Title:
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Expression and roles of the lipid-responsive receptors GPR119 and GPR120 in pancreatic islets
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The various endocrine cell types present in mammalian Islets of Langerhans
express a range of lipid-responsive G-proteln coupled receptors (GPCRs)
including GPR119 and GPR120. These are each reported to be expressed In
islet beta-cells and GPR 119 has been Implicated In the augmentation of
glucose-stimulated insulin secretion by certain derivatives of long chain
unsaturated fatty acids. By contrast GPR 120 does not appear to regulate
insulin secretion and its role is unclear
In addition to their ability to regulate hormone secretion long-chain fatty
acids and their derivatives can also influence beta-cell viability but It IS
unclear whether GPCRs are involved in mediating this response Therefore.
the work undertaken in thesis has explored the possible involvement of
GPR119 and GPR120 in the regulation of beta-cell viability.
Long chain fatty acids exert differential effects on beta-cell viabilty according
to their chain length and degree of unsaturation. Saturated molecules with
chain lengths of C16 or greater are cytotoxic to beta-cells dunng chronic
exposure, whereas the equivalent monounsaturates are well tolerated and
can be cytoprotective Since GPR 119 and GPR 120 predominantly bind long
chain unsaturated fatty acids (or their derivatives) it is possible that they
might play a role. This has been studied using the clonal rat beta-cell lines
BRIN-BD11 and INS-1 as well as a knockout mouse model in which GPR 120
expression was ablated.
An endogenous ligand for GPR119 (oleoytetnanolamide OEA) was a potent
cytoprotective agent in both clonal rat beta-cell lines However hydrolysis of
OEA by endogenous fatty acid amide hydrolase (FAAH) appeared to be
necessary for cytoprotection. suggesting that free oleate rather than the
parent molecule. OEA. might be the protective species Since free oleate
does not activate GPR 119. this implies that cytoprotection does not require
GPR 119 IIgatlon In support of this. four synthetic GPR119 aqonists failed to
replicate the cytoprotection seen with OEA Manipulation of GPR120
production in clonal beta-cell lines (either by shRNA mediated knock-down or
by inducible over-expression) did not alter the cytoprotective capacities of
unsaturated fatty acids, suggesting that GPR120 is also unlikely to be
involved in the cytoprotection. However, changes in GPR 120 expression
were found to lead to alterations in the levels of a number of beta-cell genes
including many that regulate inflammatory responses. Consistent with this,
mice fed a diet enriched in long chain fatty acids displayed enhanced
macrophage Infiltration into the islets suggesting the development of a pro-
Inflammatory response Further study revealed, however, that this was not
Influenced by ablation of GPR 120 and that it may reflect the change in islet
volume associated with high fat feeding rather than altered GPR 120
signalling per se More surprisingly, it was established in the mouse, that
GPR 120 is expressed predominantly in delta-cells rather than in beta-cells
and a potential role in reputation of somatostatin secretion was revealed.
Overall, therefore. the studies demonstrate that GPR119 and GPR120 may
play roles in the control of islet hormone secretion but they do not appear to
be involved in the regulation of cell viability mediated by long chain fatty
acids.
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