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      Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016


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          Obesity results from a synergistic relationship between genes and the environment. The phenotypic expression of genetic factors involved in obesity is variable, allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. This is mainly due to autosomal recessive mutations in genes of the leptin-melanocortin pathway which plays a key role in the hypothalamic control of food intake. Melanocortin 4 receptor(MC4R)-linked obesity is characterized by the variable severity of obesity and no notable additional phenotypes. Mutations in the MC4R gene are involved in 2-3% of obese children and adults; the majority of these are heterozygous. Syndromic obesity is associated with mental retardation, dysmorphic features, and organ-specific developmental abnormalities. Additional genes participating in the development of hypothalamus and central nervous system have been regularly identified. But to date, not all involved genes have been identified so far. New diagnostic tools, such as whole-exome sequencing, will probably help to identify other genes. Managing these patients is challenging. Indeed, specific treatments are available only for specific types of monogenic obesity, such as leptin deficiency. Data on bariatric surgery are limited and controversial. New molecules acting on the leptin-melanocortin pathway are currently being developed.

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          A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction.

          The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.
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            Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor.

            The melanocortin-4 receptor (MC4R) is critically involved in regulating energy balance, and obesity has been observed in mice with mutations in the gene for brain-derived neurotrophic factor (BDNF). Here we report that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH) where its expression is regulated by nutritional state and by MC4R signaling. In addition, similar to MC4R mutants, mouse mutants that expresses the BDNF receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets. Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higher-fat diets in mice with deficient MC4R signaling. These results show that MC4R signaling controls BDNF expression in the VMH and support the hypothesis that BDNF is an important effector through which MC4R signaling controls energy balance.
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              Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene.

              Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse. We have previously described a women with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. Gly-->Arg483 prevents processing of proPC1 and leads to its retention in the endoplasmic reticulum (ER). A-->C+4 of the intro-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.

                Author and article information

                Obes Facts
                Obesity Facts
                S. Karger AG
                June 2016
                01 June 2016
                : 9
                : 3
                : 158-173
                aGHICL, Saint-Vincent de Paul Hospital, Department of Pediatrics, Lille, France; bINSERM, Nutriomics UMR_S U1166, University Pierre et Marie Curie-Paris 6, Paris, France; cInstitute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, Paris, France; dDepartment of Pediatric Nutrition and Gastroenterology, Armand-Trousseau Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; eNutrition Department, French Reference Centre for Prader-Willi Syndrome, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
                Author notes
                *Dr. Christine Poitou, Nutrition Department, ICAN, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l'hôpital, 75013 Paris, France, christine.poitou-bernert@psl.aphp.fr
                445061 Obes Facts 2016;9:158-173
                © 2016 The Author(s) Published by S. Karger GmbH, Freiburg

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                Page count
                Figures: 3, Tables: 3, References: 75, Pages: 16
                Review Article

                Nutrition & Dietetics,Health & Social care,Public health
                Whole-exome sequencing,Leptin-melanocortin pathway,Bariatric surgery,Genetics,Obesity


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