GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells

Usui, Ryota; Yabe, Daisuke; Fauzi, Muhammad; Goto, Hisanori; Botagarova, Ainur; Tokumoto, Shinsuke; Tatsuoka, Hisato; Tahara, Yoshiro; Kobayashi, Shizuka; Manabe, Toshiya; Baba, Yoshifumi; Kurosaki, Tomohiro; Herrera, Pedro Luis; Ogura, Mariko; Nagashima, Kazuaki; Inagaki, Nobuya

doi:10.1038/s41598-019-52048-1

Cited by 30 publications

(33 citation statements)

References 48 publications

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“…Studies have shown that the role of GPR40/120 activation is controversial in the occurrence of obesity, inflammation and T2DM. Usui et al found that after stimulated by FFAs, GPR40 and GPR120 on the surface of pancreatic β-cells can activate ERK1/2 and PI3K/Akt signaling pathways to inhibit inflammatory response and improve IR as well as glucose homeostasis [ 36 , 39 , 40 ]. But with the in-depth study, more and more results indicate that GPR40 and GPR120 do not play a beneficial role fully.…”

Section: Discussionmentioning

confidence: 99%

Obesity-induced elevated palmitic acid promotes inflammation and glucose metabolism disorders through GPRs/NF-κB/KLF7 pathway

et al. 2022

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Objective Our previous results have shown that obesity-induced excessive palmitic acid (PA) can promote the expression of KLF7, which plays a vital role in regulation of inflammation, glucose metabolism. But the exact mechanism of PA up-regulating the expression of KLF7 is not clear yet. This study is intend to explore whether PA promoting KLF7 expression through GPRs/NF-κB signaling pathway, causing inflammation and glucose metabolism disorders. Methods Cells were blocked GPRs/NF-κB under PA stimulation in vitro to demonstrate the molecular mechanism of PA up-regulates KLF7 expression. The regulatory effect of p65 on KLF7 was detected by luciferase reporter gene assay. Blocking GPRs/NF-κB in diet-induced obesity mice to detect the expression of KLF7, inflammatory cytokines and glucose metabolism related factors, clarifying the effects of GPRs/NF-κB on KLF7 in vivo. Results In 3T3-L1 adipocytes and HepG2 cells, PA could up-regulate the expression of KLF7 by promoting the GPR40/120-NF-κB signaling pathway, leading to inflammation and reduced glucose consumption (p < 0.05 for both). Luciferase reporter gene assay and ChIP assay showed that p65 could transcriptionally up-regulates the expression of KLF7. In high-fat diet (HFD) mice, after intraperitoneal injection of GPR40 or GPR120 blocker, the levels of p-p65 and KLF7 in epididymal white adipose tissue and liver were significantly decreased (p < 0.05 for both). Pharmacological inhibition of p-p65 significantly attenuated KLF7 expression and improved glucose tolerant and insulin sensitive (p < 0.05 for both). Conclusions Our results indicate that obesity-induced elevated palmitic acid promotes inflammation and glucose metabolism disorders through GPRs/NF-κB/KLF7 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Obesity-induced elevated palmitic acid promotes inflammation and glucose metabolism disorders through GPRs/NF-κB/KLF7 pathway

et al. 2022

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“…In particular, increased levels of FFA in the blood enhances insulin secretion by pancreatic β-cells ( Figure 4B ). This is because β-cells express the fatty acid receptor GPR40 ( Itoh et al, 2003 ), which, as a G-protein-coupled receptor, activates the phospholipase C pathway that triggers release of calcium ions from the endoplasmic reticulum and stimulates exocytosis of insulin from cytoplasmic insulin granules ( Rorsman and Ashcroft, 2018 ; Usui et al, 2019 ). Alternatively, FFA can also promote upregulation of CYPD and increase the mitochondrial proton leak in β-cells, which enhances non-glucose-stimulated insulin secretion ( Taddeo et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

Cadez

Zafer

et al. 2020

eLife

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Cell cycle progression and lipid metabolism are well-coordinated processes required for proper cell proliferation. In liver diseases that arise from dysregulated lipid metabolism, proliferation is diminished. To study the outcome of CDK1 loss and blocked hepatocyte proliferation on lipid metabolism and the consequent impact on whole-body physiology, we performed lipidomics, metabolomics, and RNA-seq analyses on a mouse model. We observed reduced triacylglycerides in liver of young mice, caused by oxidative stress that activated FOXO1 to promote expression of Pnpla2/ATGL. Additionally, we discovered that hepatocytes displayed malfunctioning β-oxidation, reflected by increased acylcarnitines (ACs) and reduced β-hydroxybutyrate. This led to elevated plasma free fatty acids (FFAs), which were transported to the adipose tissue for storage and triggered greater insulin secretion. Upon aging, chronic hyperinsulinemia resulted in insulin resistance and hepatic steatosis through activation of LXR. Here, we demonstrate that loss of hepatocyte proliferation is not only an outcome but also possibly a causative factor for liver pathology.

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“…12 Previous research has confirmed that the activation of GPR40 can increase the secretion of insulin. 13,14 Owing to this function, many GPR40 agonists have the potential for extensive applications in type II diabetes mellitus (T2DM). 15,16 In contrast, little research has been done to investigate the physiological effects of GPR40 in other fields.…”

Section: Introductionmentioning

confidence: 99%

<p>Activation of GPR40 Suppresses AGE-Induced Reduction of Type II Collagen and Aggrecan in Human SW1353 Chondrocytes</p>

Lin

Zhang

et al. 2020

DDDT

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Introduction: Osteoarthritis (OA) is an age-related chronic degenerative disease. Accumulation of advanced glycation end products (AGEs) induces degradation of the articular extracellular matrix (ECM) and is considered a critical step toward the development and progression of OA. GPR40 is a well-known free fatty acid receptor, which possesses pleiotropic effects in different types of diseases. However, the biological function of GPR40 in OA is indistinct. The purpose of the present study was to determine the impact of the GPR40 agonist GW9508 on AGEs-treated chondrocytes. Materials and Methods: Cultures of human SW1353 chondrocytes were stimulated with GW9508, followed by exposure to 100 µg/mL AGEs. Gene and protein expression of TNF-α, IL-6, MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5 were measured by real-time PCR and ELISA analysis. The levels of type II collagen, aggrecan, and nuclear NF-κB p65 were measured by Western blot analysis. A luciferase assay measured the transcriptional activity of NF-κB. Results: The results show that treatment with AGEs decreased the expression of GPR40 in human SW1353 chondrocytes. Treatment with GW9508 plays a beneficial role in protecting type II Collagen and aggrecan from degeneration by attenuating the expression of MMP-3, MMP-13, ADAMTS-4, and ADAMTS-5. Additionally, GW9508 reduces the appearance of proinflammatory cytokines and suppresses NF-κB activation in AGEs-induced chondrocytes. Notably, co-treatment with GW1100, a specific antagonist of GPR40, abolishes the beneficial role of GW9508 against AGEs, implying that GPR40 mediates these effects of GW9508. Conclusion: Our results suggest that GPR40 is a novel therapeutic target for OA and that GPR40 agonists, including GW9508, may have therapeutic potential in preventing and slowing the progression of OA.

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GPR40 activation initiates store-operated Ca2+ entry and potentiates insulin secretion via the IP3R1/STIM1/Orai1 pathway in pancreatic β-cells

Cited by 30 publications

References 48 publications

Obesity-induced elevated palmitic acid promotes inflammation and glucose metabolism disorders through GPRs/NF-κB/KLF7 pathway

Obesity-induced elevated palmitic acid promotes inflammation and glucose metabolism disorders through GPRs/NF-κB/KLF7 pathway

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

<p>Activation of GPR40 Suppresses AGE-Induced Reduction of Type II Collagen and Aggrecan in Human SW1353 Chondrocytes</p>

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