Unraveling the Genetics of Human Obesity

Abstract

The use of modern molecular biology tools in deciphering the perturbed biochemistry and physiology underlying the obese state has proven invaluable. Identifying the hypothalamic leptin/melanocortin pathway as critical in many cases of monogenic obesity has permitted targeted, hypothesis-driven experiments to be performed, and has implicated new candidates as causative for previously uncharacterized clinical cases of obesity. Meanwhile, the effects of mutations in the melanocortin-4 receptor gene, for which the obese phenotype varies in the degree of severity among individuals, are now thought to be influenced by one's environmental surroundings. Molecular approaches have revealed that syndromes (Prader-Willi and Bardet-Biedl) previously assumed to be controlled by a single gene are, conversely, regulated by multiple elements. Finally, the application of comprehensive profiling technologies coupled with creative statistical analyses has revealed that interactions between genetic and environmental factors are responsible for the common obesity currently challenging many Westernized societies. As such, an improved understanding of the different “types” of obesity not only permits the development of potential therapies, but also proposes novel and often unexpected directions in deciphering the dysfunctional state of obesity.

Genetic influence on appetite in children

“…Most attention has been paid to energy expenditure and fat storage as mechanisms underlying the genetic effects. 9,10 However, genes could also affect weight through appetiterelated behavioural traits. 11 There is evidence for genetic influence on circulating peptides and steroids that affect appetite in humans, 12 but much of the endocrinological research derives from studies of rare monogenic obesity syndromes, which may or may not apply to population weight variation.…”

The genetics of childhood obesity and interaction with dietary macronutrients

“…4 The three different types of childhood obesity based on distinct genetic and phenotypic characteristics disabilities, some with undefined neuroendocrine abnormalities. It is the latter abnormality believed responsible for adversely affecting function of the hypothalamus which serves as the brain appetite center regulating energy balance through food consumption and energy expenditure (Farooqi and O'Rahilly 2005;Mutch and Clement 2006;Goldstone and Beales 2008;Schaefer et al 2010). As a result, children with syndromic obesity are usually characterized with severe hyperphagia and diminished satiety which promotes weight gain (Bray 1992;Sahoo et al 2008;Marshall et al 2011).…”

Bariatric surgery, adipose tissue and gut microbiota

“…23 Susceptibility may also result from intrauterine or postnatal genetic imprinting. 24 There is a wide spectrum ranging from genetically determined obesity to behaviorally determined obesity, with most individuals containing a mix of these factors (i.e., geneenvironment interaction).…”

“…The genetic basis of syndromic obesities (e.g., Prader-Willi and Bardet-Biedl) is complex. 23,25 As naturally occurring mutations and the targeted disruption of genes in mouse models (LEP, LEP receptor, proopiomelanocortin, MC4R, MC3R) were found to have pivotal roles in the same molecular pathway, genes in and associated with the LEP/melanocortin pathway were explored in human cases. Mutations in genes encoding major proteins involved in the LEP/melanocortin pathways indeed explain rare forms of monogenic obesities.…”

“…Unlike other monogenic obesities with individuals being carriers of homozygous or compound heterozygous mutations, most individuals are heterozygous carriers of mutated hMC4R with an autosomic dominant inheritance, variable expression of obesity with age (i.e., from severe obesity to normal weight in MC4R-mutated carriers) and generational influences (i.e., children are more severely affected than their parents). 23,26 Although these mutated genes influence unambiguously the dynamics of weight gain in individual carriers, characterizing the impact of genetic determinants on phenotypes of common forms of obesity is more complex. In recent months, vast progress has been made in the understanding of the genetics of common obesity owing to the rapid development of large-scale genetic screening (genome-wide association) in large populations grouped in very large consortiums.…”