this issue of The Journal. In one of the largest studies of brown fat in children done to date, the authors examined BAT activity in a cohort of 71 children and adolescents who underwent PET/CT scanning for clinical indications. Their findings reinforce several epidemiologic features of pediatric BAT. Most notably, the frequency of detection of BAT was considerably higher than that seen in free-living adults scanned for cancer surveillance—nearly 40%. In addition, the prevalence of detection was the same in boys and girls, suggesting that BAT plays a more central role in pediatric metabolism. The particularly novel finding in this study—something that had not yet been shown in either children or adults—is a correlation between BAT activity and the size of certain regions of body musculature. Specifically, the authors found
EDITORIALS significantly greater muscle mass in the neck and gluteal regions in both boys and girls who had detectable brown fat. This correlation was independent of age, BMI, or subcutaneous fat content. The reason that this finding was even possible is that the authors cleverly took advantage of their powerful imaging methodology. PET/CT is currently the only modality that provides both functional and precise structural information at a whole-body level. We should now expect an increased number of studies examining the relationship between BAT activity and the structure and function of other body tissues. A principal limitation of this study is that as good as PET/ CT is in measuring BAT activity, its accuracy is both limited and unknown. This is particularly challenging in retrospective studies, in which the experimental conditions are not explicitly controlled. The authors relied on two independent radiologists to identify BAT, which necessarily will differ from the criteria used in other studies. This difference is to be expected given that the field has not yet identified a common standard for defining BAT based on PET/CT findings. In part this is because we do not know how much of the total BAT mass is present but not sufficiently stimulated to allow detection. We also do not know whether there are multiple sites in which the density of brown adipocytes is too low for detection but nonetheless could affect metabolism in aggregate. For example, histological studies have revealed BAT depots surrounding the great vessels and viscera, but these are rarely detectable via PET/CT. Unfortunately, the entire field is suffering from this limitation, and there is no obvious resolution in the study of human BAT, although there is the hope that magnetic resonance imaging can improve on our current methodologies. Retrospective studies such as the one published in this issue of The Journal are particularly valuable, because prospective experiments involving healthy children using PET/ CT are virtually impossible to carry out given the radiation exposure. Thus the work of Gilsanz et al is important not only for the new information it provides, but also for emphasizing what future studies should address. For example, the lineages of the adipocytes in the different human BAT depots remain unknown. Which ones have a muscle-based origin, and which ones are fat-based? The link between BAT and muscle mass could suggest a common progenitor. Alternatively, it could indicate that muscle and brown fat are two separate, complementary arms of a response to cold exposure and the need for thermogenesis. An even larger, more fundamental physiological question arising from this study and the limited previous studies involves the purpose of brown fat in children. Compared with adults, children have a quite high rate of detectable basal BAT activity, and there appears to be no difference between boys and girls and no association with BMI. Perhaps brown fat plays a significant role in regulating energy expenditure in children, involved in the response to both cold and nutritional status. At what stage of development does the rate of basal BAT activity begin to decline to adult levels? When does the difference between males and females begin? 697
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Are there hormones or cytokines that maintain BAT activity and increased energy expenditure in children that can be used to treat obesity? Although there are far more questions than answers, it is exciting to see that our understanding of pediatric BAT is now coming of age. n Aaron M. Cypess, MD, PhD, MMSc Joslin Diabetes Center Boston, Massachusetts
Vol. 158, No. 5
7. 8. 9.
Reprint requests: Aaron M. Cypess, MD, PhD, MMSc, Joslin Diabetes Center, One Joslin Place, Boston, MA, 02215. E-mail: [email protected]
10.
References
11.
1. Crocker MK, Yanovski JA. Pediatric obesity: etiology and treatment. Endocrinol Metab Clin North Am 2009;38:525-48. 2. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007;293:E444-52. 3. Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006;444:847-53. 4. Heaton JM. The distribution of brown adipose tissue in the human. J Anat 1972;112:35-9. 5. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509-17. 6. Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, et al. The presence of UCP1 demonstrates that metabolically active adi-
12. 13.
14. 15.
pose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 2009;23:3113-20. Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009;360:1500-8. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360:1518-25. Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 2009;58:1526-31. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 2008; 454:961-7. Aherne W, Hull D. Brown adipose tissue and heat production in the newborn infant. J Pathol Bacteriol 1966;91:223-34. Gelfand MJ, O’Hara SM, Curtwright LA, Maclean JR. Pre-medication to block [(18)F]FDG uptake in the brown adipose tissue of pediatric and adolescent patients. Pediatr Radiol 2005;35:984-90. Zukotynski KA, Fahey FH, Laffin S, Davis R, Treves ST, Grant FD, et al. Constant ambient temperature of 24 degrees C significantly reduces FDG uptake by brown adipose tissue in children scanned during the winter. Eur J Nucl Med Mol Imaging 2009;36:602-6. Cypess AM, Kahn CR. The role and importance of brown adipose tissue in energy homeostasis. Curr Opin Pediatr 2010;22: 478-84. Gilsanz V, Chung SA, Jackson H, Dorey F, Hu HH. Functional brown adipose tissue is related to muscle volume in children and teenagers. J Pediatr 2011;158:722-6.
Adiposity and Bone: The Influence of Subcutaneous versus Visceral Fat and Insulin Resistance
I
s obesity bad for bones? Does the presence of comorbidities the same research group showing that insulin resistance was of obesity, particularly insulin resistance, make it even associated with lower adjusted whole-body BMC.5 Thus obesity or its complications may result in low BMC. worse? The literature on the impact of adiposity on bone The term ‘‘adjusted’’ when describing whole body BMC health in children and adolescents has been confusing. results warrants careful consideration. Studies, including this Some studies conclude that overweight children and adolesone,4 show that whole-body BMC increases cents, compared with healthy-weight peers, See related article, p 727 in proportion to body weight.2,3 At first have a lower bone mineral content 1 glance, bone health appears to be better among children and (BMC), whereas other studies found a higher BMC or no difadolescents who are overweight or obese compared with their ference.2,3 Data presented by Pollock et al 4 in this issue of The Journal provide an additional twist. They found that overlean counterparts. Recognizing that children of similar age weight adolescents with at least one cardiometabolic risk facmay differ in stature and body composition, the International tor (high waist circumference, blood pressure, fasting glucose, Society of Clinical Densitometry recommended that the and triglycerides or low high-density lipoprotein cholesterol) assessment of bone health should account for the size of the had lower adjusted BMC than overweight adolescents withchild.6 However, guidelines for size adjustment have not been established and have proved challenging. Clearly accounting out cardiometabolic risk factors. Adjusted BMC in adolesfor stature is important because tall individuals have a larger cents with $2 cardiometabolic risk factors was even lower. skeleton than short individuals. Less clear is whether to account Notably, the degree of adiposity was higher in adolescents for differences in fat-free soft tissue (FFST) mass between indiwith cardiovascular risk factors. These findings are similar viduals of similar stature. Muscles place large forces on bone, to those in overweight prepubertal children published by and bones adapt (in size and in mineral content) to forces BMC FFST
Bone mineral content Fat-free soft tissue
0022-3476/$ - see front matter. Copyright ª 2011 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2011.01.021
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