Yan, Anqi;
(2019)
Role of PI3K p110α in adrenergic regulation of adipose tissue metabolism.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The insulin signalling pathway plays a pivotal role in the regulation of cellular and organismal metabolism. The phosphoinositide 3-kinase (PI3K) catalytic subunit p110a is the principal PI3K catalytic subunit engaged in signalling downstream of insulin receptor (IR). Recent research has demonstrated that inhibition of PI3K has beneficial effects on adipose tissue metabolism and protects mice as well as primates from obesity and metabolic syndrome. Mice with global inactivation of the p110a subunit accumulate less body weight with age and have less fat tissue compared to wild type mice. Here we have investigated the effects of adipose tissue-specific p110a deletion on the metabolic physiology of mice over the course of ageing. We found that adipose tissue-specific inactivation of p110a conferred protection from age-related weight gain. At the molecular level, this was mediated by potentiation of beta-adrenergic receptor signalling, as a result of PI3K p110a inhibition, which impacted on cellular phosphodiesterase activity and cAMP levels. The beta-adrenergic receptor signalling pathway is well-known to regulate adipose tissue metabolism. The potentiating effect of p110a inhibition on adrenergic signalling was evident in young mice and middle- age mice, but not in very old mice. Inactivation of PI3K p110a potentiated beta- adrenergic signalling in subcutaneous, but not in visceral, white adipose tissue. Similar results were obtained in a cell line of adipocytes derived from mesenchymal stem cells isolated from human subcutaneous adipose tissue (hMADS). Moreover, pharmacologic inhibition of PI3K p110a promoted mitochondrial metabolism in adipocytes. Consistently, beta-adrenergic agonists increased lipolysis and expression of uncoupling protein 1 to a greater extent under conditions of p110a inhibition in the adipose tissue. Thus, p110a inactivation promoted a so-called ‘browning’ effect in white adipose tissue which increased fatty acid catabolism and energy dissipation as heat. This might be producing a beneficial metabolic effect by preventing lipotoxicity induced by fatty acid accumulation. This in turn might be protecting the adipose tissue from fatty acid-induced senescence.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Role of PI3K p110α in adrenergic regulation of adipose tissue metabolism |
| Event: | University College London |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10070639 |
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