Publication Date

2017-11-15

Availability

Embargoed

Embargo Period

2019-05-09

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Molecular and Cellular Pharmacology (Medicine)

Date of Defense

2017-10-13

First Committee Member

Deborah Mash

Second Committee Member

Vladlen Slepak

Third Committee Member

Peter Buchwald

Fourth Committee Member

Stefan Wuchty

Fifth Committee Member

Lily Wang

Abstract

Obesity is one of the leading causes of global deaths. WHO estimates that 39% of adults over 18 years of age are overweight (BMI ≥ 25kg/m2) and, currently 13% meet criteria for obesity (BMI ≥ 30kg/m2). Increased food-energy supply and a mismatched biological response patterns that evolved in a scare environment, were suggested to be major drivers of the obesity epidemic. The palatable energy dense food is excessively consumed for its hedonic characteristics; its ubiquitous availability has increased the relevance of brain reward systems in controlling food intake. Increasing evidence shows that obesity shares many mechanisms with addiction. Food addiction is associated with 4.6 higher BMI units, 8.2% more body fat, and it is considered to be a valid phenotype of obesity. Both of these two pathologies show similarly exaggerated saliency of food or drug reward. Obesity overlaps addiction in terms of similar neural adaptions in the brain regions which process reward. Proof-of-concept studies in animals demonstrate a relationship between defective signaling in dopamine reward pathways and the onset and maintenance of obesity. Laboratory rats fed a cafeteria diet for fifteen weeks develop obesity, which is associated with reduced extracellular dopamine. The dopaminergic system is a reward pathway that contributes to excessive food or drug intake. The A9 nigrostriatal dopamine neurons originating from the substantia nigra pars compacta (SNpc) innervate the striatum. The midbrain dopamine neurons and their efferent projections to the striatum play central roles in the addiction circuitry. In this thesis, we quantified DAT, DRD2 and TH gene expression in the substantia nigra (SN) with quantitative measures of the number of DAT binding sites in the striatum from obese subjects that came to autopsy over a range of body mass indices. Radioligand binding assays of [3H] WIN35,428 demonstrated that the number of striatal DAT binding sites was inversely correlated with increasing BMI (r = -0.47; p < 0.01). DAT and TH gene expression were significantly decreased in the somatodendritic compartment of obese subjects (p < 0.001), with no significant change in D2R compared to normal weight subjects. The reduced density of striatal DAT with corresponding reductions in DAT and TH gene expression in substantia nigra suggests, that obesity is associated with hypodopaminergic function. A dopamine reward deficiency syndrome has been suggested to underlie abnormal eating behavior that leads to obesity. Neurobiological changes in presynaptic dopamine markers of the human brain supports a link between hedonic dopamine dysregulation and obesity. We speculate that the obesity phenotype may be associated with dysregulation of coordinated gene networks of striatum that process reward saliency. A survey of whole-genome transcriptome in the brain reward system was performed to determine whether gene-expression changes are shared with substance use disorders. We conducted the first RNA sequencing (RNA-Seq) analyses in human dorsal and ventral striatum with BMI values over a range from 18.65 to 40.68 kg/m2. The primary aim in this thesis was to identify dysregulated genes and gene pathways that are associated with obesity in the brain reward system. Weighted gene co-expression network analysis was performed to define modules of highly correlated genes and hub genes. We reported 1435 BMI-related genes in the caudate and 2286 in the nucleus accumbens at the false discovery rate (FDR) < 0.1. A significant correlation was observed in BMI-associated gene expression changes (r = 0.81) between the caudate and NAc. GSEA showed 74 (80%) overlap between enriched pathways, suggesting a consistency of regulated genes expression between these two brain regions. Functional annotation identified pathways enlightening the association between obesity and other diseases, like type 2 diabetes, and immune-related complications (complement and coagulation cascades) and addiction pathways (amphetamine addiction, morphine addiction). WGCNA revealed five modules which were strongly correlated with BMI as an obesity-related phenotype (correlations ranging from -0.51 to 0.50, P < 0.01). For the first time, to the best of our knowledge, we provided a comprehensive, unbiased gene list and pathways that are associated with BMI in the human postmortem brain. Of note, we confirmed that genes in addiction pathways showing a significant, coordinated decrease as BMI increases in both the caudate and NAc. Additionally, these analyses yielded novel mechanisms like GABAergic-neurotransmission, glutamatergic-neurotransmission, insulin signaling, and neuroinflammation that may underlie impaired control of food intake in the dorsal and ventral striatum.

Keywords

Brain; Transcriptome; Obesity; RNA Sequencing; Addiction; Gene expression

Available for download on Thursday, May 09, 2019

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