Purinergic signalling in human adipose-derived mesenchymal stromal cells and in vitro differentiated adipocytes

Ali, Seema (2019) Purinergic signalling in human adipose-derived mesenchymal stromal cells and in vitro differentiated adipocytes. Doctoral thesis, University of East Anglia.

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Abstract

Obesity is now a global epidemic, which represents a significant health problem. Obesity is defined as an excessive accumulation of adipose tissue mass, thus understanding adipose biology has become imperative to uncovering novel drug targets in the fight against obesity. Purinergic signalling has been implicated in a wide variety of physiological functions, however very little is currently known about the role of purinergic signalling in human adipocytes and their progenitor cells. This project aimed to characterise the P2 receptor profiles in both primary human adipose-derived mesenchymal stromal cells (AD-MSCs) and in vitro differentiated adipocytes and then determine the functional roles of these receptors in each cell type.
AD-MSCs and in vitro differentiated adipocytes express almost all of the known subtypes of P2 receptors and transient elevations of intracellular calcium levels are observed in both cell types in response to exogenous application of ATP, ADP and UTP. However subtype-selective antagonism revealed that only P2Y2 and P2Y6 receptors are functionally active in AD-MSCs, and P2Y1, P2Y2 and P2Y12 receptors mediate nucleotide-evoked calcium responses in adipocytes. It is unclear what physiological functions P2Y2 and P2Y6 receptors mediate in AD-MSCs, but in adipocytes, P2Y2 receptors appear to regulate basal lipolysis. Selective antagonism and shRNA-mediated knockdown of P2Y2 receptors resulted in an increase in basal glycerol release. In this study, it was determined that continuous P2Y2 activation suppresses basal lipolysis by maintaining calcium tone within adipocytes to tonicly inhibit calcium-sensitive isoforms of adenylate cyclase. This prevents the cytoplasmic accumulation of cAMP, thus inhibiting the activation of protein kinase A-mediated stimulated lipolytic pathways. These findings imply that P2Y2 receptors may be a novel and interesting drug target for modulating adipose tissue expansion. Further research is required to fully investigate the physiological roles of all of the P2 receptor subtypes expressed in these cells.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Stacey Armes
Date Deposited: 12 Apr 2019 11:23
Last Modified: 12 Apr 2019 11:23
URI: https://ueaeprints.uea.ac.uk/id/eprint/70548
DOI:

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