The molecular genetics of human obesity.

摘要

Human obesity results from the interaction between a genetic predisposition and deleterious environmental factors and is considered to be a global epidemic associated with mortality. Therefore, research to understand the pathogenic mechanisms underlying obesity is of great importance and is required in order to develop rational and effective treatments. This thesis work includes three separate research projects with the common intention of exploring the molecular genetics of the central control of energy homeostasis.;The major central regulator of long-term regulation of body weight in humans is the leptin-melanocortin axis and it is centered in the hypothalamus. This pathway senses peripheral energy stores and signal satiety, and it's disruption leads to the most severe forms of human obesity. Melanocortin-4 receptor (MC4R) plays a key role in transmitting the anorexigenic signal of the adipocyte secreted hormone leptin. We systematically and comparatively evaluated the functional consequences of rare mutations found in both MC4R and melanocortin-3 receptor (MC3R) in a large cohort of severely obese North American adults and lean controls. We demonstrated that naturally occurring MC4R mutations but not the MC3R mutations are strongly associated with human obesity.;Both common variants with small effects and rare variants with larger individual effects have been shown to contribute to the genetic predisposition to obesity. We also investigated whether common genetic variants in and around MC4R are associated with adiposity in a population-based cohort, Health ABC. We found that the strongest association with adiposity was with a SNP in the 3' non-coding DNA of MC4R. A conserved region near this associated nsSNP was tested for possible enhancer activity.;Using mice heterozygote for Rab23 nonsense mutations we explore the novel mechanistic link between syndromic and non-syndromic human forms of obesity. We explore the hypothesis that Rab23 deficiency causes obesity through functional impairment of the first order hypothalamic neurons involved in leptin-mediated regulation of energy homeostasis. This functional impairment is through disruption of leptin signaling at the level of the pro-opiomelanocortin neurons.