Evolucion De La Obesidad

nature publishing group

articles
Gene-Behavior interactions and oBesity

Obesity Genes and Gene–Environment– Behavior Interactions: Recommendations for a Way Forward
Alan R. Shuldiner1
Obesity is a classical complex trait, influenced by both genetic and lifestyle factors. The number of obesity gene variants is currently unknown but, based on sound evolutionary principles, likely to bemany, each with a modest effect on the phenotype. Recent advances in our knowledge of variation in the human genome and high throughput genotyping technologies have made possible genome-wide association (GWA) analysis and the identification of bona fide susceptibility genes for many complex diseases and phenotypes, including obesity and its comorbid conditions. GWA analysis in even larger numbers ofindividuals through collaborative efforts of many investigators will likely identify those polygenes of moderate and modest effect size that manifest in our typical environment. Once the subset of real-world-relevant obesity susceptibility variants is identified, follow-up studies, including detailed molecular analysis of the loci, stratified analyses, prospective and interventional studies inhumans, and mechanistic studies in cells and animals will allow us to define the genetic architecture of the locus and dissect how these genes interact with specific environmental and other factors. The molecular and analytical tools to accomplish these goals are now in hand, but cooperation among investigators will be necessary to amass the requisite numbers of phenotyped and genotyped individuals.Identification of susceptibility genes for obesity and determining how they interact with each other and the environment will lead to new insights into the molecular, cellular, and physiological basis of energy homeostasis, and novel strategies for prevention and treatment.

introduction: how complex a trait is obesity?

This two-day meeting of experts in the area of genetics, energyhomeostasis, and eating behavior highlighted the complexity and multifactorial nature of obesity and its complications. Clearly, both genetics and the environment play important roles, with gene variants having been selected over the course of about 1 billion years of evolution, followed by the expression of these “thrifty” genes in an obesogenic environment over just the last 50–100 years (1). One billionyears of selection for thrifty genes would predict that obesity susceptibility genes in humans will be many (perhaps 100–1,000) and most will have modest effects. Furthermore, there will likely be great genetic heterogeneity both within and between populations, and important gene–gene and gene–environment interactions. Clinically, we know that there is great interindividual variation not only insusceptibility to obesity in a similar obesogenic environment, but also in where body fat accretion occurs (subcutaneous vs. visceral), and to what extent the obesity-related comorbid conditions such as insulin resistance, glucose intolerance, hypertension, hyperlipidemia, sleep apnea, and cancer will manifest. Furthermore, there is great interindividual variation in response to lifestyle and
1pharmacological interventions to prevent and treat obesity, further demonstrating enormous heterogeneity of the phenotype, which is due in part to genetics. Clearly, finding the obesity susceptibility genes as well as those that predispose to the malignant comorbidities of obesity will be challenging.
current state of knowledge

Many candidate genes for obesity based on our currentunderstanding of energy homeostasis have been studied, but results to date have been disappointing (reviewed in ref. 2). This may be due to the fact that our current understanding of the pathophysiology of energy homeostasis is incomplete and thus the correct candidate genes have not been studied. Furthermore, most candidate genes that have been studied have not been investigated thoroughly based on...