Molecular characterization in human neurons of genes associated with the control of bodyweight and feeding behaviour
type: CreativeWork
description: Obesity is a major risk factor for many common diseases and has a significant heritable component. It is well documented that a powerful genetic component underlies the large variation in human body size in response to the modern day ‘obesogenic’ environment. Therefore, genetic approaches can be leveraged to help characterise the underpinning physiological and molecular mechanisms controlling food intake and body weight. Those genetic approaches can be furthered by increasingly abundant transcriptomic studies of murine and human hypothalamus – a brain area known to be a key regulator of food intake. The overarching aim of the project was to shed light on new appetitive control pathways and uncover new potential therapeutic targets to affect obesity. AgRP and POMC neurons in the hypothalamic arcuate nucleus show reciprocal response to feeding and fasting cues, so it can be speculated that reciprocally regulated genes in these neurons could have a role in regulating food intake and body-weight. Thus, in the first part of my thesis, we have identified novel genes downstream of POMC/AgRP that play a role in the control of energy homeostasis and compared expression profiles of candidate genes between mice and humans to assess relevance for human obesity. The five candidate genes uncovered include VGF, SCG2, PTPRN, RGS4 and RAB3B. We then turned to leveraging genetic information to uncover new genes with a role in energy homeostasis. Saeed et.al. have used the consanguineous Pakistani population to identify mutations in several novel obesity genes, including homozygous mutations in ROCK1 and KSR2. In parallel, whole exome-sequence analyses for adult BMI in up to 587,027 individuals revealed rare loss of function variants in the BSN gene that lead to severe obesity in humans. We anticipated involvement of the novel genes of interest in brain control of food intake. We have developed a human neuronal cell model method for characterizing novel obesity-linked genes of interes…
abstract: Obesity is a major risk factor for many common diseases and has a significant heritable component. It is well documented that a powerful genetic component underlies the large variation in human body size in response to the modern day ‘obesogenic’ environment. Therefore, genetic approaches can be leveraged to help characterise the underpinning physiological and molecular mechanisms controlling food intake and body weight. Those genetic approaches can be furthered by increasingly abundant transcriptomic studies of murine and human hypothalamus – a brain area known to be a key regulator of food intake. The overarching aim of the project was to shed light on new appetitive control pathways and uncover new potential therapeutic targets to affect obesity. AgRP and POMC neurons in the hypothalamic arcuate nucleus show reciprocal response to feeding and fasting cues, so it can be speculated that reciprocally regulated genes in these neurons could have a role in regulating food intake and body-weight. Thus, in the first part of my thesis, we have identified novel genes downstream of POMC/AgRP that play a role in the control of energy homeostasis and compared expression profiles of candidate genes between mice and humans to assess relevance for human obesity. The five candidate genes uncovered include VGF, SCG2, PTPRN, RGS4 and RAB3B. We then turned to leveraging genetic information to uncover new genes with a role in energy homeostasis. Saeed et.al. have used the consanguineous Pakistani population to identify mutations in several novel obesity genes, including homozygous mutations in ROCK1 and KSR2. In parallel, whole exome-sequence analyses for adult BMI in up to 587,027 individuals revealed rare loss of function variants in the BSN gene that lead to severe obesity in humans. We anticipated involvement of the novel genes of interest in brain control of food intake. We have developed a human neuronal cell model method for characterizing novel obesity-linked genes of interes…
author: Chukanova, Maria
language: eng
keywords: Feeding behaviour, Genetics of obesity, Metabolism, Neuroscience
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/98cf8013-a076-4965-9670-af3b1d68cb3b/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2023-11-01
date modified: 2026-07-22T22:24:10Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.108652