A longitudinal study of serum insulin and insulin resistance as predictors of weight and body fat gain in African American and Caucasian children.

BACKGROUND: The influence of insulin and insulin resistance (IR) on children's weight and fat gain is unclear. OBJECTIVE: To evaluate insulin and IR as predictors of weight and body fat gain in children at high risk for adult obesity. We hypothesized that baseline IR would be positively associated with follow-up body mass index (BMI) and fat mass. SUBJECTS/METHODS: Two hundred and forty-nine healthy African American and Caucasian children aged 6-12 years at high risk for adult obesity because of early-onset childhood overweight and/or parental overweight were followed for up to 15 years with repeated BMI and fat mass measurements. We examined baseline serum insulin and homeostasis model of assessment-IR (HOMA-IR) as predictors of follow-up BMI Z-score and fat mass by dual-energy X-ray absorptiometry in mixed model longitudinal analyses accounting for baseline body composition, pubertal stage, sociodemographic factors and follow-up interval. RESULTS: At baseline, 39% were obese (BMI⩾95th percentile for age/sex). Data from 1335 annual visits were examined. Children were followed for an average of 7.2±4.3 years, with a maximum follow-up of 15 years. After accounting for covariates, neither baseline insulin nor HOMA-IR was significantly associated with follow-up BMI (Ps>0.26), BMIz score (Ps>0.22), fat mass (Ps>0.78) or fat mass percentage (Ps>0.71). In all models, baseline BMI (P<0.0001), body fat mass (P<0.0001) and percentage of fat (P<0.001) were strong positive predictors for change in BMI and fat mass. In models restricted to children without obesity at baseline, some but not all models had significant interaction terms between body adiposity and insulinemia/HOMA-IR that suggested less gain in mass among those with greater insulin or IR. The opposite was found in some models restricted to children with obesity at baseline. CONCLUSIONS: In middle childhood, BMI and fat mass, but not insulin or IR, are strong predictors of children's gains in BMI and fat mass during adolescence.

Accelerated Skeletal Maturation in Disorders of Retinoic Acid Metabolism: A Case Report and Focused Review of the Literature.

Nutritional excess of vitamin A, a precursor for retinoic acid (RA), causes premature epiphyseal fusion, craniosynostosis, and light-dependent retinopathy. Similarly, homozygous loss-of-function mutations in CYP26B1, one of the major RA-metabolizing enzymes, cause advanced bone age, premature epiphyseal fusion, and craniosynostosis. In this paper, a patient with markedly accelerated skeletal and dental development, retinal scarring, and autism-spectrum disease is presented and the role of retinoic acid in longitudinal bone growth and skeletal maturation is reviewed. Genetic studies were carried out using SNP array and exome sequencing. RA isomers were measured in the patient, family members, and in 18 age-matched healthy children using high-performance liquid chromatography coupled to tandem mass spectrometry. A genomic SNP array identified a novel 8.3 megabase microdeletion on chromosome 10q23.2-23.33. The 79 deleted genes included CYP26A1 and C1, both major RA-metabolizing enzymes. Exome sequencing did not detect any variants that were predicted to be deleterious in the remaining alleles of these genes or other known retinoic acid-metabolizing enzymes. The patient exhibited elevated plasma total RA (16.5 vs. 12.6±1.5 nM, mean±SD, subject vs. controls) and 13-cisRA (10.7 nM vs. 6.1±1.1). The findings support the hypothesis that elevated RA concentrations accelerate bone and dental maturation in humans. CYP26A1 and C1 haploinsufficiency may contribute to the elevated retinoic acid concentrations and clinical findings of the patient, although this phenotype has not been reported in other patients with similar deletions, suggesting that other unknown genetic or environmental factors may also contribute.

Analysis of variants and mutations in the human winged helix FOXA3 gene and associations with metabolic traits.

BACKGROUND/OBJECTIVES: The forkhead factor Foxa3 is involved in the early transcriptional events controlling adipocyte differentiation and plays a critical function in fat depot expansion in response to high-fat diet regimens and during aging in mice. No studies to date have assessed the potential associations of genetic variants in FOXA3 with human metabolic outcomes. SUBJECTS/METHODS: In this study, we sequenced FOXA3 in 392 children, adolescents and young adults selected from several cohorts of subjects recruited at the National Institute of Child Health and Human Development of the National Institutes of Health based on the availability of dual-energy X-ray absorptiometry data, magnetic resonance imaging scans and DNA samples. We assessed the association between variants present in these subjects and metabolic traits and performed in vitro functional analysis of two novel FOXA3 missense mutations identified. RESULTS: Our analysis identified 14 novel variants and showed that the common single-nucleotide polymorphism (SNP) rs28666870 is significantly associated with greater body mass index, lean body mass and appendicular lean mass (P values 0.009, 0.010 and 0.013 respectively). In vitro functional studies showed increased adipogenic function for the FOXA3 missense mutations c.185C>T (p.Ser62Leu) and c.731C>T (p.Ala244Val) compared with FOXA3-WT. CONCLUSIONS: Our study identified novel FOXA3 variants and mutations, assessed the adipogenic capacity of two novel missense alterations in vitro and demonstrated for the first time the associations between FOXA3 SNP rs28666870 with metabolic phenotypes in humans.

Behavioral and neurodevelopmental precursors to binge-type eating disorders: support for the role of negative valence systems.

BACKGROUND: Pediatric loss-of-control (LOC) eating is a robust behavioral precursor to binge-type eating disorders. Elucidating precursors to LOC eating and binge-type eating disorders may refine developmental risk models of eating disorders and inform interventions. METHOD: We review evidence within constructs of the Negative Valence Systems (NVS) domain, as specified by the Research Domain Criteria framework. Based on published studies, we propose an integrated NVS model of binge-type eating-disorder risk. RESULTS: Data implicate altered corticolimbic functioning, neuroendocrine dysregulation, and self-reported negative affect as possible risk factors. However, neuroimaging and physiological data in children and adolescents are sparse, and most prospective studies are limited to self-report measures. CONCLUSIONS: We discuss a broad NVS framework for conceptualizing early risk for binge-type eating disorders. Future neural and behavioral research on the developmental trajectory of LOC and binge-type eating disorders is required.

Effects of metformin on energy intake and satiety in obese children.

AIMS: To investigate the effects of metformin on appetite and energy intake in obese children with hyperinsulinaemia. METHODS: We conducted a 6-month randomized, double-blind, placebo-controlled trial to evaluate the effects of metformin 1000 mg twice daily on body weight and energy balance in 100 obese children with hyperinsulinaemia aged 6-12 years. The children ate ad libitum from standardized food arrays on two separate occasions before and after 6 months of study medication. The first test meal was consumed after an overnight fast. The second was preceded by a pre-meal load. For each test meal, energy intake was recorded, and the children completed scales of hunger, fullness and desire to eat. RESULTS: Data from the meal studies at baseline and after treatment with study medication were available for 84 children (metformin-treated, n = 45; placebo-treated, n = 39). Compared with placebo, metformin treatment elicited significant reductions from baseline in adjusted mean ± standard error of the mean energy intake after the pre-meal load (metformin: -104.7 ± 83.8 kcal vs. placebo: +144.2 ± 96.9 kcal; p = 0.034) independently of changes in body composition. Metformin also significantly decreased ratings of hunger (-1.5 ± 5.6 vs. +18.6 ± 6.3; p = 0.013) and increased ratings of fullness (+10.1 ± 6.2 vs. -12.8 ± 7.0; p = 0.01) after the pre-meal load. CONCLUSIONS: These data suggest that decreased perceived hunger resulting in diminished food intake are among the mechanisms by which metformin treatment reduces body weight in overweight children with hyperinsulinaemia.

Serum leptin and loss of control eating in children and adolescents.

BACKGROUND: Both insufficiency and resistance to the actions of the adipocyte-derived hormone leptin promote hunger, increased food intake and greater body weight. Some studies suggest that adults reporting binge eating have increased serum leptin compared with those without binge eating, even after adjusting for the greater adiposity that characterizes binge eaters. Pediatric binge or loss of control (LOC) eating are prospective risk factors for excessive weight gain and may predict development of metabolic abnormalities, but whether LOC eating is associated with higher leptin among children is unknown. We therefore examined leptin and LOC eating in a pediatric cohort. METHODS: A convenience sample of 506 lean and obese youth (7-18 years) was recruited from Washington, DC and its suburbs. Serum leptin was collected after an overnight fast. Adiposity was measured by dual-energy X-ray absorptiometry or air displacement plethysmography. LOC eating was assessed by interview methodology. RESULTS: Leptin was strongly associated with fat mass (r=0.79, P<0.001). However, even after adjusting for adiposity and other relevant covariates, youth with LOC eating had higher serum leptin compared with those without LOC episodes (15.42±1.05 vs 12.36±1.04 ng ml(-1), P<0.001). Neither reported amount of food consumed during a recent LOC episode nor number of LOC episodes in the previous month accounted for differences in leptin (P>0.05). The relationship between LOC eating and leptin appeared to be significant for females only (P=0.002). CONCLUSIONS: Reports of LOC eating were associated with higher fasting leptin in youth, beyond the contributions of body weight. Prospective studies are required to elucidate whether LOC eating promotes greater leptin or whether greater leptin resistance may promote LOC eating.

An evolving scientific basis for the prevention and treatment of pediatric obesity.

The 2013 Pennington Biomedical Research Center's Scientific Symposium focused on the treatment and management of pediatric obesity and was designed to (i) review recent scientific advances in the prevention, clinical treatment and management of pediatric obesity, (ii) integrate the latest published and unpublished findings and (iii) explore how these advances can be integrated into clinical and public health approaches. The symposium provided an overview of important new advances in the field, which led to several recommendations for incorporating the scientific evidence into practice. The science presented covered a range of topics related to pediatric obesity, including the role of genetic differences, epigenetic events influenced by in utero development, pre-pregnancy maternal obesity status, maternal nutrition and maternal weight gain on developmental programming of adiposity in offspring. Finally, the relative merits of a range of various behavioral approaches targeted at pediatric obesity were covered, together with the specific roles of pharmacotherapy and bariatric surgery in pediatric populations. In summary, pediatric obesity is a very challenging problem that is unprecedented in evolutionary terms; one which has the capacity to negate many of the health benefits that have contributed to the increased longevity observed in the developed world.

Brain-derived neurotrophic factor in human subjects with function-altering melanocortin-4 receptor variants.

BACKGROUND: In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. OBJECTIVE: The objective of this study is to compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants with those of controls with common sequence MC4R. METHODS: Circulating BDNF was measured in two cohorts with known MC4R sequence: 148 subjects of Pima Indian heritage ((mean±s.d.): age, 15.7±6.5 years; body mass index z-scores (BMI-Z), 1.63±1.03) and 69 subjects of Hispanic heritage (10.8±3.6 years; BMI-Z, 1.57±1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding and cyclic AMP response after agonist administration. BDNF single-nucleotide polymorphisms (SNPs) rs12291186, rs6265 and rs7124442 were also genotyped. RESULTS: In the Pima cohort, no significant differences in serum BDNF was observed for 43 LOF subjects versus 65 LOF-matched controls (age, sex and BMI matched; P=0.29) or 20 GOF subjects versus 20 GOF-matched controls (P=0.40). Serum BDNF was significantly associated with genotype for BDNF rs12291186 (P=0.006) and rs6265 (P=0.009), but not rs7124442 (P=0.99); BDNF SNPs did not interact with MC4R status to predict serum BDNF. In the Hispanic cohort, plasma BDNF was not significantly different among 21 LOF subjects, 20 GOF subjects and 28 controls (P=0.79); plasma BDNF was not predicted by BDNF genotype or BDNF-x-MC4R genotype interaction. CONCLUSIONS: Circulating BDNF concentrations were not significantly associated with MC4R functional status, suggesting that peripheral BDNF does not directly reflect hypothalamic BDNF secretion and/or that MC4R signaling is not a significant regulator of the bulk of BDNF expression in humans.

Pharmacotherapy for childhood obesity: present and future prospects.

Pediatric obesity is a serious medical condition associated with significant comorbidities during childhood and adulthood. Lifestyle modifications are essential for treating children with obesity, yet many have insufficient response to improve health with behavioral approaches alone. This review summarizes the relatively sparse data on pharmacotherapy for pediatric obesity and presents information on obesity medications in development. Most previously studied medications demonstrated, at best, modest effects on body weight and obesity-related conditions. It is to be hoped that the future will bring new drugs targeting specific obesity phenotypes that will allow clinicians to use etiology-specific, and therefore more effective, anti-obesity therapies.

Construct validity of the emotional eating scale adapted for children and adolescents.

BACKGROUND: Emotional eating, defined as eating in response to a range of negative emotions, is common in youths. Yet, there are few easily administered and well-validated methods to assess emotional eating in pediatric populations. OBJECTIVE: The current study tested the construct validity of the Emotional Eating Scale (EES) Adapted for Children and Adolescents (EES-C) by examining its relationship to observed emotional eating at laboratory test meals. METHOD: A total of 151 youths (8-18 years) participated in two multi-item lunch buffet meals on separate days. They ate ad libitum after being instructed to 'eat as much as you would at a normal meal' or to 'let yourself go and eat as much as you want'. State negative affect was assessed immediately before each meal. The EES-C was completed 3 months, on average, before the first test meal. RESULTS: Among youths with high EES-C total scores, but not low EES-C scores, higher pre-meal state negative affect was related to greater total energy intake at both meals, with and without the inclusion of age, race, sex and body mass index (BMI) standard deviation as covariates (ps<0.03). DISCUSSION: The EES-C demonstrates good construct validity for children and adolescents' observed energy intake across laboratory test meals designed to capture both normal and disinhibited eating. Future research is required to evaluate the construct validity of the EES-C in the natural environment and the predictive validity of the EES-C longitudinally.

Children's binge eating and development of metabolic syndrome.

BACKGROUND: Binge eating predisposes children to excessive weight gain. However, it is unknown if pediatric binge eating predicts other obesity-associated adverse health outcomes. OBJECTIVE: The objective of this study was to investigate the relationship between binge eating and metabolic syndrome (MetS) in children. METHOD: Children aged 5-12 years at high risk for adult obesity, either because they were overweight/obese when first examined or because their parents were overweight/obese, were recruited from Washington, DC and its suburbs. Children completed a questionnaire assessment of binge eating at baseline and underwent measurements of MetS components at baseline and at a follow-up visit approximately 5 years later. Magnetic resonance imaging was used to measure the visceral adipose tissue (VAT) in a subset. RESULTS: In all, 180 children were studied between July 1996 and August 2010. Baseline self-reported binge eating presence was associated with a 5.33 greater odds of having MetS at follow-up (95% confidence interval (CI): 1.47, 19.27, P=0.01). The association between binge eating and body mass index (BMI) only partially explained changes in MetS components: baseline binge eating predicted higher follow-up triglycerides, even after accounting for baseline triglycerides, baseline BMI, BMI change, sex, race, baseline age and time in study (P = 0.05). Also, adjusting for baseline VAT and demographics, baseline binge eating predicted greater follow-up L(2-3) VAT (P = 0.01). DISCUSSION: Children's reports of binge eating predicted development of MetS, worsening triglycerides and increased VAT. The excessive weight gain associated with children's binge eating partly explained its adverse metabolic health outcomes. Reported binge eating may represent an early behavioral marker upon which to focus interventions for obesity and MetS.

Prediction of maximal oxygen uptake by bioelectrical impedance analysis in overweight adolescents.

AIM: Maximal oxygen uptake (VO(2max)), the gold standard for measurement of cardiorespiratory fitness, is frequently difficult to assess in overweight individuals due to physical limitations. Reactance and resistance measures obtained from bioelectrical impedance analysis (BIA) have been suggested as easily obtainable predictors of cardiorespiratory fitness, but the accuracy with which ht(2)/Z can predict VO(2max) has not previously been examined in overweight adolescents. METHODS: The impedance index was used as a predictor of VO(2max) in 87 overweight girls and 47 overweight boys ages 12 to 17 with mean BMI of 38.6 + or - 7.3 and 42.5 + or - 8.2 in girls and boys respectively. The Bland Altman procedure assessed agreement between predicted and actual VO(2max). RESULTS: Predicted VO(2max) was significantly correlated with measured VO(2max) (r(2)=0.48, P<0.0001). Using the Bland Altman procedure, there was significant magnitude bias (r(2)=0.10; P<0.002). The limits of agreement for predicted relative to actual VO(2max) were -589 to 574 mL O(2)/min. CONCLUSIONS: The impedance index was highly correlated with VO(2max) in overweight adolescents. However, using BIA data to predict maximal oxygen uptake over-predicted VO(2max) at low levels of oxygen consumption and under-predicted VO(2max) at high levels of oxygen consumption. This magnitude bias, along with the large limits of agreement of BIA-derived predicted VO(2max), limit its usefulness in the clinical setting for overweight adolescents.

A pilot study of the effects of niacin administration on free fatty acid and growth hormone concentrations in children with obesity.

CONTEXT: Children with obesity have low spontaneous growth hormone (GH) secretion. High circulating free fatty acid (FFA) concentration is believed to inhibit GH secretion in those with obesity. In adults, lipolytic inhibition with niacin lowers FFA and increases GH, but there are no prior studies in children with obesity. OBJECTIVE: The objective of the study was to determine the dose and frequency of niacin administration required to lower FFA and stimulate GH in children with obesity. DESIGN: Dose-finding study of nondiabetic children ages 6-12 years with body mass index (BMI) ≥ 95th percentile given niacin 250 mg q2h × 3 doses (n = 2), 500 mg q2h × 3 doses (n = 5) or 500 mg q1h × 4 doses (n = 5). PARTICIPANTS: Eight boys and four girls (age 9.7 ± 1.8 years; BMI 26.4 ± 3.1 kg m-2 ; BMIz 2.2 ± .25) were studied. MAIN OUTCOME: Percentage of serum FFA values that were below 0.2 mEq L-1 . GH, insulin and glucose were also measured serially. RESULTS: FFA decreased as the dose and frequency of niacin increased (p = .01). Niacin 500 mg q1h 4 doses suppressed FFA < 0.2 mEq L-1 and significantly increased GH (p = .04). Adverse effects were flushing/warmth (100%), tingling (60%) and GI complaints (20-40%). CONCLUSIONS: Niacin 500 mg q1h significantly lowered serum FFA and increased GH. These pilot data suggest that high FFA is an important suppressor of GH secretion in children with obesity.

Evaluating the contribution of differences in lean mass compartments for resting energy expenditure in African American and Caucasian American children.

BACKGROUND: Resting energy expenditure (REE), adjusted for total lean mass (LM), is lower in African American (AA) than Caucasian American (CA) children. Some adult studies suggest that AA-CA differences in lean mass compartments explain this REE difference. Similar data are limited in children. OBJECTIVE: To evaluate differences in compartment-specific lean mass between AA and CA children and examine the individual contributions of high-metabolic rate-at-rest trunk lean mass (TrLM) and low-metabolic-rate-at-rest appendicular lean mass (AppLM) for AA-CA differences in REE. METHODS: We studied a convenience sample of 594 AA (n = 281) and CA (n = 313) children. REE was measured by using indirect calorimetry; dual-energy X-ray absorptiometry was used to assess body composition. ANCOVAs were performed to examine AA-CA differences in TrLM, AppLM and REE. After accounting for age, sex, height, pubertal development, bone mass and adiposity, REE was evaluated adjusting for total LM (model A) and separately adjusting for TrLM and AppLM (model B). RESULTS: African American children had greater adjusted AppLM (17.8 ± 0.2 [SE] vs. 16.0 ± 0.2 kg, p < 0.001) and lower TrLM (17.2 ± 0.2 vs. 17.7 ± 0.2 kg, p = 0.022) than CA children. REE adjusted for total LM was 77 ± 16 kcal/d lower in AA than CA (p < 0.001). However, after accounting separately for AppLM and TrLM, the discrepancy in REE between the groups declined to 28 ± 19 kcal/d (p = 0.14). In the adjusted model, both TrLM (p < 0.001) and AppLM (p < 0.027) were independently associated with REE. CONCLUSION: In children, AA-CA differences in REE appear mostly attributable to differences in body composition. Lower REE in AA children is likely due to lower TrLM and greater AppLM.

Relationship of pressure to be thin with gains in body weight and fat mass in adolescents.

BACKGROUND: Sociocultural pressure to be thin is commonly reported by adolescents; yet, to what extent such pressure is associated with weight gain has not been evaluated longitudinally. OBJECTIVE: Examine whether pressure to be thin was positively associated with weight and fat gain in adolescents. METHODS: Participants were 196 healthy adolescent (age 15 ± 1 years old) girls (65%) and boys of varying weights (BMI 25 ± 7 kg/m2 ) studied at baseline and 1-year follow-up. At baseline, adolescents and their mothers reported pressure to be thin by questionnaire. At baseline and follow-up, BMI was calculated, and fat mass was assessed with air displacement plethysmography. Multiple regression was used to examine associations between baseline pressure to be thin and 1-year changes in BMI and fat mass. RESULTS: Accounting for multiple covariates, including baseline BMI or fat, adolescent-reported pressure from parents and peers and mother-reported pressure toward their teen were associated with greater gains in either adolescent BMI or fat (ps < .05). Adolescent weight status was a moderator of multiple effects (ps < .05). CONCLUSIONS: Parental and peer pressure to be thin were associated with increases in BMI and fat mass during adolescence, particularly in heavier adolescents. Further research is necessary to clarify how this association operates reciprocally and to identify underlying explanatory mechanisms.

Inferior petrosal sinus sampling in healthy subjects reveals a unilateral corticotropin-releasing hormone-induced arginine vasopressin release associated with ipsilateral adrenocorticotropin secretion.

Arginine vasopressin (AVP) acts synergistically with corticotropin-releasing hormone (CRH) to stimulate ACTH release from the anterior pituitary. In a previous study of bilateral simultaneous inferior petrosal sinus (IPS) sampling in healthy human subjects, we observed lateralized ACTH secretion, suggesting lateralized secretion of an ACTH-regulating hypothalamic factor. To investigate this possibility, we measured ACTH, CRH, AVP, and oxytocin (OT) levels in the IPS and the peripheral circulation in nine normal volunteers, before and after 1 microgram/kg i.v. bolus ovine CRH (oCRH). At baseline, ACTH, AVP, and OT exhibited a significant (P < 0.05) two to threefold intersinus gradient (ISG), indicating the existence of a dominant petrosal sinus. Endogenous CRH was undetectable in all samples. Despite similar exogenous oCRH levels in both petrosal sinuses, oCRH caused a significant increase (P < 0.001) in the ACTH ISG (15.8 +/- 5.6, mean +/- SEM), suggesting increased responsiveness of one dominant side of the anterior pituitary. This was associated with an ipsilateral CRH-induced AVP release and a significant increase (P < 0.01) in the AVP ISG (8.6 +/- 2.3), suggesting lateralized AVP secretion by the hypothalamus. Furthermore, the increased AVP ISG after oCRH correlated strongly with the ACTH ISG (r = 0.92, P < 0.01). oCRH administration did not affect OT. These findings suggest that there is a dominant petrosal sinus in healthy volunteers that appears to reflect a dominant side of the adenohypophysis, characterized by increased functional activity and/or responsiveness of the pituitary corticotrophs. This may reflect lateralized hypothalamic and/or suprahypothalamic function resulting in CRH-responsive lateralized secretion of AVP from parvocellular and/or magnocellular axons in the median eminence and the posterior pituitary. Although the functional and teleologic significance of these findings remains to be investigated, our data suggest a novel mechanism for CRH-mediated ACTH release, namely CRH-induced release of AVP which then enhances CRH action on the corticotrophs. Furthermore, our data represent the first direct evidence for the concept of brain lateralization with respect to neuroendocrine secretion.

Associations between adiposity and indicators of thyroid status in children and adolescents.

BACKGROUND: In adults, obesity is associated with abnormalities of thyroid function; there are fewer studies in paediatric cohorts. OBJECTIVES: To examine associations of weight and adiposity with indices of thyroid function and thyroid-related metabolic factors in children. DESIGN/METHODS: A sample of 1203 children without obesity (body mass index [BMI] < 95th percentile; N = 631) and with obesity (BMI ≥ 95th percentile; N = 572), age 5-18 years, had height and weight measured (to calculate BMI-Z score for age and sex) and had blood collected in the morning for thyroid-stimulating hormone (TSH), free thyroxine (FT4) and leptin. A subset (N = 829) also underwent measurement of fat mass by dual-energy X-ray absorptiometry. Analyses examined associations of TSH and FT4 with adiposity and obesity-related conditions accounting for sociodemographic factors. RESULTS: Thyroid-stimulating hormone was positively related to BMIz and fat mass (both p-values < 0.001). FT4 was negatively related to BMIz and fat mass (both p-values < 0.001). TSH was positively correlated to leptin (p = 0.001) even after accounting for fat mass. CONCLUSIONS: Paediatric obesity is associated with higher TSH and lower FT4 concentrations and with a greater prevalence of abnormally high TSH. Leptin concentrations may in part explain obesity's effects on thyroid status, perhaps through leptin's effects on TSH secretion.

Metabolic and anthropometric consequences of interruption of highly active antiretroviral therapy.

BACKGROUND: HAART has been associated with metabolic abnormalities (hyperlipidemia, insulin resistance, alterations in cortisol metabolism) and fat redistribution. SETTING: A prospective study of 26 Caucasian men (median age 43.5 years) with HIV-1 viral loads < 500 copies/ml for 12 months while on highly active antiretroviral therapy (HAART) who interrupted treatment for a median of 7.0 weeks (range 4.9-10.3 weeks). Seventeen (65.4%) patients reported at least one fat redistribution symptom at baseline. METHOD: Serum lipids, glucose and insulin levels during an oral glucose tolerance test, 24-h urinary free cortisol and 17-hydroxycorticosteroids, and anthropometric parameters were measured before HAART cessation and prior to its reinstitution. RESULTS: When baseline values were compared with those obtained after HAART interruption (means +/- SD), there was a significant decrease in total cholesterol (194+/-47.3 versus 159+/-29.3 mg/dl; P < 0.0001), low density lipoprotein (LDL) cholesterol (114+/-32.6 versus 96+/-24.7 mg/dl; P = 0.0013), triglycerides (261+/-244.3 versus 185+/-165.4 mg/dl; P = 0.008), and 24-hour urinary 17-hydroxycorticosteroids (15+/-7.9 versus 5+/-2.5 mg/24 h, P < 0.0001) and a significant increase in 24-hour urinary free cortisol (45+/-34.1 versus 62+/-32.2 microg/24 h; P = 0.016). There were no significant changes in glucose or insulin levels or in anthropometric measurements. CONCLUSIONS: A relatively brief interruption of HAART resulted in significant improvements in total cholesterol, LDL cholesterol, and triglyceride levels. No changes were observed in insulin resistance profiles or anthropometric measurements, perhaps because of the brief duration of HAART interruption. These results suggest that hyperlipidemia and alterations in corticosteroid metabolism in the setting of HAART are a direct drug effect that reverses with drug withdrawal. However, glucose metabolism and fat redistribution do not change over the short term.

Dexamethasone increases growth hormone receptor messenger ribonucleic acid levels in liver and growth plate.

Glucocorticoid inhibits linear growth and renders target tissues, particularly liver and growth plate, insensitive to GH. We hypothesized that glucocorticoid-induced GH insensitivity is due to decreased gene expression of the GH receptor at the messenger RNA (mRNA) level. To test this hypothesis, we treated 4.5-wk-old male rabbits (n = 6-9 per group) with ip dexamethasone or vehicle and measured GH receptor mRNA levels (by RNase protection assay) and serum GH-binding protein levels (by radioimmunoprecipitation assay). Contrary to our hypothesis, dexamethasone administered in growth-suppressing doses did not decrease GH receptor mRNA levels in liver or growth plate. Instead a tissue-specific stimulation of GH receptor mRNA levels was observed. The dose-response relationship of this effect was biphasic, since the lower growth-suppressing dose of dexamethasone (0.1 mg/kg.day) caused the greater increase in GH receptor mRNA levels, whereas the higher growth-suppressing dose (4 mg/kg.day) had less effect. The dexamethasone-induced increase in GH receptor mRNA was observed in growth plate and liver, target tissues important for linear growth, but not in kidney. Serum GH-binding protein levels also showed a stimulatory response to dexamethasone treatment, with a biphasic dose-response relationship. These data suggest that glucocorticoid-induced GH insensitivity cannot be explained by decreased GH receptor mRNA levels. To the contrary, dexamethasone causes a tissue-specific stimulation in GH receptor mRNA levels with a biphasic dose-response relationship.

Induction of growth plate cartilage ossification by basic fibroblast growth factor.

In mammals, longitudinal bone growth results from the precise coupling of chondrogenesis and osteogenesis within the epiphyseal growth plate, a process termed endochondral ossification. The mechanisms coupling chondrogenesis and osteogenesis are unknown. Previous studies have shown that both basic fibroblast growth factor (bFGF) and acidic FGF are expressed by growth plate chondrocytes. Here we show that bFGF, infused directly into the rabbit proximal tibial growth plate, accelerates vascular invasion and ossification of growth plate cartilage. Our results suggest the possibility that bFGF (or a related member of the FGF family) couples osteogenesis to chondrogenesis by attracting vascular and bone cell invasion from the adjacent metaphyseal bone.