Functional characterization of obesogenic neural circuitries

Abstract

Obesity can be characterized as a disorder in which affected individuals fail to properly regulate the balance between energy intake and expenditure. Recently, genome-wide association studies have identified over 30 genetic variants that associate with increased body weight and thus provide clues on the existence of unknown mechanisms that regulate energy balance. As a first step, the expression levels of a subset of these obesity-associated genes (genes of which variants associate with increased BMI) were measured in the hypothalamus and midbrain as a consequence of nutritional state. The expression levels of four out of five investigated genes were dependent on nutritional state, which confirms a role for these genes in the etiology of obesity. Next, two of those genes were selected for further functional characterization, namely E-twenty six version 5 (Etv5) and neural growth regulator 1 (Negr1). Athough in vitro experiments pointed towards a function for Etv5 in the synthesis of dopamine (a neurotransmitter that has been suggested to play an important role in overeating) in vivo evidence for this theory could not be obtained. In addition, none of the behavioral tests showed that increased levels of Etv5 mRNA in the midbrain had an effect on the regulation of energy balance. Viral-mediated techniques were also used to influence the expression of Negr1 in the hypothalamus (a region that is important for the regulation of energy balance). Although increased expression of Negr1 did not have any dramatic effects on the regulation of energy balance, decreased expression of Negr1 in the hypothalamus led to increased food intake and body weight, confirming its role in etiology of obesity. The two remaining studies in this thesis were directed at the dopaminergic system. Two dopaminoceptive populations exist, namely the D1-population and the D2-population. The combined activity of these populations will determine which action is selected from a range of possibilities. By looking at expression levels of the opioidergic, endocannabinoidergic and melanotonergic receptors in either of the two populations it was found that the two dopaminoceptive populations are differentially modulated by the opioidergic and melanotonergic systems, giving more insight in the molecular mechanisms that lead to action selection. The dopaminergic system was also subject of investigation in the validation of a novel technique that can be used to activate a specific neural pathway in vivo and determine subsequent effects on behavior. Activation of the dopaminergic system led to an increase in effort to obtain a sucrose pellet, which could be expected from earlier studies and as such validated this novel technique for use in behavioral neuroscience. In sum, the results from this thesis underscore the fact that obesity is a complex and multifactorial disorder, which is not caused by one gene or one mechanism. Therefore it is necessary to use a combination of genetic and physiological approaches (of which some are described in this thesis) to fully grasp all the elements that are involved in the regulation of energy balance and as such better understand the etiology of obesity.