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physiology, psychology and geneticsof obesity
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Jack A. Yanovski, MD, PhD, Head, Unit on Growth and Obesity Ning-Ping Feng, PhD, Postdoctoral Fellow Jennifer McDuffie, PhD, Postdoctoral Fellow Marian Tanofsky-Kraff, PhD, Postdoctoral Fellow Lisa Yanoff, MD, Postdoctoral
Fellow Renee Freedman, MD, Clinical Fellow, Endocrine Training Program Diane Adler-Wailes, MS, Scientific Technician Deborah Glasofer, BA, Graduate Student Samareh Ghorbani, BS, Postbaccalaureate Fellow Margaret Mirch, BS, Postbaccalaureate Fellow Amanda Spitalnik, BS, Postbaccalaureate Fellow Kelly Theim, BA, Postbaccalaureate
Fellow Anne-Caroline Norman, BA, Clinical Research Training Program Nazrat Mirza, MD, Volunteer Elena Puricelli, MD, Volunteer |
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The prevalence of overweight and obesity in
children and adults has tripled during the past 30 years. The alarming rise
in body weight has likely occurred because the current environment affords
easy access to calorie-dense foods and requires less voluntary energy
expenditure. However, today’s environment leads to obesity only in
those individuals whose body weight–regulatory systems are not able to
control body adiposity with sufficient precision in our
high-calorie/low-activity environment, suggesting that subgroups in the
United States have a uniquely high susceptibility to weight gain under the
prevailing environmental conditions. Our research is directed at increasing
our understanding of the metabolic and behavioral factors involved in
determining body weight regulation and body composition during childhood,
with a special emphasis on minority populations. The ongoing research program
prospectively evaluates risk factors for the development of obesity and its
complications in children, studies the effects of medications on body weight
and obesity-related comorbid conditions in children, and seeks to identify
the genetic and environmental factors important for the markedly greater
incidence of obesity and its comorbid conditions in some Molecular studies of factors important for
childhood body weight regulation Feng,
Adler-Wailes, Ning, Puricelli, Tanofsky-Kraff, Glasofer, Yanovski J Using classical association studies, we are
studying polymorphisms in genes involved in the leptin signaling pathway. Our
goal is to identify gene variants affecting body composition, genes whose
frequencies in African American children differ from those in their Caucasian
counterparts. Genes currently under study include those encoding
proopiomelanocortin (POMC), POMC processing enzymes, the melanocortin
receptors 3, 4, and 5, and neuropeptide Y and its receptors. In addition, we
have studied genes important for energy expenditure, such as those encoding
the mitochondrial uncoupling proteins, and genes potentially involved in
cortisol metabolism that may affect intra-abdominal adipose tissue, such as
that encoding 11-beta-hydroxysteroid dehydrogenase. We have found that an
intronic polymorphism in the 11-beta-hydroxysteroid dehydrogenase gene is
associated with several features of metabolic syndrome in children. We have
also identified novel polymorphisms in the POMC sequence that are more
prevalent in African American than Caucasian children but do not appear to
play a role in the greater body adiposity of African American children. We are currently studying a variant
melanocortin 3 receptor that is associated with adiposity in a large cohort
of children and appears to have functional significance for melanocortin 3
receptor signal transduction. We directly sequenced the human MC3R proximal
promoter region and the entire coding region in 88 children, of whom 47 were
extremely overweight (BMI 41.8 ±10.5 kg/m2) and 41 were lean (BMI
16.8 ± 2.2 kg/m2). By sequencing, we found two previously
identified missense sequence variants: C17A (Thr6Lys) and G241A (Val81Ile).
Thr6Lys was located in the N-terminal extracellular domain where it might
disrupt a putative site of post-translational phosphorylation by the
serine/threonine kinase casein kinase II; Val81Ile was located in the first
transmembrane helix. Of 282 children studied by RFLP analysis, 45 percent
carried at least one of the mutant alleles. The two variants showed marked
linkage disequilibrium. Therefore, we characterized the genotypes based on
the combination of the two variants. African American children were more
likely to carry the variant alleles than Caucasian children: 70.3 percent of
African Americans (versus 19.9 percent of Caucasians) carried at least one
mutant allele, and 15.3 percent of African Americans (versus 1.4 percent of
Caucasians) were homozygous for both polymorphisms. Overweight children
evidenced higher frequencies of the variants than normal-weight children.
Children homozygous for both variants were identified only among children at
risk for becoming overweight (9.7 percent) or already overweight (13.9
percent). Compared with unaffected or heterozygous children, those homozygous
for both MC3R alleles exhibited significantly greater BMI-SD score, fat mass,
and body circumference measurements and higher plasma levels of insulin and
leptin. Analysis by race showed greater BMI-SD score and DXA body fat mass
for both African American and Caucasian children homozygous for both variants
of the two MC3R loci. To study the functional consequences of these
MC3R missense variants, we transiently expressed both singly and doubly variant
MC3R receptors in HEK293 cells and compared ligand affinity and cAMP
generation with that of the wild-type receptor. Saturation curves for binding
of 125I-NDP alpha-MSH showed that the doubly mutant Thr6Lys and
Val81Ile MC3R bound approximately 60 percent less 125I-NDP
alpha-MSH than the wild-type receptor. A Scatchard analysis showed that the Kd
for the singly or doubly variant MC3R did not differ significantly from the
wild type. However, the level of surface expression, as reflected by the estimated
maximum binding (Bmax), was significantly lower for the doubly
mutant MC3R (56.9pM) than for the wild-type MC3R (137.7pM). The decreased
maximum binding without an affinity change suggests that the doubly mutant
receptor has fewer available alpha-MSH binding sites. By examining coupling to adenylyl cyclase upon
stimulation by NDP alpha-MSH in transiently transfected HEK293 cells, we then
measured the functional activity of the mutants. The Val81Ile+Thr6Lys double
mutant MC3R had significantly lower maximal intracellular cAMP generation
than wild-type MC3R. We also studied the functional activity of the mutant
MC3R in LVIP2.0Zc cells stably transfected with a cAMP-responsive
beta-galactosidase reporter gene. Upon stimulation by NDP alpha-MSH, the doubly
mutant MC3R produced significantly less maximal beta-galactosidase activity
without change in EC50, paralleling the changes in intracellular
cAMP accumulation. To study translational efficiency, we transiently
expressed MC3R-GFP fusion proteins in LVIP2.0Zc cells, finding decreased
protein expression. In sum, we found that the co-occurrence of two previously
identified variants was associated with impaired cAMP generation in vitro
and with greater BMI-SD, greater body fat mass, and higher plasma insulin and
leptin levels, both in African American and Caucasian children. Our findings
represent the first report of a significant relationship between these
variants and pediatric obesity. Homozygocity
for the MC3R double mutant may contribute to the greater prevalence of
overweight in African Americans. Ongoing studies focus on understanding the
mechanisms by which these sequence alterations may affect body weight. Feng NP, Adler-Wailes D, Elberg J, Chin J,
Fallon E, Carr A, Fraser del Llado T, Yanovski JA. Sequence variants of the
proopiomelanocortin (POMC) gene and their associations with body composition
in lean and overweight children. Obes Res 2003;11:619-624. Gelernter-Yaniv LG, Feng NP, Sebring NG,
Hochberg Z, Yanovski JA. Associations between a polymorphism in the 11 beta
hydroxysteroid dehydrogenase type I gene and body composition. Int J Obes
2003;27:983-986. Physiology, metabolism, and psychology of
childhood body weight regulation McDuffie,
Tanofsky-Kraff, Norman, Yanovski J; in collaboration with Keil, Schoeller,
Warden, Yanovski S, Young-Hyman Our studies are directed at understanding the
physiological, psychological, and metabolic factors that identify children at
risk for undue weight gain. As part of these studies, we have examined how
best to measure psychopathology, insulin sensitivity, and changes in body
composition. We found a noninvasive air displacement plethysmographic
approach that is highly correlated with results from dual energy X-ray
absorptiometry. In recent studies, we found that the hyperglycemic clamp
procedure was highly correlated with the more technically demanding
euglycemic, hyperinsulinemic clamp study in children and suitable for
assessing insulin sensitivity in children. We then found that African
American children have greater insulin secretion, a greater prevalence of
acanthosis nigricans, and less insulin sensitivity than Caucasian children of
similar body composition. The results imply that the relationships between
visceral fat and complications of obesity differ in African Americans and
Caucasians. The susceptibility to weight gain in African Americans may also
result from differences in metabolic efficiency. We also found that resting
energy expenditure is approximately 90 kcal/d less in African American than
in Caucasian normal-weight and overweight boys and girls. Our studies suggest
that the differences are not explained by differences in the hormone leptin.
We also studied the effects of adiposity on skeletal maturation in African
American and Caucasian children, finding that a substantial portion of the
advancement of sexual and skeletal maturation observed in African American
children may be explained by their greater adiposity. Studies concentrating
on binge eating behaviors in children suggest that such behaviors also are
associated with adiposity in children, and ongoing investigations suggest
that binge-eating behavior may predict future weight gain in children at risk
for becoming overweight. To determine the factors that are most
important for development of the complications of obesity in African American
and Caucasian youth, we are involved in two ongoing protocols to study
normal-weight African American and Caucasian children and adolescents,
already obese African American and Caucasian children, and nonobese African
American and Caucasian children of obese parents. We are assessing body
composition, metabolic rate, insulin sensitivity, glucose disposal, and
genetic factors believed to regulate metabolic rate, such as the uncoupling
proteins, leptin and its receptor, and the beta-3 adrenergic receptor. We are
also studying psychological and behavioral factors, such as propensity to
engage in binge-eating behavior. We have recently found that children who
report binge eating during childhood have greater adiposity than those not
reporting such behavior. These children are being studied longitudinally into
adulthood. We hypothesize that differences in the above-mentioned factors
predict the development of obesity and may be of great importance in
developing rational approaches for the prevention and treatment of obesity in
the diverse Elberg J, McDuffie JR, Sebring NG, Salaita C,
Keil M, Robotham D, Reynolds JC, Yanovski JA. Comparison of methods to assess
change in children’s body composition. Am J Clin Nutr
2004;80:64-69. Field AE, Laird N, Steinberg E, Fallon E,
Semega-Janneh M, Yanovski JA. Which metric of relative weight best captures
body fatness in children? Obes Res 2003;11:1345-1352. Tanofsky-Kraff M, Morgan CM, Yanovski SZ, Marmarosh
C, Wilfley DE, Yanovski JA. Comparison of assessments of children’s
eating disordered behaviors by interview and questionnaire. Int J Eat
Disord 2003;33:213-224. Tanofsky-Kraff M, Yanovski SZ, Wilfley DE,
Marmarosh C, Morgan CM, Yanovski JA. Eating disordered behaviors, body fat,
and psychopathology in overweight and normal weight children. J Consult
Clin Psychol 2004;72:53-61. Uwaifo GI, Nguyen TT, Russell DL, Keil MF,
Nicholson JC, Bonat SH, McDuffie JR, Yanovski JA. Differences in insulin
secretion and sensitivity of Caucasian and African American prepubertal
children. J Pediatr 2002;140:673-680. Treatment of children and adolescents with
comorbid conditions associated with obesity McDuffie,
Uwaifo, Cohen,a Fallon,b Freedman, Parikh,c
Tanofsky-Kraff, Yanovski J; in collaboration with Calis, Drinkard, Krakoff,
Reynolds, Riggs, Rolls, Semega-Janneh, Sebring, Salaita, Young-Hyman, Given the rapid increase in the prevalence of
obesity, the development of treatments for obesity in childhood is urgently
needed. In two ongoing clinical protocols, we are studying novel approaches
to the control of body weight in children. We have completed a pilot study
demonstrating that severely overweight adolescents can lose weight when
enrolled in a comprehensive weight management program that includes the novel
gastrointestinal lipase inhibitor orlistat as an adjunct to a behavior
modification program. We have also found evidence that one mechanism through
which orlistat may affect body weight is by changing the hedonic value of
dietary fat. A placebo-controlled randomized trial will determine whether the
use of orlistat improves weight loss of African American and Caucasian
children and adolescents with obesity-related comorbidities. A second study
examines the mechanism by which metformin, another novel weight loss agent,
may affect the body weight of younger children with hyperinsulinemia. Heck AM, McDuffie J, Carobene SE, Calis K,
Yanovski JA. Additive gastrointestinal effects with concomitant use of
olestra and orlistat. Ann Pharmacother 2002;36:1003-1005. McDuffie JR, Calis KA, Booth S, Uwaifo GI,
Yanovski JA. Effects of orlistat on fat-soluble vitamins in obese
adolescents. Pharmacotherapy 2002;22:814-822. McDuffie JR, Calis KA, Uwaifo GI, Freedman RJ,
Sebring NG, Fallon EM, Frazer TE, Hubbard VS, Yanovski JA. Efficacy of
orlistat as an adjunct to behavioral treatment in overweight African American
and Caucasian adolescents with obesity-related co-morbid conditions. J
Pediatr Endocrinol Metab 2004;17:307-319. Yanovski JA, Yanovski SZ. Treatment of
pediatric and adolescent obesity. JAMA 2003;289:1851-1852. Yanovski SZ, Yanovski JA. Obesity. N Engl J
Med 2002;346:591-602. Environmental factors affecting adult weight
gain Yanovski
J, Yanoff; in collaboration with Yanovski S We are also interested in assessing the impact
of the environment on body weight gain. To determine the role of seasonal
variation in weight change, we prospectively studied 200 We are also interested in the role of dietary
calcium in determining body weight change. A new protocol is designed to
examine the impact of dietary calcium supplementation on body weight in a
randomized, controlled trial of 340 adults. One hypothesis for how calcium
intake may affect body adiposity points to alteration of plasma
concentrations of calcitropic hormones such as 1,25 dihydroxy vitamin D. 1,25
dihydroxy vitamin D has been found in vitro to stimulate lipogenesis.
Others have hypothesized that deficient calcium intake stimulates parathyroid
hormone and promotes conversion of 25 hydroxy vitamin D to 1,25 dihydroxy
vitamin D, thereby stimulating lipogenesis and leading to greater body weight
in humans. We have determined that 1,25 dihydroxy vitamin D concentrations
are not increased in overweight and obese adults; rather, we observed vitamin
D deficiency (and lower 1,25 dihydroxy vitamin D concentrations) among severely
obese adults. The ongoing randomized controlled trial will answer important
questions about the value of calcium supplementation for the prevention of
future weight gain. Freedman RJ, Aziz N, Albanes D, Hartman T,
Danforth D, Hill S, Sebring N, Reynolds JC, Yanovski JA. Weight and body
composition changes during and after adjuvant chemotherapy in women with
breast cancer. J Clin Endocrinol Metab 2004;88:2248-2253. Leser M, Yanovski SZ, Yanovski JA. Low fat
intake and greater activity level are associated with lower weight regain 3
years after completing a very-low-calorie diet. J Amer Dietetic Assoc
2002;102:1252-1256. Parikh SJ, Edelman M, Uwaifo GI, Freedman RJ,
Semega-Janneh M, Reynolds J, Yanovski JA. The relationship between obesity
and serum 1, 25 dihydroxy vitamin D concentrations in healthy adults. J
Clin Endo Metab 2004;89:1196-1199. Parikh SJ, Yanovski JA. Calcium intake and
adiposity. Am J Clin Nutr 2003;77:281-287. aMarc bErica cShamik
COLLABORATORS Silva Arslanian, MD, Sarah Booth, PhD, Karim Calis, DPharm, Pharmacy
Department, Warren Grant Magnuson Clinical Center, NIH, Bethesda, MD Bart Drinkard, PT, Rehabilitation
Medicine Department, Warren Grant Magnuson Clinical Center, NIH,
Bethesda, MD Leonard H. Epstein, PhD,
State Alison Field, DSc, Brigham
and Women’s Hospital, Margaret Keil, RN, PNP, Developmental
Endocrinology Branch, NICHD, Jonathan Krakoff, MD, Clinical
Diabetes and Nutrition Section/Phoenix Epidemiology and Clinical Research
Branch, NIDDK, Rudolph L. Leibel, MD, Constantine
Londos, DDS, PhD, Laboratory of Cellular and Developmental Biology, NIDDK, James D. Malley, PhD, Mathematical
and Statistical Computing Laboratory, CIT, Vincent Manganiello, MD, Pulmonary
Critical Care Medicine Branch, NHLBI, James Reynolds, MD, Nuclear
Medicine, Warren Grant Magnuson Clinical Center, NIH, Patti Riggs, RD, Nutrition
Department, Warren Grant Magnuson Clinical Center, NIH, Bethesda, MD Barbara Rolls, PhD, Christine
Salaita, MS, RD, Nutrition Department, Warren Grant Magnuson Clinical, NIH, Dale Schoeller, PhD, Nancy
Sebring, MEd, RD, Nutrition Department, Warren Grant Magnuson Clinical
Center, NIH, Craig Warden, PhD, Denise E. Wilfley, PhD, Susan Z. Yanovski, MD, Obesity
and Eating Disorders Program, NIDDK, Debra Young-Hyman, PhD, Risk,
Prevention, and Health Behavior Integrated Review Group, Center for
Scientific Review, NIH, For
further information, contact yanovskj@mail.nih.gov |
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