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Title: Mechanisms involved in human thermogenesis
Author: Talbot, Fleur Katharine FitzRoy
ISNI:       0000 0004 7961 8136
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Energy expenditure in humans is partially understood. Sympathetic drive is an important stimulator of brown-adipose tissue-mediated increases in energy expenditure, and it is known that leptin-mediated pathways in part contribute to this. This thesis has sought to understand human energy expenditure further by two different methods. Firstly, we have characterised the first rare human mutations in G protein-coupled receptor 10 (GPR10), a G protein coupled receptor expressed in key brain areas associated with energy homeostasis. GPR10-mediated signalling in the dorsomedial hypothalamus is necessary for the thermogenic effects of leptin. We have undertaken a detailed functional study of the mutations found from the whole exome and targeted resequencing of patients with severe early onset obesity, recruited to the Genetics of Obesity Study (GOOS). We have demonstrated that thirteen of the fifteen mutations found result in a complete or partial loss of function in vitro. We have additionally demonstrated that the mutations resulting in a complete loss of function on wild type receptor. This is important because the human mutations are found in heterozygous form. Secondly, we have conducted a randomised cross-over study of the effects of mild cooling on healthy lean men. We have demonstrated that exposure to temperatures of 16oC for two hours results in an increase in systolic blood pressure and pulse rate, relative to thermoneutral conditions. Cold exposure resulted in a drop in circulating leptin, which in common with previous studies on macronutrient preference in patients with disrupted leptin-melanocortin signalling, is associated with an increase in consumption of high fat food. Cooling is known to be neuroprotective in acute brain injury, and recent published data suggests a protective effect in chronic neurodegenerative conditions by improvements in synaptic plasticity. We have demonstrated an improvement in neurocognition after two hours of mild cooling. We have additionally shown increases in docoshexaenoic acid, a polyunsaturated fatty acid known to play a role in neuroprotection, with a role in maintaining membrane fluidity. These studies broaden our knowledge of human energy homeostasis. They provide evidence for the role of GPR10 in human energy homeostasis, and a rationale for the targeting of GPR10-mediated signalling pharmacologically, and provide some evidence for a role in improved neurocognition in humans.
Supervisor: Farooqi, Ismaa Sadaf Sponsor: Wellcome Trust ; Evelyn Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Obesity ; Thermogenesis ; Cooling ; Genetics of Obesity ; GPR10 ; Lipidomics