Haq, Naila Arzumand; (2019) Role of brain-gut axis in obesity initiation and progression in Bardet-Biedl syndrome. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Obesity is the major cause of the rising world-wide prevalence of metabolic syndrome, type 2 diabetes mellitus and cardiovascular disease. Despite extensive research in understanding the aetiology of obesity, much of its pathophysiology remains elusive. The overarching aim of this thesis was to determine the dysregulated signalling pathways and genes responsible for the onset and development of obesity. Where complex genetic, environmental and cultural factors make it very difficult to decipher the primary mechanism of obesity, models of monogenic obesity such as Bardet-Biedl syndrome (BBS) may be utilized to identify the pathways associated with obesity and dysregulated food intake that may have an impact on the understanding of the mechanisms of more common eating disorders. BBS is a ciliopathy where a majority of the patients develop morbid obesity (BMI>35) from very early age and moreover, this phenotype is recapitulated in mice models. The brain, specifically the arcuate nucleus of hypothalamus receives, and processes input from a number of peripheral orexigenic and anorexigenic signals to regulate food intake and energy expenditure. These signals include leptin, insulin, ghrelin, cholecystokinin (CCK) and PY that are projected to the second order neuron populations of the lateral and paraventricular nucleus of the hypothalamus. As a first step in understanding this phenomenon, whole transcriptome and bioinformatics analyses of Bbs5 pre-obese (5 weeks) and obese (12 weeks) mice were performed on core hypothalamic tissue. Various bioinformatic methods highlighted a number of dysregulated pathways associated with neurodevelopment and brain-gut axis. Evidence of altered axonal guidance and indication of hypothalamic neurogenesis as a result of obesity, were inferred. Compelling evidence suggests, in addition to circulating hormones such as leptin and insulin, gut hormones also modulated ingestive behaviour through vagal afferent neuron signalling. The cell bodies of vagal afferent neurons reside in the inferior (nodose) ganglia. Follow-up from the hypothalamic RNAseq findings, resulted in investigation of qualitative and quantitative study of the nodose ganglia of male and female wild-type and knockout Bbs mice under metabolic challenges. For the first time, this study demonstrated the disparity between wild type, left and right nodose ganglia signalling genes. Comparison between wild types and knockouts highlighted decreased satiety and neuronal signals in knockouts. Concomitant findings in the nucleus of the solitary tract, revealed synaptic remodelling. Taken together, this study demonstrates altered vagal plasticity in obese condition. Additionally, the presence of primary cilia on nodose ganglia were detected, together with increased expression of cilia genes during energy restriction, suggesting a novel role of these genes during negative energy balance. These studies demonstrated the complex relationship between the hypothalamus and the components of brain-gut axis, highlighting the role of vagal afferent neuron signalling in developing obesity in Bbs using Bbs5 knockout models

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