Targeted expression of plasminogen activator inhibitor(PAI)-1 to the stomach inhibits gut-brain signalling by the satiety hormone cholecystokinin (CCK)

Gamble, Joanne
Targeted expression of plasminogen activator inhibitor(PAI)-1 to the stomach inhibits gut-brain signalling by the satiety hormone cholecystokinin (CCK). Doctor of Philosophy thesis, University of Liverpool.

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Energy homeostasis is a tightly regulated system that is vital for survival involving anorectic and orexigenic signals. Obesity is a maladaptive response where the balance becomes disrupted. Obesity is one of the most concerning health problems of our time. It is no longer considered a consequence of a western lifestyle, with more developing countries now reporting an increased incidence of obesity and associated illnesses. While obesity itself can be debilitating and decrease quality of life, it is the associated comorbidities that are the main cause for concern; including type two diabetes, cancer and thrombo-occlusive diseases. One of the molecules thought to be responsible for occlusive events is plasminogen activator inhibitor (PAI)-1. This inhibitor of the plasminogen system is also reported to be up to 5 fold higher in obese subjects in plasma, and similar to leptin, is released from adipose tissue. PAI-1 is considered to play a protective role in circumstances of gastric mucosal attack, thus a transgenic mouse (PAI-1HKβ) was generated, with targeted expression of PAI-1 to the gastric parietal cells, to study this. However, an unexpected phenotype emerged, most notably hyperphagia and increased body weight, which formed the basis of these present studies. The gut-brain axis is a major and well-studied regulator of energy homeostasis and this was the focus of this project. The PAI-1HKβ mice when compared to wild-type had decreased brain stem responses to the satiety hormone, Cholecystokinin (CCK). Brainstem responses were also attenuated in wild types pre-treated with exogenous PAI-1. Furthermore, it was shown that the urokinase plasminogen activator (uPA) receptor by which PAI-1 binds, was required to influence the observed decrease in brainstem responses. CCK also has other physiological functions in the role of energy homeostasis, including gastric emptying. While delayed gastric emptying was observed following a protein rich liquid test meal in C57BL/6 mice, PAI-1HKβ mice had a blunted response. Blockade of the CCK1 receptor in C57BL/6 mice also attenuated the delay in gastric emptying. Moreover, exogenous PAI-1 attenuated CCK-mediated inhibition of gastric emptying. The PAI-1HKβ mice had an attenuated inhibition of gastric emptying of a non-nutrient containing liquid test meal in response to CCK. Treatment with gastrin was shown to increase plasma PAI-1 and attenuated delayed gastric emptying in C57BL/6 mice. Food intake is stimulated by orexigens, most notably ghrelin, working via appetite-stimulating neurons in the arcuate nucleus. While ghrelin stimulated feeding in fed ad libitum C57BL/6 mice, PAI-1 increased feeding in previously fasted C57BL/6 mice only. This response to ghrelin and PAI-1 was also replicated in PAI-1 -/- mice, suggesting PAI-1 is not required for the orexigenic effect of ghrelin. Moreover, intrapertoneal (ip.) administered ghrelin increased fos expression in arcuate neurons of both C57BL/6 and PAI-1 -/- mice, whereas ip. PAI-1 did not. Weight loss in the PAI-1HKβ mice appeared to reverse the insensitivity to CCK in terms of gastric emptying. PAI-1HKβ mice were also found to be insensitive to other gut-derived satiety hormones, suggesting gastric PAI-1 is an anti-satiety factor. However, mice null for wild-type gastric PAI-1 responded normally to CCK prior to feeding, indicating that wild type is necessary for CCK insensitivity in the PAI-1HKβ mice. The current findings demonstrate that PAI-1 plays a role in the control of food intake. PAI-1 is an example of a novel anti-satiety factor that can modulate gut-brain signalling via the vagus nerve in order to preserve nutrient intake. This work provides a platform for future investigations into novel pathways implicated in the development and treatment of obesity.

Item Type: Thesis (Doctor of Philosophy)
Additional Information: alt_title: Targeted expression of plasminogen activator inhibitor(PAI)-1 to the stomach inhibits gut-brain signalling by the satiety hormone cholecystokinin (CCK) Date: 2013-10 (completed)
Uncontrolled Keywords: PAI-1 Obesity, Gut-Brain signalling, Feeding, in vivo, CCK
Divisions: Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 07 Aug 2014 08:42
Last Modified: 17 Dec 2022 00:12
DOI: 10.17638/00017373
  • Dockray, Graham
  • Varro, Andrea