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2p25.3 deletion syndrome is a rare genetic disorder that accompanies various phenotypic features, including early‐onset obesity and intellectual disability. Here, we report the first Japanese case of this deletion associated with severe obesity and diabetes mellitus. Microarray‐based comparative genomic hybridization analysis identified a 3.1‐Mb deletion of distal chromosome band 2p25.3, which was suspected as de novo. The patient also presented bilateral cataracts and adolescent‐onset muscular weakness of the upper limbs, both of which were uncommon in previously reported cases. It is possible that these symptoms are also important clinical features suggestive of this syndrome.

Background Severe early-onset obesity (SEOO) in children is a common feature of monogenic obesity. Gene defects of the leptin-melanocortin pathway can be analysed biochemically and genetically. The aim of this study was to search for children with leptin deficiency or biologically inactive leptin in a cohort of children with SEOO and to study associations between leptin parameters and anthropometric data. Methods The cohort included n = 50 children with SEOO (22 boys) who were recruited at one of four study centres (Germany: Ulm; Poland: Katowice, Szczecin, Rzeszow) between October 2015 and October 2017. Weight (kg) and height (m) were measured, Tanner stage was obtained and a fasting serum blood sample was taken. Serum levels of total leptin (LEP, ng/mL), biologically active leptin (bioLEP, ng/mL) and soluble leptin receptor (sLEPR, ng/mL) were measured. The body mass index (BMI [kg/m2]), BMI z-score (World Health Organization [WHO]), quotient of bioLEP/LEP and leptin-standard deviation score (LEP-SDS) (Tanner stage, BMI and sex-adjusted) were calculated. Results We did not find any child with leptin deficiency or biologically inactive leptin in our cohort. The serum LEP and bioLEP levels were strongly correlated with age (r = 0.50, p 0.05) as well as lower LEP-SDS than boys (−1.77 ± 2.61 vs. −1.40 ± 2.60, p > 0.05). sLEPR levels were negatively correlated with BMI values (r = −0.44; p Conclusions In this cohort with SEOO, we identified no new cases of children with leptin deficiency or bioinactive leptin. A strong negative correlation between the LEP-SDS and BMI values could be interpreted as relative leptin deficiency in children with SEOO. In case this hypothesis can be confirmed, these children would benefit from a substitution therapy with methionyl human leptin (metreleptin™).

Background Leukocyte telomere length (LTL) is associated with obesity and obesity-related traits, and there are ethnic-specific determinants of LTL. Objective To evaluate LTL associations with obesity and metabolic parameters in Asian children with early-onset obesity. Methods Genomic DNA was extracted from peripheral blood leukocytes of a cohort of children with (N = 371) and without obesity (N = 23), and LTL was measured using quantitative PCR (qPCR). Blood plasma was used for metabolic phenotyping. Statistical analysis was performed using SPSS and STATA. Results Children with obesity had shorter LTL (coefficient = -0.683, PAdj = 1.24 × 10-3 ) as compared to children who were lean. LTL was found to be associated with waist circumference (coefficient = -0.326, PAdj = 0.044) and skin-fold measures (coefficient between 0.267 and 0.301, PAdj between 4.27 × 10-4 and 7.06 × 10-7 ) in children with obesity. However, no significant associations were observed between LTL and metabolic parameters, and between LTL and inflammatory cytokines. LTL also did not significantly mediate the risk of non-alcoholic fatty liver disease (NAFLD) in children with obesity. Conclusions We showed for the first time that Asian children with severe obesity had shorter LTL, and the shortening of LTL was associated with other adiposity measures including waist circumference and skin-fold measurements.

The leptin melanocortin signaling pathway is playing a pivotal role for body weight regulation. Genetic defects within this cascade are leading to severe hyperphagia and early onset obesity. In most cases, due to persistent hyperphagia the affected patients are not able to stabilize body weight for a longer period of time with conservative treatment strategies based on lifestyle interventions. Therefore, it is of importance to implement alternative treatment options for these patients. This review provides an overview about the published pharmacological treatment attempts in respect to monogenic forms of obesity and summarizes recent research progress about the role of MC4R signaling and POMC derivatives for body weight regulation.

Es gilt Patienten mit sehr seltenen Formen der monogenen Adipositas zu identifizieren um ihnen eine optimierte oder bestenfalls sogar kausale Therapie anbieten zu konnen. Hinweise fur eine monogene Adipositasform sind insbesondere extreme Adipositas, fruhkindlicher Beginn der Adipositas, sowie auffalliges Essverhalten mit Hyperphagie, ausgepragtem nahrungssuchendem Verhalten und fehlendem Sattigungsgefuhl. Mutationen in Genen, die den Leptin-Melanocortin-Signalweg betreffen, verursachen die wichtigsten Formen der monogenen Adipositas. Dabei sind Mutationen im Melanocortin-4-Rezeptor Gen (MC4R) am haufigsten. Zu einer ausgepragten fruhkindlichen Adipositas kommt es bei autosomal rezessiv vererbten Mutationen in den Genen fur Leptin (LEP), Leptinrezeptor (LEPR), Proopiomelanocortin (POMC) und Prohormonkonvertase 1/3 (PCSK1). Eine kausale Therapie ist bei biologisch inaktivem Leptin oder Leptinmangel durch die Gabe von humanem rekombinantem Leptin verfugbar. Zudem gibt es mit dem MC4R -Agonisten (Setmelanotide) eine kausale Therapieoption fur Patienten mit POMC-Mutation. Fur Patienten mit Mutationen in MC4R, LEPR, PCSK1 finden aktuell klinische Studien hierzu statt, so dass in Zukunft eine kausale Therapie denkbar ist. Though rare, it is important to identify patients with monogenic obesity in order to be able to offer them an optimized or even causal therapy. Hints for monogenic obesity are in particular extreme obesity, early onset obesity, as well as pathological eating-behaviour with hyperphagia, pronounced food seeking and lack of satiety. Mutations in genes of the leptinergic-melanocortinergicpathway lead to the main forms of monogenic obesity. Here, mutations in the melanocortin-4-receptor gene (MC4R) are the most common. A pronounced early childhood obesity occurs in autosomal recessive mutations in genes for leptin (LEP), leptin receptor (LEPR), pro-opiomelanocortin (POMC) and prohormone convertase 1/3 (PCSK1). Causal therapy is available for biologically inactive leptin or leptin-deficiency by the administration of human recombinant leptin. In addition, the MC4R agonist (Setmelanotide) provides a causal therapy for patients with POMC mutation. Clinical studies with this medication are currently undertaken for patients with mutations in MC4R, LEPR, PCSK1, so that causal therapy is conceivable in the future.

Congenital Leptin receptor (LEPR) deficiency is a rare genetic cause of early-onset morbid obesity characterised by severe early onset obesity, major hyperphagia, hypogonadotropic hypogonadism and immune and neuroendocrine/metabolic dysfunction. We identified a homozygous loss-of-function mutation, NM_002303.5:c.464 T > G; p.(Tyr155*), in the LEPR in an extended consanguineous family with multiple individuals affected by early-onset severe obesity and hyperphagia. Interestingly, the LEPR-deficient adult females have extremely high body mass index (BMI) with hypogonadal infertility, the BMI of the affected males began to decline around the onset of puberty (13–15 years) with fertility being preserved. These findings lead to the speculation that LEPR deficiency may have a gender-specific effect on the regulation of body weight. In order to elucidate gender-specific effects of LEPR deficiency on reproduction further investigations are needed. The limitations of this study are that our conclusion is based on observations of two males and two females. Further LEPR deficient males and females are required for comparison in order to support this finding more confidently.

Background: Leptin is secreted by white adipocytes in response to fat storage and binds to leptin receptors (LEPR) expressed all over the body particularly in hypothalamic neurons. This hormone regulates several physiologic functions including energy expenditure and appetite. Clinical Case: We describe the clinical and hormonal findings in 3 adult brothers with body mass index (BMI) of 36.7, 50.7, and 46.1 kg/m2, respectively. There is no history of consanguinity in the family and none of the patients exhibited dysmorphic features. A rapid weight gain was noticed during their first few months of life, associated with permanent hyperphagia. At 2 years old, their BMI was already above 25 kg/m2 (> +3SD), and at 10 years old, it was over 40 kg/m2 (> +3SD). The linear growth was within the expected target heights for their parents. They did not seem to present cognitive impairment. The pubertal development began at 16 to 18 years old, and since then they maintained levels and FSH and LH above the upper limit of normal (15.6±3.7mUI/mL and 12.3±2.2mUI/mL, reference range 1.5–12.4 and 1.7–8.6, respectively), but with normal sexual steroids (estradiol 36.4±16.1pg/mL and total testosterone 445±401ng/dL, reference range 11–44 and 249–836, respectively). The thyroid function was normal and none of the patients suffered from dyslipidemia or diabetes, despite high serum insulin levels 26.4±15.8 mU/L (normal 5–10). Genetic sequencing identified a homozygous mutation of the leptin receptor gene in the 3 brothers: c.2357T> C, p. (Leu786Pro). Their parents were heterozygous for the mutation as well as the patients’ daughters. Homozygous carriers of the mutation presented a significantly higher BMI than their heterozygous family members, 44.5±7.1 Kg/m2 vs 32.2±1.7 Kg/m2 (p=0.023), a significantly increased leptin levels, 80±36.4 ng/ml vs 26.3±9.3 ng/ml (p=0.028), and significantly higher weight, 134.6±16.9 vs 89.2±15,2 kg (p=0.021), respectively. Women had higher BMI than men (42.0 ±12.2 Kg/m2 vs 37.9±7.5 Kg/m2, p=0.496) and also higher percentage of fat (46.4±3.1% vs 34.9±6.8%, p=0.108). Serum levels of leptin in homozygous patients were not significantly higher than those measured in 10 patients with adult-onset morbid obesity, 80± 36.4 ng/ml vs 53.8±24.1 ng/ml, respectively (p=0.149). Therefore, serum leptin is not a useful discriminative maker of LEPR gene mutations. Conclusion: Patients with severe early-onset obesity should have a genetic diagnosis workup. Firstly, because clinical trials with MC4R-agonists have raised expectations regarding the treatment of patients with mutations of the LEPR gene. Secondly, and in contradiction to other reports in the literature, our patients were fertile. Therefore, identification of the mutation allows genetic counseling of these patients and their families, including the possibility of Pre-Natal Diagnosis or Pre-Implantation Genetic Diagnosis.

The peptide derivatives of proopiomelanocortin molecule are involved in energy homeostasis, regulation of food intake, skin pigmentation and augment biliary flow. Homozygous mutation in POMC gene, which is inherited in an autosomal recessive pattern, is associated with hyperphagia leading to early onset obesity, hypoglycaemia and neonatal cholestasis due to cortisol deficiency and red hair pigmentation as a result of alpha MSH deficiency. We report a child having multiple episodes of hypoglycemia with this disorder who presented like liver disease. Our case report highlights the importance of early suspicion of this rare condition and confirmation with genetic analysis.

Identification of obesity at well-child care (WCC) examinations is a step toward intervention. Studies have shown suboptimal documentation in primary care clinics that can improve with the use of electronic health records (EHRs). This study investigated the impact of a standardized EHR template on documentation of obesity at WCC visits and its impact on physician behavior. A cohort of 585 children with severe early onset obesity (body mass index >99th percentile, age

The aim of this study was to determine the prevalence of leptin (LEP), leptin receptors (LEPR), melanocortin-4-receptor (MC4R), proopiomelanocortin (POMC), single-minded 1 (SIM1), and SH2B1 gene variations in Turkish children and adolescents, and to conduct a detailed examination of the clinical and laboratory findings of patients with variants. In this study, we included 49 children and adolescents (29 male/20 female) who presented to the Pediatric Endocrinology clinic of Erzurum Regional Training and Research Hospital between 2017 and 2020 with obesity. Family history with regards to obesity, parental consanguinity, obesity-related comorbidities, anthropometric measurements, and laboratory tests of the patients were recorded in the clinical evaluation. LEP, LEPR, MC4R, POMC, SIM1, and SH2B1 genes, which are associated with monogenic obesity, were evaluated by the next generation sequencing analysis in all patients. The mean age of 49 patients included in the study was 8.4 ± 5.2 years (range: 0.616.8), their mean height standard deviation score (SDS) was 0.9 ± 1.6, mean body mass index (BMI) was 31.3 ± 8.1 kg/m2, and their mean BMI SDS was 3.5 ± 0.6. A total of four different variants (c.380C>T and c.870delG variants in MC4R gene; c.2992A>C and c.448delA variants in LEPR gene) were detected in four patients. The determination of a molecular etiology in patients with monogenic obesity is important in view of the treatment options to be introduced in the near future (MC4R agonist) and for the family to receive appropriate genetic counseling. In this study, we evaluated the clinical and genetic findings of the patients with monogenic obesity in detail, and contributed the findings of the novel variants to the literature. [Med-Science 2021; 10(2.000): 328-33]

Maternal nutritional status and the early growth rates of offspring influence the development of the melanocortin system and later susceptibility to metabolic dysregulation, but it is difficult to assess causality. A recent study by van der Klaauw et al. (Cell 2019;176:729–742) provides direct evidence that disrupting systems regulating neuronal circuit formation leads to early-onset obesity in zebrafish, mouse, and humans.

This case report of an infant with severe early-onset obesity illustrates the societal condemnation of persons with obesity. In addition, it underlines the importance of diagnosing rare forms of monogenic obesity, even if no drug treatment is available. Here, we describe a 2-year-old girl with severe progressive obesity from birth onwards due to insatiable hunger. Genetic studies eventually reveal that the girl has a monogenic form of obesity caused by two mutations in the LEPR gene. No drug treatment is available (as yet) for this disease. Parents describe the stigmatic remarks they have to deal with every day. Diagnosing this rare genetic disorder was very important for understanding that satiety regulation is a complex system, of which willpower is only a small portion. In these patients, reduction of obesity can be achieved, but a different approach to lifestyle intervention is needed.

Background and Objectives.The prevalence of severe obesity in children has doubled in the past decade. The objective of this study is to identify the clinical documentation of obesity in young children with a BMI ≥ 99th percentile at two large tertiary care pediatric hospitals.Methods.We used a standardized algorithm utilizing data from electronic health records to identify children with severe early onset obesity (BMI ≥ 99th percentile at age Results.A total of 9887 visit records of 2588 children with severe early onset obesity were identified. Based on predefined criteria for documentation of obesity, 21.5% of children (13.5% of visits) had positive documentation, which varied by institution. Documentation in children first seen under 2 years of age was lower than in older children (15% versus 26%). Documentation was significantly higher in girls (29% versus 17%,p<0.001), African American children (27% versus 19% in whites,p<0.001), and the obesity focused specialty clinics (70% versus 15% in primary care and 9% in other subspecialty clinics,p<0.001).Conclusions.There is significant opportunity for improvement in documentation of obesity in young children, even years after the 2007 AAP guidelines for management of obesity.

for higher organisms to survive, they must efficiently procure, utilize, and conserve energy. Accordingly, mammalian species have developed complex mechanisms to ensure a constant supply of energy for cellular functions during fluctuations in their environment. Despite imbalances between day-to-day

Large, rare chromosomal deletions associated with severe early-onset obesity Bochukova et al. (2010) Nature 463(7281):666–670

OBJETIVO: Avaliar o efeito de 12 semanas de exercícios físicos em variáveis associadas a fatores de risco cardiovascular e na atividade da butirilcolinesterase (BChE) em adolescentes obesos. SUJEITOS E MÉTODOS: A amostra foi composta por 24 obesos e 51 eutróficos controles. Inicialmente e após 12 semanas foram avaliados: peso, estatura, IMC, circunferência abdominal (CA), percentual de gordura (%G), consumo máximo de oxigênio (VO2máx), pressão arterial sistólica (PAS) e diastólica (PAD), glicemia (GLI) e insulinemia (INS) basal e após 120 min, triacilglicerol (TG), colesterol total (CT), colesterol LDL, colesterol HDL e a atividade da BChE (kU/l). RESULTADOS: Após a intervenção, houve redução significativa no IMC, CA, %G, PAD, PAD, TG, GLI 120, INS, INS 120 min e na atividade da BChE. CONCLUSÃO: A redução da atividade da BChE, observada após a intervenção, foi acompanhada da redução de variáveis associadas a risco cardiovascular e à obesidade, indicando que a BChE pode ser utilizada como marcador secundário para os riscos associados à obesidade precoce. OBJECTIVE: To evaluate the effect of 12 weeks of physical exercise (PE) on cardiovascular risk factors and BChE activity in obese adolescents. SUBJECTS AND METHODS: The sample consisted of 24 obese adolescents and 51 normal weight controls. The following variables were measured in the initial stage and after 12 weeks: weight, height, BMI, waist circumference (WC), fat percentage (% F), maximal oxygen uptake (VO2max), systolic (SBP) and diastolic (DBP) blood pressure, glucose (GLY) and insulin (INS) at baseline and after 120 min, triacylglycerol (TG), total cholesterol (TC), LDL cholesterol, HDL cholesterol, and BChE activity (kU/l). RESULTS: After the intervention, there was significant reduction in BMI, WC, %F, TG, GLI 120, INS 120 min, and BChE activity. CONCLUSION: The reduction in BChE activity, observed after physical exercise, was accompanied by the reduction of the variables associated with cardiovascular risk and obesity, indicating that BChE can be used as a secondary marker for the risk associated with early onset obesity.

We administered the Symptom Checklist (Derogatis, 1975; SCL-90-R) to 37 obese subjects in outpatient treatment for obesity. Patients with early onset obesity demonstrated a greater frequency and higher levels of emotional distress and psychiatric symptomatology than patients with late onset obesity. Individuals who developed obesity in childhood showed more psychopathology than those who developed obesity later in life. Overall, these findings support the belief that obesity is characteristically associated with greater internal psychological conflict. These findings further suggest that childhood obesity could serve as a predictor variable for possible future psychological disturbance in obese populations.

Methods We conducted a case control study in ten elementary schools in Medan, North Sumatera, Indonesia. Case group (n=105) were children with early onset obesity and control group (n=55) were normal weight children. The inclusion criteria were Bataknese and Chinese children, aged 6-12 years with early onset obesity. We examined body weight and height, body mass index, waist circumference. Genotyping was performed using a TaqMan assay for rs9939609 polymorphism.

a Inserm, U1016, Institut Cochin, Paris, France b CNRS UMR 8104, Paris, France c Univ. Paris Descartes, Sorbonne Paris Cite, Paris, France d Institut de Genetique et Developpement, CNRS UMR6290, Universite de Rennes 1, IFR140 GFAS, Faculte de Medecine, Rennes, France e Laboratoire de Cytogenetique, CHU Pontchaillou, Rennes Cedex, France f Service de Genetique Medicale, Centre Hospitalier Bretagne Atlantique, Vannes, France g Laboratoire de Genetique Moleculaire, CHU Pontchaillou, Rennes Cedex, France

OBJECTIVE: To test whether ghrelin variants could play a role in modulating some aspects of the obese phenotype during childhood. DESIGN: We screened the ghrelin gene in 300 Italian obese children and adolescents (mean age 10.573.2 y; range 4–19 y) and 200 controls by using the single-strand conformation polymorphism and the restriction fragment length polymoprhism analysis. RESULTS: No mutations were detected with the exception of two previously described polymorphisms, Arg51Gln and Leu72Met. For both variations, allelic frequencies were similar between patients and controls. Interestingly, we showed that the Leu72Met polymorphism was associated with differences in the age at obesity onset. Patients with the Met72 allele became obese earlier than homozygous patients for the wild Leu72 allele. The logrank test comparing the plots of the complement of Kaplan–Meier estimates between the two groups of patients was statistically significant (Po0.0001). CONCLUSIONS: It is unlikely that ghrelin variations cause the obesity due to single-gene mutations. The Leu72Met polymorphism of the ghrelin gene seems to play a role in anticipating the onset of obesity among children suggesting, therefore, that ghrelin may be involved in the pathophysiology of human adiposity.

Vielfältige Hinweise zeigen die Beteiligung genetischer Faktoren an der Entstehung von Adipositas. Die Bedeutung des Melanin-konzentrierenden Hormons (MCH)-Systems an der Regulation der Energie-Homöostase und des Körpergewichts wurde bei Nagetieren gezeigt. Wir haben die Relevanz des Kandidatengens Rezeptor 1 des Melanin-konzentrierenden Hormons (MCHR1) bezüglich der Gewichtsregulation beim Menschen untersucht. In dem beschriebenen Mutationsscreen wurden 13.379 bp des MCHR1-Locus bei extrem adipösen Kindern und Jugendlichen und untergewichtigen Kontrollen mittels Einzelstrang-Konformations-Analyse (SSCP), denaturing High-Performance-Liquid-Chromatography (dHPLC) und Re-Sequenzierung gescreent. Innerhalb der mutmaßlich kodierenden Sequenz wurden 11 seltene Varianten, ein Missense-SNP sowie ein stummer SNP identifiziert. In den 5 - und 3 -Regionen des MCHR1 wurden zusätzlich 18 SNPs (8 neu) identifiziert. Es wurden sowohl eine Assoziation mit Adipositas als auch ein Transmissions-Ungleichgewicht für SNPs in einem Bereich von 41 kb 5 bis 20 kb 3 des MCHR1 in umfangreichen und unabhängigen Studiengruppen aus deutschen übergewichtigen Kindern sowie übergewichtigen, normalgewichtigen und untergewichtigen jungen Erwachsenen festgestellt. Der mit Adipositas assoziierte Haplotyp des MCHR1 umfasst das A-Allel eines SNPs, der mutmaßlich zu einer Missense-Mutation (D32N) am N-Terminus des 422-Aminosäure-MCHR1 führt. Das A-Allel des Missense-SNPs bewirkt in in vitro-Studien mittels Messung der Inositolphosphat-Bildung eine Erhöhung der Sensitivität des MCHR1 für den Agonisten MCH. Das relative Risiko, Adipositas zu entwickeln, ist für adipöse Träger (BMI > 90. Perzentile) des A-Allels (Asn32) mit 1,51 (heterozygot) bzw. 1,95 (homozygot) gering. Das attributable Risiko des selben Allels für Adipositas ist dagegen mit 24 % hoch. Der Versuch der Bestätigung der initialen Befunde ergab in zwei weiteren unabhängigen deutschen Studiengruppen, eine epidemiologische Studie mit 4.056 Individuen eingeschlossen, einen Trend zu einer Assoziation mit Adipositas, wohingegen keine Bestätigung in dänischen, französischen und amerikanischen Studiengruppen gelang. Aus den erzielten Daten kann postuliert werden, dass der MCHR1-Haplotyp nur für eine frühmanifeste Adipositas unter der Annahme eines besonderen genetischen und/oder Umwelt-Hintergrundes relevant ist., Several genetic studies indicate that genetic factors are involved in the development of obesity. The importance of the melanin-concentrating hormone (MCH)-system in regulation of energy homeostasis and body weight was demonstrated in rodents. We analysed the MCH receptor 1 (MCHR1) gene with respect to human obesity. We screened 13,379 bp of the MCH receptor-1 locus in extremely obese children and adolescents and underweight controls using single-stranded conformation polymorphism analysis (SSCP), denaturing High-Performance-Liquid-Chromatography (dHPLC) and genomic re-sequencing. Within the putative coding sequence (CDS) 11 rare variants, one missense SNP and one silent SNP were identified. In the 5 - and 3 -regions of the CDS 18 additional SNPs (8 novel) were found. Both association and transmission disequilibrium to obesity were detected for several SNPs in a region of 41 kb 5 to 20 kb 3 in large and independent study groups of German obese children, overweight, normal weight and underweight young adults, respectively. The MCHR1-haplotype associated with obesity comprises the A-allele of rs133072 that putatively leads to a missense mutation (D32N) within the N-terminus of the 422 amino acid MCHR1. MCH is a more potent agonist in COS-7 cells transiently expressing Asn32-MCHR1 when compared to Asp32-MCHR1 as measured by inositol phosphate production. The relative risks to develop obesity (BMI > 90th percentile) were estimated as 1.51 for heterozygous and 1.95 for homozygous carriers of the A-allele of rs133072, the attributable risk of the A-allele was 24 %. Two German samples, including an epidemiological sample encompassing 4,056 probands, genotyped to re-confirm our original findings, showed trends towards association. Findings based on Danish, French and American samples were negative. We discuss the association with respect to obesity of juvenile onset, conditional on a particular genetic and/or environmental background.

Previous studies on mice with melanocortin-4 receptor gene ( MC4r) knockout have focused on obese adults. Because humans with functional MC4r mutations show early-onset obesity, we determined the onset of excessive fat deposition in 10- to 56-day-old mice, taking into account sex and litter influences. Total body fat content of MC4r−/−on day 35 and MC4r+/−on day 56 significantly exceeds that of MC4r+/+. Plasma leptin levels increase in proportion to fat mass. According to cumulative food intake and energy expenditure measurements from day 21 to 35, onset of excessive fat deposition in MC4r−/−is fueled by hyperphagia and counteracted partially by hypermetabolism. In 35- to 56-day-old mice, arcuate nucleus neuropeptide Y (NPY) mRNA decreases and pro-opiomelanocortin (POMC) mRNA increases with fat content and plasma leptin levels independently of genotype. Taking into account fat content by ANCOVA reveals, however, increases in both NPY mRNA and POMC mRNA due to melanocortin-4 receptor (MC4R) deficiency. We conclude that hyperphagia, not hypometabolism, is the primary disturbance initiating excessive fat deposition in MC4R-deficient mice at weaning and that the overall changes in NPY and POMC expression tend to antagonize the onset of excessive fat deposition.

Melanocortin-4 receptor (MC4R) mutations have been reported as the most common single genetic cause of obesity in some populations and it has been suggested that they may be responsible for more than 4% of early-onset obesity.To verify the presence of mutations of the MC4R coding region in children from southern Italy with early-onset obesity.Two-hundred and eight unrelated obese children and adolescents were included in the study. The average age at obesity onset was 4.5+/-2.6 y. MC4R coding region was screened using both single-strand conformation polymorphism (SSCP) analysis and denaturing high-performance liquid chromatography (DHPLC). Automatic sequencing of PCR products of all individuals that showed an aberrant SSCP and/or DHPLC pattern was performed.One novel missense mutation and one previously described polymorphism (Vall03Ile) were identified. The missense mutation C142T, resulting in the substitution of proline with serine at codon 48, within the first MC4R transmembrane domain, was detected at the heterozygous state in a 15-y-old obese girl (body mass index (BMI)=35 kg/m(2)) who has been obese since she was 8 y old. The mutation co-segregated with the obesity phenotype for over three generations and was not found in the control population.Our data show MC4R obesity causing mutations in less than 0.5% of the patients (ie 1 out of 208 patients) and therefore indicate a low prevalence of MC4R variants in the obese population from southern Italy. The specific genetic background of the Mediterranean population could make it difficult for MC4R mutations to produce an essentially polygenic trait such as common obesity, at least during childhood.

Very recently, Montague et al 1 described a mutation in the leptin gene, resulting in congenital leptin deficiency, associated with severe early onset obesity in humans. This report provided the first genetic evidence that leptin is an important regulator of energy balance in humans. The deletion of a guanine nucleotide between postions 393 and 398 of the leptin gene was detected in two cousins of Pakistani origin. Both children had a normal birth weight, but gained weight very rapidly. The body mass index (BMI; kg=m 2 )o f the girl now aged 8 y is 45.82 kg=m 2 and the BMI of the boy aged 2 y is 36.62 kg=m 2 . Both had a clear history of marked hyperphagia with impaired satiety. We screened 366 extremely obese German children and adolescents by SSCA for the mutation in the leptin gene. The BMI of the probands mostly exceeded the 99th BMI-percentile (mean BMI 32.5 5.9; mean age 14.0 2.3; for detail

The number of Na/K pump units and the cation transport activity of the pump were measured in erythrocytes from two etiologically different groups of obese adolescents and a group of normal controls. There was a significant reduction in the number of pump units, as measured by saturation ouabain binding, in erythrocytes from adolescents with idiopathic, early onset obesity. Individuals whose obesity developed subsequent to the appearance of a variety of hypothalamic lesions showed no reduction in the red cell complement of Na/K pump when compared to controls and the cation transport activity of their cells was higher than both the controls and the subjects with idiopathic obesity. These results support data obtained in adults that reduced red cell Na/K pump levels are seen in a group of individuals with idiopathic obesity. They further suggest that such reductions are not likely to be secondary to the obese state per se.

BACKGROUND: Obesity is a complex disorder and has been increasing globally at alarming rates including Pakistan. However, there is scarce research on understanding obesity genetics in Pakistan. Leptin is a hormone secreted by adipocytes in response to satiety and correlates with body weight. Any mutations in the LEP gene have an adverse effect on energy regulation pathway and lead to severe, early onset obesity. To date, only eight mutations have been described in the LEP gene of which p. N103K is one. METHODS: We aimed to analyze the prevalence of this mutation in Pakistani subjects. A total of 475 subjects were genotyped by PCR-RFLP analysis and their serum profiling was done. RESULTS: Results showed that this mutation was present only in one male child with early onset obesity (10 year). He had very low serum leptin levels suggestive of functional impact of the mutation. The prevalence of such mutations is, however, low due to the drastic effects on the energy regulation. CONCLUSION: In conclusion, LEP gene mutations contribute significantly to the monogenic forms of obesity and are important due to the availability of treatment options. Such mutations may exert their effect by directly affecting energy regulation pathway and are more prominent in the early stages of life only.