Exploring GPR120-mediated regulatory actions on lipid metabolism, inflammation and autophagy in islet beta cells: its potential as a therapeutic target for obesity and type 2 diabetes
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AbstractBackground and aims: The current therapies for obesity-related type 2 diabetes mellitus (T2DM) are suboptimal. In this regard, G protein-coupled receptor 120 (GPR120) is a novel potential therapeutic target for the prevention and treatment of T2DM. Recent studies have shown that GPR120 activation in pancreatic islet β cells promotes insulin secretion; however, there have been no report to further examine the modulatory roles of resident GPR120 in islet β-cell survival and function under lipotoxicity-induced diabetic conditions. In the present study, we therefore aimed to investigate into the potential roles of islet β-cell GPR120 in regulating lipid metabolism, inflammation and autophagy under lipotoxic conditions.
Materials and methods: Rat β-cell line INS-1E and isolated c57/BL6J mouse islets were used as in vitro and ex vivo models, respectively. GPR120 knockout (KO) mouse islets were used to validate the roles of GPR120. To induce lipotoxicity, β cells and islets were exposed to palmitic acid; GPR120 agonism was achieved by two agonists, namely docosahexenoic acid (DHA) and GSK137647 (GSK); the regulatory roles of GPR120 in β-cell/islet lipid metabolism and inflammation, as well as autophagy were then elucidated; the related signaling pathways involved in the GPR120-mediated protective actions were further examined.
Results: GPR120 agonists DHA and GSK inhibited the mRNA expression of the lipid uptake/synthesis-related genes, such as SREBP-1c, FAS and CD36, in mouse islets and INS-1E cells under lipotoxic conditions. In addition, DHA reversed the lipotoxicity-induced mRNA expression of pro-inflammatory genes in both mouse islets and INS-1E cells, of which these inhibitory effects were abrogated in mouse islets with GPR120 KO. Moreover, the GPR120 KO mouse islets exhibited alterations in the expression of autophagy-related genes. On the other hand, INS-1E cells with GPR120 knockdown exhibited reductions in insulin expression and intracellular insulin content; consistently, GPR120 KO mice were characterized with higher fasting blood glucose levels. Our mechanistic studies further showed that the gene expression related to β-cell proliferation, function and insulin synthesis were reduced in GPR120-knocked-down INS-1E cells. In corroboration, the stimulatory effects of DHA on protein kinase B (also known as Akt) and extracellular signal-regulated kinases (ERK) phosphorylation were abolished in GPR120 KO mouse islets.
Conclusion: These data indicate that GRP120 agonism in β cells/islets may have therapeutic potential in regulating lipid accumulation, lipotoxicity-induced inflammation, and autophagy, as well as being associated with β-cell proliferation and insulin synthesis, probably via the mediation of Akt/ERK signaling pathway.

Supported by: Research Grants Council of Hong Kong (CUHK470413)
All Author(s) ListDan ZHANG, Po Sing LEUNG
Name of Conference53rd Annual Meeting of the European Association for the Study of Diabetes
Start Date of Conference11/09/2017
End Date of Conference15/09/2017
Place of ConferenceLisbon
Country/Region of ConferencePortugal
Proceedings TitleDiabetologia
Title of PublicationDIABETOLOGIA
Year2017
Month9
Volume Number60
Issue NumberSuppl. 1
PublisherSPRINGER
PagesS279 - S279
ISSN0012-186X
eISSN1432-0428
LanguagesEnglish-United Kingdom
Web of Science Subject CategoriesEndocrinology & Metabolism;Endocrinology & Metabolism

Last updated on 2020-05-07 at 00:37