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Title: Hypothalamic energy balance : the impact of fatty acids and a novel G protein-coupled receptor
Author: Sergi, Domenico
ISNI:       0000 0004 5993 2208
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2016
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Obesity is a global health issue. Treatment or prevention of obesity via lifestyle changes remains elusive, particularly due to the lack of patient compliance and the onset of counter-regulatory mechanisms which ultimately lead to weight regain. The hypothalamus is pivotal in regulating energy homeostasis by balancing energy intake and expenditure. Thus, identifying novel mechanisms underlying these processes and unveiling novel hypothalamic druggable targets may provide new insights into the treatment of obesity. In this regard, the uracil nucleotide/cysteinyl-leukotriene receptor, GPR17, has emerged as a novel hypothalamic target in energy balance: intracerebroventricular administration of putative GPR17 agonists (UDP-glucose and leukotriene D4) has been reported to promote food intake in mice, while cangrelor, a presumptive GPR17 antagonist, curtailed it. However, this remains controversial. The data presented in this thesis do not support the possibility that uridine nucleotides or leukotrienes are ligands for GPR17 or that this receptor has a role in energy balance. Hypothalamic regulation of energy balance appears to fail in obesity particularly as a consequence of a high-fat diet which has been reported to induce inflammation as well as reactive gliosis in the hypothalamus. Transcriptomic studies, investigating the effect of a high-fat diet on the hypothalamus, identified a novel hypothalamic protein whose expression is regulated by high-fat diet and leptin: SerpinA3N. SerpinA3N encodes the acute-phase protein, alpha 1-antichymotrypsin, which, in the periphery, is upregulated by inflammation. However, its association with the expression of pro-inflammatory cytokines in hypothalamic neurons has not been reported to date. In the present study, using cultured hypothalamic neurons, SerpinA3N was upregulated by palmitic acid (PA), endoplasmic reticulum stress and inhibition of glucose metabolism, whereas inhibition of NF-?B and challenge with unsaturated fatty acids, well known for their anti-inflammatory properties, downregulated this gene. Furthermore, the expression of SerpinA3N followed the same pattern as IL-6 and TNFa suggesting this gene being a new marker of hypothalamic inflammation. Nonetheless, the mechanisms underpinning the upregulation of pro-inflammatory markers in the hypothalamus remains controversial with some authors suggesting that it is the consequence of a direct interaction between long-chain saturated fatty acid and toll-like receptor 4 (TLR4) and other studies denying it. The present data do not support the possibility that PA upregulates pro-inflammatory cytokines via TLR4 in cultured hypothalamic neurons (N42), microglia (N9) or primary hypothalamic neurons. In contrast, this study reveals that PA-induced expression of pro-inflammatory markers is dependent, at least in part, on the intracellular accumulation of ceramide which, not only was responsible for the upregulation of pro-inflammatory markers, but also decreased insulin signalling. This is supported by the fact that L-cycloserine, an inhibitor of ceramide synthesis, decreased intracellular ceramide content, inhibited the upregulation of pro-inflammatory cytokine genes induced by PA and rescued insulin signalling. In contrast to PA, the monounsaturated fatty acid, oleic acid, and the polyunsaturated fatty acid, eicosapentaenoic acid, were anti-inflammatory, decreasing both the upregulation of pro-inflammatory genes and the increase in cellular ceramide content induced by PA.
Supervisor: Not available Sponsor: Scottish Universities Life Sciences Alliance (SULSA) ; MSD
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Bioenergetics ; Fatty acids ; G proteins