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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™).

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.

Monogenic obesity, caused by mutations in one of the genes involved in the control of hunger and satiety, is a rare cause of early onset obesity (EOO). The most common of the single gene alterations affect the leptin gene (LEP), resulting in congenital leptin deficiency that manifests as intense hyperphagia, EOO and severe obesity associated with hormonal and metabolic alterations. Only eight mutations of (LEP associated with congenital leptin deficiency have been described in humans to date. In this study, we report a novel, homozygous, missense mutation in exon 3 of the (LEP gene (chr7:127894610;c.298G>A) resulting in the amino acid substitution of asparagine for aspartic acid at codon 100 (p.Asp100Asn) in a 10-month-old infant who presented to us with severe hyperphagia and EOO. She was subsequently found to have low serum leptin concentrations. Additionally, a homozygous missense variation of unknown significance in exon 11 of Bardet-Biedl syndrome-1 gene (chr11:66291279; G>A; Depth 168x) was detected. Significant abnormalities of lipid parameters were also present in our patient. Both parents were thin but there was a family history suggestive of EOO in a paternal uncle and a cousin. In conclusion, we report the second patient from India with a novel mutation of the (LEP gene associated with severe obesity.

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.

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.

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

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.

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.