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Congenital leptin deficiency (CLD) is a rare cause of monogenic form obesity due to homozygous or compound heterozygous mutations in the LEP gene. To date, nine pathogenic mutations have been reported. In this study, we present are; an 18-year-old morbidly obese girl and a 14-year-old obese brother, both with homozygous mutation in the LEP gene [p.R105W (c313C> T)] and their data after three years of recombinant leptin treatment. To date, few cases of CLD have been reported in the literature. The cases reported here were siblings who were not diagnosed despite presentation at the clinic due to obesity in childhood, and diagnosis was delayed until adolescence. Clinicians need to consider CLD, a monogenic form of obesity in children with early severe obesity onset, especially if they are the child of a consanguineous marriage.

Background: Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Targeted therapy is available in the form of recombinant human leptin (metreleptin). Previous case series have reported dramatic weight loss and metabolic improvements with treatment, but metreleptin’s only FDA-approved indication is acquired generalized lipodystrophy (AGL). Metreleptin has a black box warning for risk of T-cell lymphoma, which has been reported in AGL patients, both treated and untreated with metreleptin. Clinical Case: Two sisters ages 18 yrs (sister A; BMI 45.2 kg/m2) and 20 yrs (sister B; 45.0 kg/m2) were referred for evaluation of obesity. They are of Pakistani origin with a family history of consanguinity. Birth weight was normal, but hyperphagia and excessive weight gain developed by age 3 months. They had been seen by endocrinologists, obesity specialists, and a geneticist during childhood but work-up for monogenic obesity was not pursued. They were treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. Sister A was diagnosed with type 2 diabetes at age 15 years. Sister B had comorbidities of hydrocephalus s/p VP shunt, developmental delay, hyponatremia, autoimmune thyroid disease, growth hormone deficiency, and prediabetes. At the time of their present evaluation, serum leptin levels were obtained and were undetectable in both sisters. After discontinuing OCPs, testing confirmed hypogonadotropic hypogonadism. Both patients were homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. On MR elastography performed for hepatic steatosis, sister B had an incidental finding of axillary lymphadenopathy. Surgical biopsy and staging work-up confirmed diagnosis of nodular lymphocyte predominant Hodgkin lymphoma (a B cell lymphoma), Stage II disease. She was treated with R-ABVD with adjuvant radiation and achieved clinical remission, prior to treatment with metreleptin. The patients were enrolled in an observational treatment protocol, and responses to metreleptin therapy will be reported in future. Conclusion: To our knowledge, these are the first cases of CLD diagnosed in the U. S. In previous reports, CLD and other monogenic obesity disorders were prevalent among children with severe obesity in a consanguineous Pakistani population. Leptin deficiency should be considered in all patients with early onset obesity and hypothalamic amenorrhea. Furthermore, to our knowledge, this is the first report of lymphoma in a patient with CLD, occurring prior to any treatment with metreleptin. The risk for lymphoma associated with metreleptin may relate to preexisting autoimmune disease or immunologic abnormalities related to leptin deficiency rather than medication adverse effect.

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.

Leptin has key roles in the regulation of energy balance, body weight, metabolism, and endocrine function. Leptin levels are undetectable or very low in patients with lipodystrophy, hypothalamic amenorrhea, and congenital leptin deficiency (CLD) due to mutations in the leptin gene. For these patients, leptin replacement therapy with metreleptin (a recombinant leptin analog) has improved or normalized most of their phenotypes, including normalization of endocrine axes, decrease in insulin resistance, and improvement of lipid profile and hepatic steatosis. Remarkable weight loss has been observed in patients with CLD. Due to its effects, leptin therapy has also been evaluated in conditions where leptin levels are normal or high, such as common obesity, diabetes (types 1 and 2), and Rabson-Mendenhall syndrome. A better understanding of the physiological roles of leptin may lead to the development of leptin-based therapies for other prevalent disorders such as obesity-associated nonalcoholic fatty liver disease, depression and dementia.

Background: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. Methods: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. Results: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G&gt, T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. Conclusions: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America.

Congenital leptin deficiency is a rare human genetic condition clinically characterized by hyperphagia and acute weight gain usually during the first postnatal year. The worldwide data on this disorder includes only 14 cases and four pathogenic mutations have been reported in the leptin gene.The objectives of this study were to measure serum leptin levels in obese children and to detect leptin gene mutations in those found to be leptin deficient.A total of 25 obese children were recruited for the study. Leptin deficiency was detected in nine of them. Leptin gene sequencing identified mutations in homozygous state in all the leptin deficient children. Two cases carried novel mutations (c.481_482delCT and c.104_106delTCA) and each of the remaining seven the previously reported frameshift mutation (c.398delG).The results suggest that leptin deficiency caused by mutations in the leptin gene may frequently be seen in obese Pakistani children from Central Punjab.

summaRy Although we have alluded to the fact that a vast number of peripheral and central signals contribute to energy homeosta-sis, in this article we focus specifically on the leptin signal as an exemplary model of body weight control. We review the evidence challenging the classic view that leptin acts primarily at the ARC to control satiety through the melanocor-tin pathway. Instead an updated picture is presented whereby leptin acts through a distributed network of intercommu-nicating neurons to control both the physiological and hedonic determinants of satiety. discLosuRe The authors declared no conflict of interest. © 2009 The Obesity Society ReFeRences 1. Considine RV, Sinha MK, Heiman ML et al . Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292–295.2. Montague CT, Farooqi IS, Whitehead JP et al . Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903–908.3. Pelleymounter MA, Cullen MJ, Baker MB

Background: The identification and characterization of monogenic obesity syndromes have improved our understanding of the inherited component of severe obesity and have had undoubted medical benefits. This knowledge has also helped to dispel the notion that obesity represents an individual defect in behaviour with no biological basis. Conclusions: For individuals at highest risk for complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for congenital leptin deficiency.

Experimental animal models are essential to obtain basic knowledge of the underlying biological mechanisms in human diseases. Here, we review major contributions to biomedical research and discoveries that were obtained in the mouse model by using forward genetics approaches and that provided key insights into the biology of human diseases and paved the way for the development of novel therapeutic approaches.

Summary The thrifty-gene hypothesis (TGH) posits that the modern genetic predisposition to obesity stems from a historical past where famine selected for genes that promote efficient fat deposition. It has been previously argued that such a scenario is unfeasible because under such strong selection any gene favouring fat deposition would rapidly move to fixation. Hence, we should all be predisposed to obesity: which we are not. The genetic architecture of obesity that has been revealed by genome-wide association studies (GWAS), however, calls into question such an argument. Obesity is caused by mutations in many hundreds (maybe thousands) of genes, each with a very minor, independent and additive impact. Selection on such genes would probably be very weak because the individual advantages they would confer would be very small. Hence, the genetic architecture of the epidemic may indeed be compatible with, and hence support, the TGH. To evaluate whether this is correct, it is necessary to know the likely effects of the identified GWAS alleles on survival during starvation. This would allow definition of their advantage in famine conditions, and hence the likely selection pressure for such alleles to have spread over the time course of human evolution. We constructed a mathematical model of weight loss under total starvation using the established principles of energy balance. Using the model, we found that fatter individuals would indeed survive longer and, at a given body weight, females would survive longer than males, when totally starved. An allele causing deposition of an extra 80 g of fat would result in an extension of life under total starvation by about 1.1-1.6% in an individual with 10 kg of fat and by 0.25-0.27% in an individual carrying 32 kg of fat. A mutation causing a per allele effect of 0.25% would become completely fixed in a population with an effective size of 5 million individuals in 6000 selection events. Because there have probably been about 24,000 famine events since the evolution of hominins 4 million years ago, there has been ample time even for genes with only very minor impacts on adiposity to move to fixation. The observed polymorphic variation in the genes causing the predisposition to obesity is incompatible with the TGH, unless all these single nucleotide polymorphisms (SNPs) arose in the last 900,000 years, a requirement we know is incorrect. The TGH is further weakened by the observation of no link between the effect size of these SNPs and their prevalence, which would be anticipated under the TGH model of selection if all the SNPs had arisen in the last 900,000 years.

BACKGROUND: The increase in the incidence of obesity has a substantial societal health impact. Contrasting reports have been published on whether overweight and obesity affect male fertility. To clarify this, we have reviewed published data on the relation between overweight/obesity, semen parameters, endocrine status and human male fertility. Subsequently, we have used results obtained in animal models of obesity to explain the human data. METHODS: Pubmed, Scopus, Web of Science and Google Scholar databases were searched between September 2009 and October 2010 for a comprehensive publication record. Available studies on adult human males were examined. The included animal studies examined obesity and fertility, and focused on leptin, leptin receptor signaling, kisspeptins and/or NPY. RESULTS: Most overweight/obese men do not experience significant fertility problems, despite the presence of reduced testosterone alongside normal gonadotrophin levels. Only a subgroup of subjects suffers from hypogonadotropic hypogonadism. Animal models offer several explanations and show that reduced leptin signaling leads to reduced GnRH neuronal activity. This may be due to decreased hypothalamic Kissl expression, a potent regulator of GnRH/LH/FSH release. As the Kissl neurons express leptin receptors, the Kissl system may participate in transmitting metabolic information to the GnRH neurons, thus providing a bridge between metabolic regulation and fertility. CONCLUSIONS: Infertility in overweight/obese males may be explained by leptin insensitivity. This implies a possible role for the KISSl system in human obesity-related male infertility. If substantiated, it will pave the way for methods to restore fertility in these subjects.

Food-grade Lactic Acid Bacteria (LAB) have been safely consumed for centuries by humans in fermented foods. Thus, they are good candidates to develop novel oral vectors, constituting attractive alternatives to attenuated pathogens, for mucosal delivery strategies. Herein, this review summarizes our research, up until now, on the use of LAB as mucosal delivery vectors for therapeutic proteins and DNA vaccines. Most of our work has been based on the model LAB Lactococcus lactis, for which we have developed efficient genetic tools, including expression signals and host strains, for the heterologous expression of therapeutic proteins such as antigens, cytokines and enzymes. Resulting recombinant lactococci strains have been tested successfully for their prophylactic and therapeutic effects in different animal models: i) against human papillomavirus type 16 (HPV-16)-induced tumors in mice, ii) to partially prevent a bovine β-lactoglobulin (BLG)-allergic reaction in mice and iii) to regulate body weight and food consumption in obese mice. Strikingly, all of these tools have been successfully transposed to the Lactobacillus genus, in recent years, within our laboratory. Notably, anti-oxidative Lactobacillus casei strains were constructed and tested in two chemically-induced colitis models. In parallel, we also developed a strategy based on the use of L. lactis to deliver DNA at the mucosal level, and were able to show that L. lactis is able to modulate the host response through DNA delivery. Today, we consider that all of our consistent data, together with those obtained by other groups, demonstrate and reinforce the interest of using LAB, particularly lactococci and lactobacilli strains, to develop novel therapeutic protein mucosal delivery vectors which should be tested now in human clinical trials.

Congenital leptin deficiency is a rare, but treatable, cause of severe early-onset obesity. To date, two United Kingdom families of Pakistani origin carrying a frameshift/premature stop mutation, c.398delG (Delta133G), and one Turkish family carrying a missense mutation, c.313CT (Arg(105)Trp), have been described. Affected subjects are homozygotes and manifest severe obesity and hyperphagia accompanied by metabolic, neuroendocrine, and immune dysfunction. The effects of recombinant leptin therapy have been reported in three children with the Delta133G mutation, and in all cases this has led to a dramatic resolution of clinical and biochemical abnormalities. We now report a Canadian child, of Pakistani origin but unrelated to the previously reported subjects, presenting with severe hyperphagia and obesity, who was found to be homozygous for the Delta133G mutation. In this child, 4 yr of therapy with sc injections of recombinant leptin provided additional evidence for the sustained beneficial effects of leptin replacement on fat mass, hyperinsulinemia, and hyperlipidemia. In addition, leptin administration corrected abnormal thyroid biochemistry and allowed the withdrawal of T(4) treatment, providing additional support for the role of leptin in the regulation of the human hypothalamic-pituitary-thyroid axis.

to the editor: the article by Paz-Filho et al. ([13][1]) addresses the potential changes in insulin sensitivity in patients with congenital leptin deficiency while on leptin therapy and off leptin therapy. Using the hyperinsulinemic euglycemic clamp technique, the investigators showed an increase in

Thyroid function is closely related to leptin's secretion by the adipose tissue. In states of leptin-deficiency, the circadian rhythm of TSH is altered, leading to central hypothyroidism in animal models. In humans, central hypothyroidism has also been described in rare cases of congenital leptin deficiency. However, the thyroid phenotype in these cases is heterogeneous, with the occurrence of central hypothyroidism in a minority of cases. Here we describe thyroid function in four leptin-deficient humans (2 males aged 5 and 27, and 2 females aged 35 and 40), before and during leptin replacement with recombinant human methionyl leptin (r-metHuLeptin). The child was evaluated for four years, and the adults, for eight years. In addition, the adults were submitted to a brief withdrawal of leptin during six weeks in the sixth year. Our results show that, regardless of leptin replacement, our leptin-deficient patients have normal thyroid function. In spite of having an important role in regulating the hypothalamic-pituitary-thyroidal axis, leptin is not required for normal thyroid function. Trial Registration ClinicalTrials.gov Identifiers: NCT00659828 and NCT00657605