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ABSTRACT: Contents:Ghrelin is implicated in meal initiation because circulating levels increase before and fall after meal consumption. In rodents, ghrelin stimulates food intake via hypothalamic circuits expressing the melanocortin 4 receptor (MC4R).Objective:The aim of the study was to investigate the impact of central melanocortinergic tone on ghrelin secretion in humans.Design/Setting/Patients/Main Outcome Measure:We measured plasma total ghrelin before and after 3 standardized meals in patients with MC4R mutations and obese and lean controls. Fasting total ghrelin, area under the curve, and early (30-min) and intermeal postprandial total ghrelin suppression (the percentage difference between the premeal and the 30-min postprandial or intermeal nadir total ghrelin concentration) were calculated.Results:Fasting total ghrelin concentrations and area under the curve for total ghrelin concentrations were significantly decreased in both obese groups compared to lean controls (fasting total ghrelin: lean controls, 1083 ± 203 pg/ml; and obese controls, 696 ± 81 pg/ml; MC4R: 609 ± 99 pg/ml, P < .05). Early and intermeal postprandial total ghrelin suppression was attenuated in MC4R-deficient patients compared to lean controls (P < .05); a similar pattern was observed for early postprandial suppression in comparison with obese controls, but this difference did not reach statistical significance (P = .09).Conclusions:These findings are consistent with a role for central melanocortinergic signaling in modulating meal-related total ghrelin suppression.
The Journal of clinical endocrinology and metabolism 01/2013; · 6.50 Impact Factor
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ABSTRACT: Insulin sensitivity is higher in patients with Prader-Willi syndrome (PWS) than in body mass index-matched obese controls (OCs). Factors contributing to the heightened insulin sensitivity of PWS remain obscure. We compared the fasting levels of various hormones, cytokines, lipids, and liver function tests in 14 PWS patients and 14 OCs with those in 14 age- and gender-matched lean children (LC). We hypothesized that metabolic profiles of children with PWS are comparable with those of LC, but different from those of OCs.
Leptin levels were comparable in PWS patients and OCs, suggesting comparable degrees of adiposity. Glucose levels were comparable among groups. However, fasting insulin concentrations and homeostasis model assessment insulin resistance index were lower in PWS patients than in OCs (P < 0.05) and similar to LC. Moreover, high-density lipoprotein levels were lower and triglycerides higher in OCs (P < 0.05) but not PWS patients. Total adiponectin, high-molecular-weight (HMW) adiponectin and the HMW to total adiponectin ratio were higher in PWS patients (P < 0.05) than in OCs and similar to LC. High-sensitivity C-reactive protein and IL-6 levels were higher in OCs than in PWS patients or LC (P < 0.05). Nevertheless, PAI-1 levels were elevated in both OC and PWS patients. There were no group differences in glucagon-like peptide-1, macrophage chemoattractant protein-1, TNFα, IL-2, IL-8, IL-10, IL-12p40, IL-18, resistin, total or low-density lipoprotein cholesterol, aspartate aminotransferase, or alanine aminotransferase.
The heightened insulin sensitivity of PWS patients relative to OCs is associated with higher levels of adiponectin and lower levels of high-sensitivity C-reactive protein and IL-6. Future studies will determine whether PWS children are protected from obesity comorbidities such as type 2 diabetes, hyperlipidemia, and nonalcoholic fatty liver disease.
The Journal of clinical endocrinology and metabolism 10/2010; 96(1):E225-32. · 6.50 Impact Factor
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ABSTRACT: Brain-derived neurotrophic factor (BDNF) haploinsufficiency is associated with hyperphagia and obesity in both animals and humans. BDNF appears to function downstream of the leptin-melanocortin signaling pathway to control energy balance. The potential role of BDNF in the etiology of the severe hyperphagia associated with PWS has not been previously explored.
The aim was to compare BDNF concentrations in subjects with PWS and obese controls (OC) and lean controls (LC).
We conducted a cross-sectional study at an outpatient clinical research center.
We studied 13 subjects with PWS [five females and eight males; mean + or - sd: age, 11.0 + or - 4.1 yr; body mass index (BMI)-Z, 2.05 + or - 0.78], 13 OC (eight females, five males; age, 12.3 + or - 2.7 yr; BMI-Z, 2.18 + or - 0.61), and 13 LC (six females, seven males; age, 12.4 + or - 2.6 yr; BMI-Z, -0.57 + or - 0.73).
BDNF was measured in serum and plasma by ELISA. Analysis of covariance adjusted for age, sex, and BMI-Z.
All groups were comparable for age (P = 0.50) and sex distribution (P = 0.49). BMI-Z was comparable between PWS and OC (P = 0.89) and lower in LC (P < 0.001). Adjusted serum BDNF was comparable (P = 0.35) in OC (mean + or - sem: 13.5 + or - 1.2 ng/ml) and LC (19.2 + or - 1.3 ng/ml), but lower in PWS (8.3 + or - 1.2 ng/ml; P = 0.01 vs. OC; P = 0.03 vs. LC). Adjusted plasma BDNF in PWS (217 + or - 130 pg/ml) was lower than OC (422 + or - 126 pg/ml; P = 0.02), but statistically comparable with LC (540 + or - 143 pg/ml; P = 0.10).
Lower BDNF in PWS suggests insufficient central BDNF production because BDNF in peripheral circulation is believed to reflect cerebral BDNF output. Decreased BDNF may be a potential cause for the disordered satiety and morbid obesity associated with PWS. Further studies are needed to confirm this preliminary pilot study in a larger cohort of patients with PWS.
The Journal of clinical endocrinology and metabolism 07/2010; 95(7):3532-6. · 6.50 Impact Factor
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Christopher B Newgard,
Jie An,
James R Bain,
Michael J Muehlbauer,
Robert D Stevens,
Lillian F Lien, Andrea M Haqq,
Svati H Shah,
Michelle Arlotto,
Cris A Slentz, [......],
Dianne Gallup,
Olga Ilkayeva,
Brett R Wenner,
William S Yancy,
Howard Eisenson,
Gerald Musante,
Richard S Surwit,
David S Millington,
Mark D Butler,
Laura P Svetkey
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ABSTRACT: Metabolomic profiling of obese versus lean humans reveals a branched-chain amino acid (BCAA)-related metabolite signature that is suggestive of increased catabolism of BCAA and correlated with insulin resistance. To test its impact on metabolic homeostasis, we fed rats on high-fat (HF), HF with supplemented BCAA (HF/BCAA), or standard chow (SC) diets. Despite having reduced food intake and a low rate of weight gain equivalent to the SC group, HF/BCAA rats were as insulin resistant as HF rats. Pair-feeding of HF diet to match the HF/BCAA animals or BCAA addition to SC diet did not cause insulin resistance. Insulin resistance induced by HF/BCAA feeding was accompanied by chronic phosphorylation of mTOR, JNK, and IRS1Ser307 and by accumulation of multiple acylcarnitines in muscle, and it was reversed by the mTOR inhibitor, rapamycin. Our findings show that in the context of a dietary pattern that includes high fat consumption, BCAA contributes to development of obesity-associated insulin resistance.
Cell metabolism 05/2009; 9(4):311-26. · 17.35 Impact Factor
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Lillian F Lien, Andrea M Haqq,
Michelle Arlotto,
Cris A Slentz,
Michael J Muehlbauer,
Ross L McMahon,
James Rochon,
Dianne Gallup,
James R Bain,
Olga Ilkayeva,
Brett R Wenner,
Robert D Stevens,
David S Millington,
Deborah M Muoio,
Mark D Butler,
Christopher B Newgard,
Laura P Svetkey
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ABSTRACT: The Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) Project uses comprehensive metabolic profiling to probe biochemical mechanisms of weight loss in humans. Measurements at baseline, 2 and 4 weeks, 6 and 12 months included diet, body composition, metabolic rate, hormones, and 80 intermediary metabolites measured by mass spectrometry. In 27 obese adults in a behavioral weight loss intervention, median weight decreased 13.9 lb over the first 6 months, then reverted towards baseline by 12 months. Insulin resistance (HOMA) was partially ameliorated in the first 6 months and showed sustained improvement at 12 months despite weight regain. Ghrelin increased with weight loss and reverted to baseline, whereas leptin and PYY fell at 6 months and remained persistently low. NPY levels did not change. Factors possibly contributing to sustained improvement in insulin sensitivity despite weight regain include adiponectin (increased by 12 months), IGF-1 (increased during weight loss and continued to increase during weight regain), and visceral fat (fell at 6 months but did not change thereafter). We observed a persistent reduction in free fatty acids, branched chain amino acids, and related metabolites that may contribute to improved insulin action. These findings provide evidence for sustained benefits of weight loss in obese humans and insights into mechanisms.
Omics: a journal of integrative biology 03/2009; 13(1):21-35. · 2.29 Impact Factor
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ABSTRACT: Prader-Willi syndrome (PWS) is associated with failure to thrive in infancy and progressive hyperphagia and obesity in childhood. This progressive weight gain is associated with hyperghrelinaemia and increased insulin sensitivity. The role of ghrelin excess in the pathogenesis of obesity is unclear.
To determine if high ghrelin levels precede the onset of obesity in young PWS children.
A cross-sectional study of 33 infants with PWS and 28 healthy control subjects (C). Fasting ghrelin and other satiety hormones were measured.
Median total serum ghrelin in young children with PWS trended higher, but did not differ significantly from those in C of similar age, weight-for-age z-score and sex. However, there was more variability in ghrelin concentrations of young PWS. Eleven of 33 PWS subjects had ghrelin levels greater than the 95th percentile for ghrelin values in the C subjects (> 2871 pg/ml). Six of the PWS subjects with high ghrelin levels had weight-for-age z-scores < 0. Ghrelin concentrations in PWS and C infants exceeded those in older children. In youngsters with PWS, leptin was higher, suggesting a relative excess of fat to lean body mass and plasma adiponectin was increased.
Young infants with PWS who have not yet developed hyperphagia or obesity have median fasting ghrelin levels similar to controls. However, a subset (33%) of young PWS is hyperghrelinaemic; approximately one-half of those with hyperghrelinaemia have BMI z-score < 0. The age-related decline in ghrelin is blunted in PWS.
Clinical Endocrinology 08/2008; 69(6):911-20. · 3.17 Impact Factor
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ABSTRACT: Increased adiposity is associated with insulin resistance (IR) and an inflammatory response in adults. We tested the hypotheses that cytokines associated with adiposity are also correlated with IR in early adolescents and that these relationships are moderated by weight status, levels of vigorous physical activity (VPA), or maximal aerobic power (pVO2max). Body mass, stature, and a fasting blood sample were obtained from 120 midpubertal adolescents (60 girls and 60 boys). Habitual VPA was obtained by a survey. Predicted VO2max was determined using a cycle ergometer test. Weight status was based on body mass index (BMI) percentiles (normal weight=BMI<75th percentile, overweight=BMI>95th percentile). Glucose, insulin, adiponectin, resistin, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 were measured; and IR index was based on the Homeostatic Model Assessment. Adiponectin, resistin, and TNF-alpha were associated with IR in all adolescents (R2=0.329, P<.001; R2=0.152, P=.001; and R2=0.141, P=.002; respectively); but interleukin-6 was not (R2=0.148, P=.114). The degree of association between adiponectin and IR was stronger in overweight than in normal-weight adolescents (P<.050). When regression models included weight status, neither TNF-alpha nor resistin was significantly related to IR (P>.050). Exercise did not moderate the association between these cytokines and IR. However, higher levels of VPA and/or pVO2max were associated with higher adiponectin, lower resistin, and lower TNF-alpha in at least one of the sexes. Our results indicate that the pathophysiology of obesity is already established in early adolescents. Increased adiposity, resulting in reduced adiponectin and increased resistin and TNF-alpha, may link these cytokines with IR in adolescents.
Metabolism 06/2008; 57(5):683-90. · 2.66 Impact Factor
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ABSTRACT: To determine the associations between field-collected surrogates of adiposity and concentrations of resistin, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and adiponectin in youth.
Cross-sectional data from 60 normal weight and 60 overweight adolescents, ages 10-14 years, were retrospectively examined. Body mass index (BMI) percentile, sum of subscapular and triceps skinfolds (SSF), and waist circumference (WC) were used to classify weight status (BMI) or adiposity (SSF and WC). Percentiles for each surrogate were used for comparison groups. Fasting TNF-alpha, IL-6, resistin, and adiponectin concentrations were measured in plasma.
Multiple regression models, controlling for sex and ethnicity, indicated that TNF-alpha was associated with BMI percentile (R(2) = 0.107, P < 0.05) and SSF (R(2) = 0.085, P < 0.05), whereas resistin was associated with SSF (R(2) = 0.118, P < 0.05). Adiponectin was associated with all 3 adiposity markers: BMI percentile (R(2) = 0.298, P < 0.05), SSF (R(2) = 0.297, P < 0.05), and waist (R(2) = 0.278, P < 0.05). Analyses of variance indicated higher TNF-alpha and lower adiponectin concentrations in youth with a BMI higher than the 95th percentile (P = 0.014; P < 0.001) or SSF higher than the 95th percentile (P = 0.025; P < 0.001). Youth with WC higher than the 90th percentile had higher resistin (P = 0.029), higher IL-6 (P = 0.028), and lower adiponectin (P < 0.001) concentrations.
Of the 3 surrogates examined, differences in cytokine concentrations were mostly observed in youth who had WC percentiles higher than the 90th percentiles versus WC lower than the 75th percentiles. Alternatively, from the multiple-regression models SSF, an estimate of subcutaneous adiposity was the surrogate most consistently related to all cytokines, although the degrees of associations were low. The results suggest that although some surrogates were more strongly associated to certain cytokines, WC and SSF seemed more closely associated with cytokines than a BMI percentile indicating obesity.
Journal of Investigative Medicine 06/2008; 56(5):786-92. · 1.96 Impact Factor
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ABSTRACT: To present a case of unrecognized female epispadias.
Case report.
University-based reproductive endocrinology and fertility clinic.
A 16-year-old girl with epispadias, history of mild urinary incontinence, auditory neuropathy, and functional hyperandrogenism.
None.
Peripheral blood array-based comparative genomic hybridization.
The patient was referred for evaluation of excessive weight gain, secondary amenorrhea, and abnormal external genitalia. Examination under anesthesia revealed bilateral labia minora hypertrophy, bifid clitoris, and a patulous urethra, consistent with female epispadias. Hormonal evaluation showed functional hyperandrogenism, and peripheral blood array-based comparative genomic hybridization showed no chromosomal deletions or duplications.
Female epispadias is a rare abnormality, not commonly recognized by most practitioners. The diagnosis is supported by a history of urinary incontinence and physical findings of bifid clitoris and patulous urethra. The condition can have serious physical and psychological consequences leading to a gross disruption of social function.
Fertility and sterility 04/2008; 90(5):2017.e1-3. · 3.97 Impact Factor
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ABSTRACT: Ghrelin increases food intake, body weight, and growth hormone (GH) secretion. Serum concentrations of ghrelin are low in obese hyperinsulinemic persons, are reduced by infusion of insulin into normal-weight subjects, and are increased in underweight hypoinsulinemic patients with anorexia nervosa. Laron syndrome is an autosomal recessive disorder of GH insensitivity that results in decreased insulinlike growth factor-I (IGF-I) synthesis and growth failure. These patients have elevated GH levels, excess adipose tissue, and are insulin resistant. Because IGF-I has insulinlike actions and patients with GH insensitivity syndrome (GHIS) exhibit excess adiposity, we sought to determine whether ghrelin levels were elevated in these patients and potentially regulated by IGF-I replacement.
Thirteen children with GHIS and 20 normal control children matched for age, sex, and body mass index underwent complete physical examination and a fasting blood draw at baseline. The GHIS subjects then underwent follow-up fasting blood draws during therapy with human recombinant IGF-I (80-120 mug/kg, given subcutaneously twice daily). Fasting glucose, insulin, and IGF-I concentrations were measured at the time of collection. Fasting total ghrelin levels were measured on stored serum samples.
The GHIS subjects had 2-fold higher fasting ghrelin levels (2926 +/- 1869 pg/mL) compared with the normal control children (1492 +/- 493 pg/mL; P = 0.009), and mean ghrelin values were reduced 56% during 6.4 +/- 0.2 years of IGF-I replacement (P < 0.05).
Growth hormone resistance and low IGF-I levels are associated with elevated ghrelin levels, which may potentiate GH secretion and adiposity in these children. Suppression of ghrelin during IGF-I treatment suggests a novel mechanism potentially regulating ghrelin levels.
Journal of Investigative Medicine 02/2008; 56(1):26-31. · 1.96 Impact Factor
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ABSTRACT: Prader-Willi syndrome (PWS) is a genetic syndrome characterized by relative hypoinsulinaemia and normal or increased insulin sensitivity despite profound obesity. We hypothesized that this increased insulin sensitivity is mediated by increased levels of total and high molecular weight adiponectin and associated with changes in levels of satiety hormones.
We measured total adiponectin and its isoforms [high molecular weight (HMW), middle molecular weight (MMW) and low molecular weight (LMW) adiponectin] and satiety hormones in 14 children with PWS [median age 11.35 years, body mass index (BMI) Z-score 2.15] and 14 BMI-matched controls (median age 11.97 years, BMI Z-score 2.34).
Despite comparable BMI Z-scores and leptin levels, the PWS children exhibited lower fasting insulin and HOMA-IR (homeostasis model assessment of insulin resistance) scores compared to obese controls. For any given BMI Z-score, the PWS children showed higher concentrations of fasting total and HMW adiponectin and higher HMW/total adiponectin ratios. The HMW/total adioponectin ratio was preserved in children with PWS at high degrees of obesity. In PWS children, fasting plasma total adiponectin, HMW adiponectin and HMW/total adiponectin ratio correlated negatively with age (P < 0.05), HOMA-IR (P < 0.01), BMI Z-score (P < 0.05), insulin (P < 0.01) and leptin (P < 0.05). In addition to higher fasting ghrelin concentrations, the PWS children showed significantly higher fasting levels of total peptide YY (PYY) and gastric inhibitory polypeptide (GIP) compared to obese controls.
Relative to controls of similar age and BMI Z-score, the PWS children had significantly higher levels of total and HMW adiponectin, and increased ratios of HMW/total adiponectin. These findings may explain in part the heightened insulin sensitivity of PWS children relative to BMI-matched controls.
Clinical Endocrinology 12/2007; 67(6):944-51. · 3.17 Impact Factor
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ABSTRACT: In the year 2000, multiple global health agencies and stakeholders convened and established eight tenets that, if followed, would make our world a vastly better place. These tenets are called the Millennium Development Goals. Most of these goals are either directly or indirectly related to nutrition. The United Nations has led an evaluation team to monitor and assess the progress toward achieving these goals until 2015. We are midway between when the goals were set and the year 2015. The first goal is to "eradicate extreme poverty and hunger." Our greatest responsibility as nutrition professionals is to understand the ramifications of poverty, chronic hunger, and food insecurity. Food insecurity is complex, and the paradox is that not only can it lead to undernutrition and recurring hunger, but also to overnutrition, which can lead to overweight and obesity. It is estimated that by the year 2015 noncommunicable diseases associated with overnutrition will surpass undernutrition as the leading causes of death in low-income communities. Therefore, we need to take heed of the double burden of malnutrition caused by poverty, hunger, and food insecurity. Informing current practitioners, educators, and policymakers and passing this information on to future generations of nutrition students is of paramount importance.
Journal of the American Dietetic Association 12/2007; 107(11):1966-72. · 3.59 Impact Factor
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ABSTRACT: The incidence of overweight and obesity is increasing among children with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or mitochondrial trifunctional (TFP) deficiency. Traditional treatment includes fasting avoidance and consumption of a low-fat, high-carbohydrate diet. A diet higher in protein and lower in carbohydrate may help to lower total energy intake while maintaining good metabolic control. To determine the short-term safety and efficacy of a high protein diet, subjects were admitted to the General Clinical Research Center and fed an ad-libitum high-protein diet and a high-carbohydrate diet for 6 days each using a randomized, crossover design. Nine subjects with LCHAD or TFP deficiency, age 7-14 were enrolled. Body composition was determined by DEXA. Total energy intake was evaluated daily. Resting energy expenditure and substrate utilization were determined by indirect calorimetry. Post-prandial metabolic responses of plasma glucose, insulin, leptin, ghrelin, acylcarnitines, and triglyceride were determined in response to a liquid meal. Subjects had a higher fat mass, lower lean mass and higher plasma leptin levels compared to reference values. While on the high protein diet energy consumption was an average of 50 kcals/day lower (p = 0.02) and resting energy expenditure was an average of 170 kcals/day higher (p = 0.05) compared to the high carbohydrate diet. Short-term higher protein diets were safe, well tolerated, and resulted in lowered energy intake and increased energy expenditure than the standard high-carbohydrate diet. Long-term studies are needed to determine whether higher protein diets will reduce the risk of overweight and obesity in children with LCHAD or TFP deficiency.
Molecular Genetics and Metabolism 02/2007; 90(1):64-9. · 3.19 Impact Factor
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Andrea M Haqq,
Lillian F Lien,
Jarol Boan,
Michelle Arlotto,
Cris A Slentz,
Michael J Muehlbauer,
James Rochon,
Dianne Gallup,
Ross L McMahon,
James R Bain,
Robert Stevens,
David Millington,
Mark D Butler,
Christopher B Newgard,
Laura P Svetkey
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ABSTRACT: This paper outlines the rationale and design of the Study of the Effects of Diet on Metabolism and Nutrition (STEDMAN) weight loss project, in which detailed biologic profiling of three hundred and fifty obese individuals (body mass index (BMI): 30-50 kg/m(2)) will be conducted as they lose weight via seven distinct interventions. These profiles will be compared to those of fifty normal, healthy, control participants (BMI: 18.5-24.9 kg/m(2)). The interventions include the following: Roux-en-Y gastric bypass surgery, dietary interventions of differing macronutrient composition and diverse pharmacologic interventions. Outcome variables include eight conventional metabolites and CRP measured by standard clinical chemistry techniques, twenty hormones of energy balance and fuel homeostasis measured by radioimmunoassay (RIA) or by enzyme-linked Immunosorbent assay (ELISA), ten pro- and anti-inflammatory cytokines measured using Luminex xMAP technology, one hundred and one intermediary metabolites measured by targeted mass-spectrometry-based methods, and physiologic variables such as body composition measured by dual energy X-ray absorptiometry (DEXA), air displacement plethysmography, and abdominal computerized tomography (CT), insulin sensitivity measured by intravenous glucose tolerance test (IV-GTT) and metabolic rate measured by indirect calorimetry. Results from this study will expand our knowledge of the biology of obesity and weight regulation and may lead to targeted strategies for its treatment and control.
Contemporary Clinical Trials 01/2006; 26(6):616-25. · 1.81 Impact Factor
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ABSTRACT: The gene dosage effect of the MC4-R (melanocortin 4 receptor) on obesity suggests that regulation of MC4-R expression and function is critically important to the central control of energy homoeostasis. In order to identify putative MC4-R regulatory proteins, we performed a yeast two-hybrid screen of a mouse brain cDNA library using the mouse MC4-R intracellular tail (residues 303-332) as bait. We report here on one positive clone that shares 63% amino acid identity with the C-terminal part of the mouse attractin gene product, a single-transmembrane-domain protein characterized as being required for agouti signalling through the melanocortin 1 receptor. We confirmed a direct interaction between this ALP (attractin-like protein) and the C-terminus of the mouse MC4-R by glutathione S-transferase pulldown experiments, and mapped the regions involved in this interaction using N- and C-terminal truncation constructs; residues 303-313 in MC4-R and residues 1280-1317 in ALP are required for binding. ALP is highly expressed in brain, but also in heart, lung, kidney and liver. Furthermore, co-localization analyses in mice showed co-expression of ALP in cells expressing MC4-R in a number of regions known to be important in the regulation of energy homoeostasis by melanocortins, such as the paraventricular nucleus of hypothalamus and the dorsal motor nucleus of the vagus.
Biochemical Journal 01/2004; 376(Pt 3):595-605. · 4.90 Impact Factor
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ABSTRACT: Prader-Willi syndrome (PWS) is characterized by severe obesity, hyperphagia, hypogonadism, and GH deficiency. Unlike individuals with common obesity, who have low fasting-plasma ghrelin concentrations, those with PWS have high fasting-ghrelin concentrations that might contribute to their hyperphagia. Treatment with octreotide, a somatostatin agonist, decreases ghrelin concentrations in healthy and acromegalic adults and induces weight loss in children with hypothalamic obesity. This pilot study was performed to determine whether octreotide administration (5 microg/kg.d) for 5-7 d lowers ghrelin concentrations and affects body composition, resting energy expenditure, and GH markers in children with PWS. Octreotide treatment decreased mean fasting plasma ghrelin concentration by 67% (P < 0.05). Meal-related ghrelin suppression (-35%; P < 0.001) was still present after intervention but was blunted (-11%; P = 0.19). Body weight, body composition, leptin, insulin, resting energy expenditure, and GH parameters did not change. However, one subject's parent noted fewer tantrums over denial of food during octreotide intervention. In conclusion, short-term octreotide treatment markedly decreased fasting ghrelin concentrations in children with PWS but did not fully ablate the normal meal-related suppression of ghrelin. Further investigation is warranted to determine whether long-term octreotide treatment causes sustained ghrelin suppression, changes eating behavior, and induces weight loss in this population.
Journal of Clinical Endocrinology & Metabolism 08/2003; 88(8):3573-6. · 6.50 Impact Factor
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ABSTRACT: The objective of this study was to investigate the effects of GH administration on pulmonary function, sleep, behavior, cognition, linear growth velocity, body composition, and resting energy expenditure (REE) in children with Prader-Willi syndrome. The study used a 12-month, balanced, randomized, double-blind, placebo-controlled, cross-over experimental design. Twelve subjects were randomized to GH (0.043 mg/kg x d) or placebo intervention for 6 months and then crossed over to the alternate intervention for 6 months. Differences in outcome variables were determined by paired t tests. Peak flow rate, percentage vital capacity, and forced expiratory flow rate improved and number of hypopnea and apnea events and duration of apnea events trended toward improvement after GH intervention. The only difference in cognition or behavior was an increase in hyperactivity scale on the Behavior Assessment System for Children after GH intervention. Linear growth velocity, REE, and lean mass were higher (67%, 19%, and 7.6%, respectively), and fat mass and percentage body fat were lower (10.3% and 8.1%, respectively) after GH intervention. GH administration did not change mean fasting ghrelin concentration. GH intervention improved body composition and REE and may contribute to better sleep quality and pulmonary function. GH administration did not impact fasting ghrelin concentration.
Journal of Clinical Endocrinology & Metabolism 06/2003; 88(5):2206-12. · 6.50 Impact Factor
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ABSTRACT: Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5-15) and body mass index (BMI) of 31.3 kg/m2 (range, 22-46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r = 0.36, P = 0.007), insulin (r = 0.55, P < 0.001), and BMI (r = 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean +/- SD; 429 +/- 374 vs. 270 +/- 102 pmol/liter; P = 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3- to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean +/- SD; 429 +/- 374 vs. 139 +/- 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3- to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.
Journal of Clinical Endocrinology & Metabolism 01/2003; 88(1):174-8. · 6.50 Impact Factor
