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Title: A comparative study of the role of PI 3-Kinase in adipose tissue metabolism and ageing
Author: Bettedi, L.
ISNI:       0000 0004 8503 1315
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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The adipose tissue has emerged as a key organ in the regulation of the rate of ageing. Moreover, excessive or dysfunctional adipose tissue appears to accelerate the onset of multiple age-related metabolic diseases. Interventions such as loss-of-function mutations in the Insulin/IGF-1 Signalling (IIS) pathway in the adipose tissue equivalent organs of experimental models enhance health span and maximum lifespan in these organisms. In this context, attenuation of the Insulin/IGF-1 Signalling (IIS) pathway through global inactivation of phosphoinositide 3-kinase (PI3K) p110α, a key downstream effector of the cascade, has been shown to protect from age-dependent fat accumulation, improve glucose homeostasis and extend the median lifespan in mice. At the signalling level, p110α inhibition protects adipocytes from nutrient overload-induced insulin resistance by disrupting an mTOR/S6K-dependent negative feedback loop of insulin signalling down-regulation. Furthermore, inhibition of p110α increases autophagy in adipocytes and this could prevent excessive fat accumulation in these cells. Also p110α inactivation reduces the fatty acid induced production of proinflammatory cytokines (such as IL-6) and increases βAR-induced lipolysis and mitochondrial oxygen consumption rate. Similar, though not identical, effects of PI3K pathway down-regulation have been documented in fruit flies. In Drosophila, fat bodyspecific PI3K inactivation increases the lipid content of this tissue and enhances the starvation resistance and the longevity of the mutant flies. These findings suggest that PI3K signalling in the adipose tissue can potentially be targeted to retard age-related adipocyte hypertrophy and improve health span and lifespan.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available