Metabolomics allows the discrimination of the pathophysiological relevance of hyperinsulinism in obese prepubertal children.

BACKGROUND/OBJECTIVES: Insulin resistance (IR) is the cornerstone of the obesity-associated metabolic derangements observed in obese children. Targeted metabolomics was employed to explore the pathophysiological relevance of hyperinsulinemia in childhood obesity in order to identify biomarkers of IR with potential clinical application. SUBJECTS/METHODS: One hundred prepubertal obese children (50 girls/50 boys, 50% IR and 50% non-IR in each group), underwent an oral glucose tolerance test for usual carbohydrate and lipid metabolism determinations. Fasting serum leptin, total and high molecular weight-adiponectin and high-sensitivity C-reactive protein (CRP) levels were measured and the metabolites showing significant differences between IR and non-IR groups in a previous metabolomics study were quantified. Enrichment of metabolic pathways (quantitative enrichment analysis) and the correlations between lipid and carbohydrate metabolism parameters, adipokines and serum metabolites were investigated, with their discriminatory capacity being evaluated by receiver operating characteristic (ROC) analysis. RESULTS: Twenty-three metabolite sets were enriched in the serum metabolome of IR obese children (P<0.05, false discovery rate (FDR)<5%). The urea cycle, alanine metabolism and glucose-alanine cycle were the most significantly enriched pathways (PFDR<0.00005). The high correlation between metabolites related to fatty acid oxidation and amino acids (mainly branched chain and aromatic amino acids) pointed to the possible contribution of mitochondrial dysfunction in IR. The degree of body mass index-standard deviation score (BMI-SDS) excess did not correlate with any of the metabolomic components studied. In the ROC analysis, the combination of leptin and alanine showed a high IR discrimination value in the whole cohort (area under curve, AUCALL=0.87), as well as in boys (AUCM=0.84) and girls (AUCF=0.91) when considered separately. However, the specific metabolite/adipokine combinations with highest sensitivity were different between the sexes. CONCLUSIONS: Combined sets of metabolic, adipokine and metabolomic parameters can identify pathophysiological relevant IR in a single fasting sample, suggesting a potential application of metabolomic analysis in clinical practice to better identify children at risk without using invasive protocols.

Insulin resistance in prepubertal obese children correlates with sex-dependent early onset metabolomic alterations.

BACKGROUND: Insulin resistance (IR) is usually the first metabolic alteration diagnosed in obese children and the key risk factor for development of comorbidities. The factors determining whether or not IR develops as a result of excess body mass index (BMI) are still not completely understood. OBJECTIVES: This study aimed to elucidate the mechanisms underpinning the predisposition toward hyperinsulinemia-related complications in obese children by using a metabolomic strategy that allows a profound interpretation of metabolic profiles potentially affected by IR. METHODS: Serum from 60 prepubertal obese children (30 girls/30 boys, 50% IR and 50% non-IR in each group, but with similar BMIs) were analyzed by using liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry and capillary electrophoresis-mass spectrometry following an untargeted metabolomics approach. Validation was then performed on a group of 100 additional children with the same characteristics. RESULTS: When obese children with and without IR were compared, 47 metabolites out of 818 compounds (P<0.05) obtained after data pre-processing were found to be significantly different. Bile acids exhibit the greatest changes (that is, approximately a 90% increase in IR). The majority of metabolites differing between groups were lysophospholipids (15) and amino acids (17), indicating inflammation and central carbon metabolism as the most altered processes in impaired insulin signaling. Multivariate analysis (OPLS-DA models) showed subtle differences between groups that were magnified when females were analyzed alone. CONCLUSIONS: Inflammation and central carbon metabolism, together with the contribution of the gut microbiota, are the most altered processes in obese children with impaired insulin signaling in a sex-specific fashion despite their prepubertal status.

Serum visfatin and vaspin levels in prepubertal children: effect of obesity and weight loss after behavior modifications on their secretion and relationship with glucose metabolism.

OBJECTIVE: To investigate the impact of obesity, weight loss and oral glucose ingestion on serum visfatin and vaspin levels in prepubertal children. SUBJECTS AND METHODS: A total of 100 prepubertal obese Caucasian children (OB) and 42 controls (C) were studied. The OB group was studied at baseline and after moderate (n=46) and extensive (n=14) body mass index (BMI) reduction by conservative treatment, undergoing body composition studies (dual-energy X-ray absorptiometry) and oral glucose tolerance tests (OGTTs). Serum visfatin and vaspin levels were studied throughout the OGTT, as were their relationships with insulin, leptin, leptin soluble receptor (sOB-R), adiponectin (total and high molecular weight), resistin, interleukin-6 (IL-6) and tumor necrosis factor-α levels at every time point. RESULTS: OB had higher visfatin (P<0.001), but similar vaspin than C. BMI reduction decreased visfatin levels (P<0.001), with BMI, waist circumference and the surrogate markers of body fat (leptin and sOB-R) showing significant correlations (P<0.05) with this peptide, but not with vaspin. Visfatin and vaspin decreased during the OGTT (P<0.001). Weight reduction did not alter visfatin dynamics in the OGTT, but decreased the area under the curve (AUC) for vaspin (P<0.001), with a correlation between the AUCs for vaspin and insulin after weight loss (P<0.05). Visfatin levels were positively correlated with resistin and IL-6, after controlling for BMI and HOMA (homeostatic model assessment) index at every time point in the study. CONCLUSION: Serum visfatin, but not vaspin, levels are influenced by body fat content in obese children, whereas both adipokines are modulated by glucose intake in a BMI-dependent manner.

Acylated ghrelin levels in pre-pubertal obese children at diagnosis and after weight reduction: effect of oral glucose ingestion.

BACKGROUND: Ghrelin isoforms are involved in energy homeostasis and carbohydrate metabolism. AIM: To determine the influence of oral glucose ingestion and weight reduction on acylated ghrelin (AG) serum levels and on the AG to total ghrelin (TG) ratio (AG/TGr) in obese pre-pubertal children. SUBJECTS AND METHODS: Seventy obese children were studied at diagnosis (D) and after reduction of their body mass index (BMI) of over 1 (-1; no.=51) and 2 SD score (-2; no.=21). Body composition was analyzed and serum levels of glucose, insulin, TG and AG, and the AG/TGr were determined at every time-point in an oral glucose tolerance test (OGTT) at D and at -2. The control group consisted of 32 lean children. RESULTS: At D AG and TG levels were lower in obese children and negatively correlated with BMI. TG levels were negatively correlated with the homeostasis model assessment (HOMA) index in the whole cohort, as with the body fat content (BFC) in the obese patients. Weight loss exclusively reduced BFC and improved HOMA, increasing AG transiently and TG sustainedly, with AG/TGr exclusively decreasing at -2. Glucose ingestion caused a sustained increase in AG and decrease in TG, thus increasing the AG/TGr throughout the entire OGTT; this remained unaltered after weight reduction. CONCLUSIONS: TG and AG levels are influenced by BMI, showing an impairment in childhood obesity that can be improved through weight loss. The different fractions of ghrelin appear to play different roles in carbohydrate metabolism and the calculation of AG/TGr could be useful in the follow up of childhood obesity.

Effect of recombinant growth hormone on leptin, adiponectin, resistin, interleukin-6, tumor necrosis factor-α and ghrelin levels in growth hormone-deficient children.

BACKGROUND: Treatment with GH promotes linear growth and decreases body fat in patients with isolated GH deficiency (GHD). However, few studies have analyzed how GH replacement modifies ghrelin levels and the adipokine profile and the relationship of these modifications with the metabolic changes. AIMS: To analyze the eventual differences between serum levels of leptin, leptin soluble receptor (sOBR), resistin, adiponectin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), total (TG) and acylated ghrelin (AG) and lipid and glycemic profiles in children with GHD, as well as to determine the effect of GH replacement on these parameters during the first year of therapy. SUBJECTS AND METHODS: Thirty pre-pubertal (Tanner stage I) GHD children and 30 matched controls were enrolled. Children with GHD were studied before and after 6 and 12 months of GH treatment. Weight, height, BMI, fasting glucose, insulin, lipid profile and serum levels of adipokines and ghrelin were studied at every visit. Adi - pokines, insulin and ghrelin levels were determined by using commercial radio- and enzymoimmunoassays. RESULTS: At baseline children with GHD had significantly higher sOBR (p<0.01) and adiponectin (p<0.01) levels than controls. Treatment with GH resulted in a decline in leptin (p<0.05) and TG (p<0.001) levels, an increase of homeostasis model assessment index and restored IGF-I levels (p<0.001). CONCLUSIONS: These data indicate that GH replacement has a negative effect on leptin levels and may also produce a slight unfavorable effect on carbohydrate metabolism. In addition, the changes observed in the adipokine profile appear to be independent of body mass index.

A novel approach to childhood obesity: circulating chemokines and growth factors as biomarkers of insulin resistance.

BACKGROUND: Insulin resistance (IR) in children with obesity constitutes a risk factor that should be precisely diagnosed to prevent further comorbidities. OBJECTIVE: Chemokines were evaluated to identify novel predictors of IR with clinical application. METHODS: We analysed the levels of cytokines (tumour necrosis factor [TNF] α and interleukins [ILs] 1ß, 4, 6 and 10), chemokines (stromal cell derived factor 1α, monocyte chemoattract protein [MCP] 1, eotaxin and fractalkine) and growth factors (brain-derived neurotrophic factor, pro-fibrotic platelet-derived growth factor [PDGF-BB] and insulin-like growth factor 1) in serum of prepubertal children with obesity (61 girls/59 boys, 50% IR and 50% non-IR) and 32 controls. Factor analysis, correlation, binary logistic regression and receiver operating characteristic analysis of combined biomarkers were used to validate their capability for preventive interventions of IR. RESULTS: Changes in MCP1, eotaxin, IL1ß and PDGF-BB were observed in IR children with obesity. Bivariate correlation between stromal cell derived factor 1α, MCP1, eotaxin, TNFα, brain-derived neurotrophic factor and/or PDGF-BB explained the high variance (65.9%) defined by three components related to inflammation and growth that contribute towards IR. The combination of leptin, triglyceride/high-density lipoprotein, insulin-like growth factor 1, TNFα, MCP1 and PDGF-BB showed a sensitivity and specificity of 93.2% for the identification of IR. The percentage of correct predictions was 89.6. CONCLUSIONS: Combined set of cytokines, adipokines and chemokines constitutes a model that predicts IR, suggesting a potential application in clinical practice as biomarkers to identify children with obesity and hyperinsulinaemia.

[Familial hypobetalipoproteinemia secondary to a mutation in the apolipoprotein B gene]. / Hipobetalipoproteinemia familiar secundaria a mutación en el gen de la apolipoproteína B.

Familial hypobetalipoproteinemia (FHB) is a rare genetically heterogeneous disorder provoking abnormally low serum levels of apoprotein (apo) B, total cholesterol, and low-density lipoprotein (LDL-C). Patients carrying heterozygous mutations in the APOB (2p24) gene are usually asymptomatic, but homozygous mutations cause clinical disturbances as a result of intestinal fat malabsorption and fat-soluble vitamin deficiency. We present an asymptomatic boy, aged 8 years and 7 months, with low serum levels of apo-B, total cholesterol, triglyceride, LDL-C and very low-density lipoprotein (VLDL-C), as well as vitamin E deficiency. Three asymptomatic relatives also exhibited low apo-B, total cholesterol and LDL-C levels. The APOB (2p24) gene was fully sequenced, demonstrating a heterozygous mutation in exon 26 (G --> T) in all four members of this family. Familial genetic studies in FHB could be useful in the early detection and treatment of homozygous carriers.

[Transitory neonatal diabetes mellitus and pericentric chromosome 9 inversion]. / Diabetes mellitus neonatal transitoria e inversión pericéntrica del cromosoma 9.

Neonatal diabetes mellitus is an infrequent carbohydrate metabolism disorder with an estimated incidence of approximately one case every 400,000 to 600,000 live newborns. We present the case of a 1-month-old girl with irritability, polyuria, and a 24-h history of eagerness to feed, without fever or other associated symptoms. The patient's karyotype, obtained by amniocentesis, was 46XX with a pericentric chromosome 9 inversion. Her birth weight and length were 2,230 g (-2.65 SD) and 46 cm (-1.8 SD), respectively. Glycemic determinations during the first 72 h of extrauterine life oscillated between 90 and 157 mg/dl. Physical examination revealed general involvement, skin and mucosal pallor, evident signs of dehydration, and impaired awareness. Laboratory tests revealed glycemia: 1552 mg/dL, pH 7.16, pCO2: 23.7 mmHg; bicarbonate: 8.1 mEq/L, base excess: -19.1, and positive ketonemia. After initial stabilization, the patient was treated with intravenous fluids and continuous intravenous regular insulin infusion (initial dose 0.03-0.05 IU/kg/h). After intensive treatment, breast feeding was restored and a short-acting insulin analog was administered subcutaneously after every feed (0.1 to 0.3 IU according to capillary glycemic determinations). Insulin requirements decreased and were discontinued when the infant was 5 months old. Currently, the patient is 2 years and 7 months old and her glycemia and glycosylated hemoglobin levels are normal. Anti-islet (ICA and GAD) and anti-tyrosin phosphatase (IA2) antibodies were absent, as were mutations in the glucokinase gene (GCK).

[Phenotypic and genetic features in neurofibromatosis type 1 in children]. / Características fenotípicas y genéticas en la neurofibromatosis tipo 1 en edad pediátrica.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disease, nevertheless the number of publications providing clinical and genetic data from a significant number of children is limited. MATERIAL AND METHODS: The available clinical, epidemiological, radiological and genetic data from 239 children with NF1, who attended at a specialist NF1 clinic between January 2011 and December 2013 were recorded. RESULTS: All the 239 patients had a clinical and/or genetic diagnosis of NF1. The mean age at diagnosis was 2.65±2.85 years. In our series 99.6% met the diagnostic criteria of café au lait spots, 93.7% those of axillary and inguinal freckling, 7.1% showed typical bone lesion, 38.1% neurofibromas, 23% plexiform neurofibromas, 31.4% optic pathway glioma, Lisch nodules were present in 43.1%, and 28% patients had a first degree relative affected with NF1. The NF1 genetic study was performed in 86 patients, and a description of the gene mutations found in 72 of them is presented. Furthermore, other clinical data previously associated with NF1, either because of their frequency or their severity, are detailed. CONCLUSIONS: The difficulty for clinical diagnosis of NF1 early ages is still evident. Although, the need for further studies in asymptomatic patients is discussed, cranial MRI in children with NF1 may be helpful in the clinical diagnosis, given the high frequency of optic glioma observed in this cohort.

[Endocrinological outcome in children and adolescents survivors of central nervous system tumours after a 5 year follow-up]. / Secuelas endocrinológicas en niños y adolescentes supervivientes de tumores del sistema nervioso central tras 5 años de seguimiento.

INTRODUCTION: Given the successful increase in survival rates with the current treatments for central nervous system tumours (CNST), survivors are at high risk for late adverse effects. PURPOSE: To evaluate the endocrine sequelae in children with CNST according to the type of tumour and treatment received. PATIENTS AND METHODS: A retrospective review of the clinical features, auxology, hormone determinations and imaging findings of 38 patients (36.8% females, 63.2% males) with CNST, with a minimum of 5 years follow-up, was performed. RESULTS: The mean age at diagnosis was 5.34 ± 3.07 years, with 76.3% of the patients having at least one hormone deficiency, of which growth hormone (GH) (73.7% of all patients) was the most prevalent, followed by thyrotropin (TSH) (68.4%), corticotropin (31.6%), antidiuretic hormone (28.9%), and gonadotropin (LH/FSH) (21.1%) deficiency. Precocious puberty was found in 21.1% of patients. After 5 years of follow-up, 28.9% were obese. Craniopharyngioma had more hormone deficiencies, obesity and recurrence rates. The most frequently administered treatment was surgery + chemotherapy + radiotherapy, in 47.4% of the patients. Mean final height (20 patients) was -1.2 1.6 SDS, with a mean difference of -0.53 SDS regarding their target height. CONCLUSIONS: 1) The type of tumour and treatment received influence the endocrinological sequelae. 2) The most frequent hormone deficiencies in all types of CNST, regardless of the treatment received, were GH and TSH. 3) Early diagnosis and prompt intervention of endocrine dysfunction can reduce the morbidity and improve quality of life over the long term.

[Adrenal tumours in childhood]. / Tumores suprarrenales en la infancia.

This special article aims to summarise the current knowledge regarding the two groups of tumours with their origin in the adrenal gland: 1) adrenocortical tumours, derived from the cortex of the adrenal gland and 2) phaeochromocytomas and paragangliomas, neuroendocrine tumours derived from nodes of neural crest derived cells symmetrically distributed at both sides of the entire spine (paragangliomas [PG]). These PGs can be functioning tumors that secrete catecholamines, which confers their typical dark colour after staining with chromium salts (chromaffin tumors). Among these, the term phaeochromocytoma (PC) is restricted to those PGs derived from the chromaffin cells in the adrenal medulla (intra-adrenal PGs), whereas the term PG is used for those sympathetic or parasympathetic ones in an extra-adrenal location. We analyse the state of the art of their pathogenic and genetic bases, as well as their clinical signs and symptoms, the tests currently available for performing their diagnosis (biochemical, hormonal, imaging and molecular studies) and management (surgery, pre- and post-surgical medical treatment), considering the current and developing strategies in chemo- and radiotherapy.

[Adipokines in healthy and obese children]. / Adipoquinas en el niño sano y con obesidad.

The worldwide increase in the prevalence of obesity in children and adolescents during the last decades, as well as the mounting evidence indicating that obesity is associated with an increased incidence of comorbidities and the risk of premature death, resulting in a high economic impact, has stimulated obesity focused research. These studies have highlighted the prominent endocrine activity of adipose tissue, which is exerted through the synthesis and secretion of a wide variety of peptides and cytokines, called adipokines. This review presents a summary of the current knowledge and most relevant studies of adipokine dynamics and actions in children, focusing on the control of energy homeostasis, metabolic regulation (particularly carbohydrate metabolism), and inflammation. The particularities of adipose secretion and actions in healthy children, from birth to adolescence, and the modifications induced by early onset obesity are highlighted.

[Blood cell chimerism in dizygotic twins conceived by in vitro fertilization]. / Quimerismo hemático en gemelos dicigóticos concebidos por fertilización in vitro.

We present a case of hematopoietic chimerism in dizygotic twins (male and female) conceived by in vitro fertilization (IVF). At 8 years of age a blood karyotype was performed on the female due to the presence of clitoromegaly. Two different lines: 46,XX (53%) and 46,XY (47%) were found. FISH studies confirmed the presence of the SRY gene in 46,XY cells. Karyotyping of the male showed two different lines: 46,XY (58%) and 46,XX (42%). SRY gene was present in 46,XY cells. Microsatellite analyses of blood DNA revealed tetra-allelic contribution at some autosomal loci with similar proportions of maternal and paternal alleles and X/Y chromosome dose. FISH in buccal mucous showed that all cells from the female were 46,XX and those from the male 46,XY. The gonadal karyotype in the female was 46,XX without SRY. Hence, we report 46,XX/46,XY chimerism in dizygotic twins. Blood chimerism was confirmed by performing FISH on the buccal cells of the patients.

[Anatomical heterogeneity in the proteome of human subcutaneous adipose tissue]. / El proteoma del tejido adiposo subcutáneo muestra heterogeneidad anatómica.

BACKGROUND: Human subcutaneous (SQ) white adipose tissue (WAT) can vary according to its anatomical location, with subsequent differences in its proteomic profile. PATIENTS AND METHODS: SQ-WAT aspirates were obtained from six overweight (BMI>25kg/m(2)) women who underwent extensive liposuction. SQ-WAT was removed from six different locations (upper abdominal, lower abdominal, thigh, back, flank, and hip), and the protein profiles were determined by two-dimensional gel electrophoresis. In addition, the proteomic profiles of upper abdominal and hip SQ-WAT were subjected to further analysis, comparing samples obtained from two layers of WAT (deep and superficial). RESULTS: Twenty one protein spots showed differential intensities among the six defined anatomical locations, and 14 between the superficial and the deep layer. Among the proteins identified were, vimentin (structural protein), heat-shock proteins (HSPs), superoxide-dismutase (stress-resistance/chaperones), fatty-acid-binding protein (FABP) 4, and alpha-enolase (lipid and carbohydrate metabolism), and ATP-synthase (energy production). Among the WAT samples analyzed, the back sub-depot showed significant differences in the levels of selected proteins when compared to the other locations, with lower level of expression of several proteins involved in energy production and metabolism (ATP-synthase, alpha-enolase, HSPs and FABP-4). CONCLUSIONS: The levels of several proteins in human SQ-WAT are not homogeneous between different WAT depots. These changes suggest the existence of inherent functional differences in subcutaneous fat depending upon its anatomical location. Thus, caution must be used when extrapolating data from one subcutaneous WAT region to other depots.

[Paediatric obesities: from childhood to adolescence]. / Obesidades pediátricas: de la lactancia a la adolescencia.

Obesity, as in every western country, is currently the most prevalent chronic disease in childhood in Spain. This has led to obesity being one of the most common consultations in general paediatrics and, particularly, in paediatric endocrinology. Furthermore, obesity associated comorbidities are increasing in prevalence in children and adolescents. It is widely accepted that this increase in the prevalence of obesity is derived from an imbalance between energy intake and expenditure, associated to the lifestyle in western countries. However, there is increasing evidence of the role of individual and familial genetic background in the risk of developing obesity. The pathophysiological basis of the mechanisms responsible for the control of appetite and energy expenditure are being discovered on the basis of the increasing known cases of human monogenic, syndromic and endocrine obesity. Thus it is no longer appropriate to talk about obesity but rather about «obesities¼, as their pathophysiological bases differ and they require different diagnostic and management approaches. In 2011, the paediatrician must be aware of this issue and focus the clinical history and physical examination towards these specific clinical sign and symptoms, to better manage the available diagnostic and therapeutic resources when faced with a child with obesity.

[Analysis of insulin and cytokines during development using a multiplexed immunoassay: implications in pediatrics]. / Determinación de insulina y citocinas durante el desarrollo mediante inmunoensayo múltiple: implicaciones en pediatría.

INTRODUCTION: Multiplexed immunoassays allow the simultaneous determination of multiple parameters from minute biological samples. Our aim was to establish the normal values of cytokines and insulin during pubertal development, as well as their relationship with adrenal and gonadal steroids. SUBJECTS AND METHODS: Serum insulin, adiponectin, resistin, leptin, tumoral necrosis factor-α, interleukin-1ß, interleukin-6 and interleukin-8 concentrations were studied in 147 healthy children (Tanner I, 18 males and 18 females; Tanner II, 17 males and 13 females; Tanner III and IV, 21 males and 19 females and Tanner V, 18 males and 23 females). The relationship of these parameters with free and total testosterone, estradiol, sex-hormone binding globulin, 17-hydroxyprogesterone, dehydroepiandrosterone sulphate, 3α-androstanediol glucuronide and Δ4-androstenedione levels were also analyzed. RESULTS: The concentrations of insulin, resistin and leptin increased during development, with higher levels found in females. Adiponectin levels did not change, although higher concentrations were also observed in females than in males. Interleukin-6 and 8 increased and interleukin-1ß levels decreased throughout development, without any evidence of sexual dimorphism. There are good correlations between adiponectin and sex-hormone binding globulin, as well as between leptin and Δ4-androstenedione. CONCLUSIONS: Changes in these parameters seem to be related with adrenal and gonadal function. Pubertal stage and sex must be taken into consideration when these data are used.

Metabolic signals in human puberty: effects of over and undernutrition.

Puberty in mammals is associated with important physical and psychological changes due to the increase in sex steroids and growth hormone (GH). Indeed, an increase in growth velocity and the attainment of sexual maturity for future reproductive function are the hallmark changes during this stage of life. Both growth and reproduction consume high levels of energy, requiring suitable energy stores to face these physiological functions. During the last two decades our knowledge concerning how peptides produced in the digestive tract (in charge of energy intake) and in adipose tissue (in charge of energy storage) provide information regarding metabolic status to the central nervous system (CNS) has increased dramatically. Moreover, these peptides have been shown to play an important role in modulating the gonadotropic axis with their absence or an imbalance in their secretion being able to disturb pubertal onset or progression. In this article we will review the current knowledge concerning the role played by leptin, the key adipokine in energy homeostasis, and ghrelin, the only orexigenic and growth-promoting peptide produced by the digestive tract, on sexual development. The normal evolutionary pattern of these peripherally produced metabolic signals throughout human puberty will be summarized. The effect of two opposite situations of chronic malnutrition, obesity and anorexia, on these signals and how they influence the course of puberty will also be discussed. Finally, we will briefly mention other peptides derived from the digestive tract (such as PYY) that may be involved in the regulatory link between energy homeostasis and sexual development.