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Chronic activation of GPR40 does not negatively impact upon BRIN-BD11 pancreatic ?-cell physiology and function.

ABSTRACT: BACKGROUND:Free fatty acids (FFAs) are known for their dual effects on insulin secretion and pancreatic ?-cell survival. Short-term exposure to FFAs, such as palmitate, increases insulin secretion. On the contrary, long-term exposure to saturated FFAs results in decreased insulin secretion, as well as triggering oxidative stress and endoplasmic reticulum (ER) stress, culminating in cell death. The effects of FFAs can be mediated either via their intracellular oxidation and consequent effects on cellular metabolism or via activation of the membrane receptor GPR40. Both pathways are likely to be activated upon both short- and long-term exposure to FFAs. However, the precise role of GPR40 in ?-cell physiology, especially upon chronic exposure to FFAs, remains unclear. METHODS:We used the GPR40 agonist (GW9508) and antagonist (GW1100) to investigate the impact of chronically modulating GPR40 activity on BRIN-BD11 pancreatic ?-cells physiology and function. RESULTS:We observed that chronic activation of GPR40 did not lead to increased apoptosis, and both proliferation and glucose-induced calcium entry were unchanged compared to control conditions. We also observed no increase in H₂O₂ or superoxide levels and no increase in the ER stress markers p-eIF2?, CHOP and BIP. As expected, palmitate led to increased H₂O₂ levels, decreased cell viability and proliferation, as well as decreased metabolism and calcium entry. These changes were not counteracted by the co-treatment of palmitate-exposed cells with the GPR40 antagonist GW1100. CONCLUSIONS:Chronic activation of GPR40 using GW9508 does not negatively impact upon BRIN-BD11 pancreatic ?-cells physiology and function. The GPR40 antagonist GW1100 does not protect against the deleterious effects of chronic palmitate exposure. We conclude that GPR40 is probably not involved in mediating the toxicity associated with chronic palmitate exposure.

SUBMITTER: Vilas-Boas EA

PROVIDER: S-EPMC7704488 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Chronic activation of GPR40 does not negatively impact upon BRIN-BD11 pancreatic β-cell physiology and function.

Vilas-Boas Eloisa Aparecida EA Karabacz Noémie N Marsiglio-Librais Gabriela Nunes GN Valle Maíra Melo Rezende MMR Nalbach Lisa L Ampofo Emmanuel E Morgan Bruce B Carpinelli Angelo Rafael AR Roma Leticia Prates LP

Pharmacological reports : PR 20200409 6

<h4>Background</h4>Free fatty acids (FFAs) are known for their dual effects on insulin secretion and pancreatic β-cell survival. Short-term exposure to FFAs, such as palmitate, increases insulin secretion. On the contrary, long-term exposure to saturated FFAs results in decreased insulin secretion, as well as triggering oxidative stress and endoplasmic reticulum (ER) stress, culminating in cell death. The effects of FFAs can be mediated either via their intracellular oxidation and consequent eff ...[more]

PMID: 32274767

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Project description:BackgroundThe G protein-coupled receptor 40 (GPR40), broadly expressed in various tissues such as the spinal cord, exerts multiple physiological functions including pain regulation. This study aimed to elucidate the mechanisms underlying GPR40 activation-induced antinociception in neuropathic pain, particularly related to the spinal glial expression of IL-10 and subsequent β-endorphin.MethodsSpinal nerve ligation-induced neuropathic pain model was used in this study. β-Endorphin and IL-10 levels were measured in the spinal cord and cultured primary microglia, astrocytes, and neurons. Double immunofluorescence staining of β-endorphin with glial and neuronal cellular biomarkers was also detected in the spinal cord and cultured primary microglia, astrocytes, and neurons.ResultsGPR40 was expressed on microglia, astrocytes, and neurons in the spinal cords and upregulated by spinal nerve ligation. Intrathecal injection of the GPR40 agonist GW9508 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia in neuropathic rats, with Emax values of 80% and 100% MPE and ED50 values of 6.7 and 5.4 μg, respectively. Its mechanical antiallodynia was blocked by the selective GPR40 antagonist GW1100 but not GPR120 antagonist AH7614. Intrathecal GW9508 significantly enhanced IL-10 and β-endorphin immunostaining in spinal microglia and astrocytes but not in neurons. GW9508 also markedly stimulated gene and protein expression of IL-10 and β-endorphin in cultured primary spinal microglia and astrocytes but not in neurons, originated from 1-day-old neonatal rats. The IL-10 antibody inhibited GW9508-stimulated gene expression of the β-endorphin precursor proopiomelanocortin (POMC) but not IL-10, whereas the β-endorphin antibody did not affect GW9508-stimulated IL-10 or POMC gene expression. GW9508 increased phosphorylation of mitogen-activated protein kinases (MAPKs) including p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK), and its stimulatory effects on IL-10 and POMC expression were blocked by each MAPK isoform inhibitor. Spinal GW9508-induced mechanical antiallodynia was completely blocked by intrathecal minocycline, IL-10 neutralizing antibody, β-endorphin antiserum, and μ-opioid receptor-preferred antagonist naloxone.ConclusionsOur results illustrate that GPR40 activation produces antinociception via the spinal glial IL-10/β-endorphin antinociceptive pathway.

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Chronic activation of GPR40 does not negatively impact upon BRIN-BD11 pancreatic ?-cell physiology and function.

Publications

Chronic activation of GPR40 does not negatively impact upon BRIN-BD11 pancreatic β-cell physiology and function.

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