Genetics of obesity in humans. Endocr Rev

University Departments of Medicine and Clinical Biochemistry, Box 232, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom.
Endocrine Reviews (Impact Factor: 19.36). 01/2007; 27(7):710-18. DOI: 10.1210/er.2006-0040
Source: PubMed

ABSTRACT Considerable attention has focused on deciphering the hypothalamic pathways that mediate the behavioral and metabolic effects of leptin. We and others have identified several single gene defects that disrupt the molecules in the leptin-melanocortin pathway causing severe obesity in humans. In this review, we consider these human monogenic obesity syndromes and discuss how far the characterization of these patients has informed our understanding of the physiological role of leptin and the melanocortins in the regulation of human body weight and neuroendocrine function.

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    • "Some evidences from animal models confirmed that MC4R mutations are potentially associated with a hypodopaminergic activity. MC4R knockout mice (MC4RKO) are hyperphagic and become obese [23]. Weight gain in the MC4R knockout animals has also been conceived as the result of increased food consumption and low locomotor activity [4]. "
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    ABSTRACT: Besides the crucial role of genetic susceptibility in the development of early-onset obesity, it has been shown that feeding behaviour could contribute to increased body weight. A significant association between obesity/overweight and ADHD has been reported, suggesting that these two conditions, despite their heterogeneity, might share common molecular pathways. Although the co-occurrence of obesity and ADHD is increasingly supported by empirical evidence, the complex pathogenetic link between these two conditions is still unclear. Here, we focus on the relationship between MC4R gene mutations and ADD in children with early-onset obesity. Mutations in the gene MC4R lead to the most common form of monogenic obesity. We hypothesize that dysregulated eating behaviour in a subset of patients with MC4R mutation might be due to comorbid ADHD symptoms, underpinned by abnormal reward mechanisms. Therefore, we speculate that it is possible to prevent obesity in a subset of patients with MC4R mutation, even if these patients are genetically programmed to “be fat”, via an appropriate treatment of ADHD symptoms. We hope that our paper will stimulate further studies testing if the early screening for ADHD symptoms and their appropriate treatment may be an effective way to prevent obesity in a subset of children with MC4R mutation.
    Medical Hypotheses 11/2014; 84(1). DOI:10.1016/j.mehy.2014.11.004 · 1.07 Impact Factor
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    • "Leptin deficiency was ruled out as the cause for obesity in the first proband (prior to our knowledge that he was homozygous for the MC4R deficiency mutation) and therefore was not measured in other probands. Other metabolic examinations will not be described since the metabolic aspects of the MC4R deficiency mutations have been previously published [Sina et al., 1999; Farooqi et al., 2003; Larsen et al., 2005; Lubrano- Berthelier et al., 2006; MacKenzie, 2006; Wang et al., 2006; Hainerova et al., 2007]. All the clinicians who participated in the comprehensive diagnostic evaluations were blind to the genotype of the subjects (the genotype was analyzed by a different team and after the diagnostic evaluations were performed). "
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    ABSTRACT: Attention deficit hyperactivity disorder (ADHD) is a heterogeneous highly heritable disorder which has recently been described to be comorbid in obese subjects. This study investigated phenotype/genotype associations in a consanguineous family with genetic obesity due to the melanocortin-4-receptor (MC4R) (C271R) mutation. MC4R deficiency disrupts hunger/satiety regulation resulting in abnormal eating behaviors. To date, the behavioral/psychiatric characteristics of MC4R deficiency have not been described except for a possible association with Binge Eating Disorder. Twenty-nine subjects of a family known to carry the MC4R (C271R) mutation, were genotyped for the mutation and underwent extensive evaluations in search for physical/psychiatric phenotype characteristics. Subjects originated from proband nuclear families with morbid obese children (BMI percentile > 97%). All probands were homozygous for the MC4R (C271R) mutation. ADHD prevalence was higher than expected only in the groups carrying the homozygous or heterozygous mutation (P = 0.00057, 0.0028, respectively). An obvious difference was observed between the homozygous group and the rest of the family in terms of obesity: homozygous subjects had childhood morbid obesity whereas heterozygous subjects included lean, normal weight and later onset obese subjects. A significant difference was found in ADHD prevalence between the homozygous MC4R (C271R) group (80%) and the rest of the family (22%) (P = 0.033) and a significant trend was found between ADHD prevalence and the number of MC4R (C271R) alleles (P = 0.0267). We conclude that in our sample, the MC4R (C271R) mutation causing obesity, is in association with ADHD. Identifying specific subgroups in which the comorbidity of obesity and ADHD occur may contribute to the understanding of the underlying molecular mechanisms.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2008; 147B(8):1547-53. DOI:10.1002/ajmg.b.30842 · 3.27 Impact Factor
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    • "Specifically, obesity caused by leptin, leptin receptor, mela- nocortin-4 receptor (MC4R), proopiomelanocortin (POMC), and prohormone convertase 1/3 (PC1/3) mutations are addressed. Because these disorders are well characterized and extensively reviewed by others [3] [4] [5], they are summarized here only to highlight key clinical points. "
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    ABSTRACT: Human obesity has a strong genetic component. Most genes that influence an individual's predisposition to gain weight are not yet known. However, the study of extreme human obesity caused by single gene defects has provided a glimpse into the long-term regulation of body weight. These monogenic obesity disorders have confirmed that the hypothalamic leptin-melanocortin system is critical for energy balance in humans, because disruption of these pathways causes the most severe obesity phenotypes. Approximately 20 different genes and at least three different mechanisms have been implicated in monogenic causes of obesity; however, they account for fewer than 5% of all severe obesity cases. This finding suggests that the genetic basis for human obesity is likely to be extremely heterogeneous, with contributions from numerous genes acting by various, yet undiscovered, molecular mechanisms.
    Endocrinology & Metabolism Clinics of North America 10/2008; 37(3):733-51, x. DOI:10.1016/j.ecl.2008.07.003 · 2.86 Impact Factor
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