Genetics of Obesity in Humans

University Departments of Medicine and Clinical Biochemistry, Box 232, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom.
Endocrine Reviews (Impact Factor: 21.06). 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.

9 Reads
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "The first PCSK1 mutation, a compound heterozygous mutation, was identified in 1997, in a patient with obesity and hypogonadotropic hypogonadism (Gly483Arg and a donor splice site mutation in intron 5, causing skipping of exon 5 and the creation of a premature stop codon) [87]. In other two patients with a similar phenotype, a compound heterozygous mutation (Glu250X and Ala213del) and a homozygous Ser307Leu substitution were identified in PCSK1 [88, 89]. So far, PCSK1 is thought to act on GnRH prohormone processing, even if the molecular mechanisms are still unclear [11, 86]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Central hypogonadotropic hypogonadism (CHH) is an emerging pathological condition frequently associated with overweight, metabolic syndrome, diabetes, and midline defects. The genetic mechanisms involve mutations in at least twenty-four genes regulating GnRH neuronal migration, secretion, and activity. So far, the mechanisms underlying CHH, both in prepubertal and in adulthood onset forms, remain unknown in most of the cases. Indeed, all detected gene variants may explain a small proportion of the affected patients (43%), indicating that other genes or epigenetic mechanisms are involved in the onset of CHH. The aim of this review is to summarize the current knowledge on genetic background of CHH, organizing the large amount of data present in the literature in a clear and concise manner, to produce a useful guide available for researchers and clinicians.
    International Journal of Endocrinology 09/2014; 2014:649154. DOI:10.1155/2014/649154 · 1.95 Impact Factor
  • Source
    • "In db/db mice, the gene encoding the leptin receptor (ObR) is mutated [14]. Similar mutations in leptin and the leptin receptor also occur in humans and have been linked to type II diabetes [15]. Full-thickness incisional wounds were generated on the back skin of db/db diabetic and C57 wild-type mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prior studies suggest that the impaired healing seen in diabetic wounds derives from a state of persistent hyper-inflammation characterized by harmful increases in inflammatory leukocytes including macrophages. However, such studies have focused on wounds at later time points (day 10 or older), and very little attention has been given to the dynamics of macrophage responses in diabetic wounds early after injury. Given the importance of macrophages for the process of healing, we studied the dynamics of macrophage response during early and late phases of healing in diabetic wounds. Here, we report that early after injury, the diabetic wound exhibits a significant delay in macrophage infiltration. The delay in the macrophage response in diabetic wounds results from reduced Chemokine (C-C motif) ligand 2 (CCL2) expression. Importantly, one-time treatment with chemoattractant CCL2 significantly stimulated healing in diabetic wounds by restoring the macrophage response. Our data demonstrate that, rather than a hyper-inflammatory state; the early diabetic wound exhibits a paradoxical and damaging decrease in essential macrophage response. Our studies suggest that the restoration of the proper kinetics of macrophage response may be able to jumpstart subsequent healing stages. CCL2 chemokine-based therapy may be an attractive strategy to promote healing in diabetic wounds.
    PLoS ONE 03/2014; 9(3):e91574. DOI:10.1371/journal.pone.0091574 · 3.23 Impact Factor
Show more