Mutations in ligands and receptors of the leptin–melanocortin pathway that lead to obesity

Abstract

Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes mellitus and certain cancers. The prevalence of obesity is increasing rapidly throughout the world and is now recognized as a major global public-health concern. Although the increased prevalence of obesity is undoubtedly driven by environmental factors, the evidence that inherited factors profoundly influence human fat mass is equally compelling. Twin and adoption studies indicate that up to 70% of the interindividual variance in fat mass is determined by genetic factors. Genetic strategies can, therefore, provide a useful tool with which to dissect the complex (and often heterogeneous) molecular and physiologic mechanisms involved in the regulation of body weight. In this Review, we have focused our attention on monogenic disorders, which primarily result in severe, early-onset obesity. The study of these genetic disorders has provided a framework for our understanding of the mechanisms involved in the regulation of body weight in humans and how these mechanisms are disrupted in obesity. The genes affected in these monogenic disorders all encode ligands and receptors of the highly conserved leptin-melanocortin pathway, which is critical for the regulation of food intake and body weight.

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…This modulation is well illustrated by the reproductive phenotype of absent pubertal development and hypogonadotropic hypogonadism in patients with inactivating mutations in the genes encoding leptin (LEP) or its receptor (LEPR). 58 Exactly how the effects of leptin are transmitted to GnRH neurons is unknown, as this neuro nal population does not express the leptin receptor. 59 Experimental data suggest that kisspeptin neurons are sensitive to changes in leptin concentrations and metabolic conditions, 43 yet they apparently do not express functional leptin receptor, which indicates the mode of action is indirect.…”

“…101,104,114,154,155 Early onset of morbid obesity associated with CHH suggests mutations in LEP, LEPR or PCSK1. 58,156 Indeed, combining CHH with specific associated phenotypes can increase the probability of finding causal mutations by targeted gene sequencing ( Figure 4). 21,28,104,157 CHH accompanied by other syndromic features such as congenital ichthyosis 158 or spherocytosis 159 is suggestive of a contiguous gene syndrome for which a karyotype or comparative genomic hybridization array analysis might be useful for identifying underlying chromosomal abnormalities.…”

The genetics of childhood obesity and interaction with dietary macronutrients

“…The eight genes responsible for non-syndromic obesity include brain-derived neurotrophic factor (BDNF), leptin (LEP), leptin receptor (LEPR), melanocortin-4 receptor (MC4R), neurotrophic tyrosine kinase receptor type 2 (NTRK2), prohormone convertase 1 (PCSK1), proopiomelanocortin (POMC), and singleminded homolog 1 (SIM1). These 8 obesity susceptibility genes code for proteins which have a central role in the integration of peripheral and neuronal signals through the leptin/melanocortin pathway present in the hypothalamus and therefore also responsible for maintaining energy balance through food consumption and energy expenditure (Farooqi and O'Rahilly 2008). In the case of LEP, genetic mutations result in leptin deficiency, and administering leptin has been shown to have beneficial effects by restoring satiety and promoting weight loss (Farooqi et al 2002).…”

Bariatric surgery, adipose tissue and gut microbiota

“…Mutations in genes encoding major proteins involved in the LEP/melanocortin pathways indeed explain rare forms of monogenic obesities. 26 MC4R mutations influence early weight gain with various degrees of severity. Admittedly, obesity associated with MC4R mutations is the most common genetic form of obesity.…”