GPR92 activation in islet macrophages controls β cell function in a diet-induced obesity model
Camila O. de Souza, … , Rana K. Gupta, Da Young Oh
Camila O. de Souza, … , Rana K. Gupta, Da Young Oh
Published September 6, 2022
Citation Information: J Clin Invest. 2022;132(21):e160097. https://doi.org/10.1172/JCI160097.
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Research Article Inflammation Metabolism

GPR92 activation in islet macrophages controls β cell function in a diet-induced obesity model

Abstract

The molecular mechanisms underlying obesity-induced increases in β cell mass and the resulting β cell dysfunction need to be elucidated further. Our study revealed that GPR92, expressed in islet macrophages, is modulated by dietary interventions in metabolic tissues. Therefore, we aimed to define the role of GPR92 in islet inflammation by using a high-fat diet–induced (HFD-induced) obese mouse model. GPR92-KO mice exhibited glucose intolerance and reduced insulin levels — despite the enlarged pancreatic islets — as well as increased islet macrophage content and inflammation level compared with WT mice. These results indicate that the lack of GPR92 in islet macrophages can cause β cell dysfunction, leading to disrupted glucose homeostasis. Alternatively, stimulation with the GPR92 agonist farnesyl pyrophosphate results in the inhibition of HFD-induced islet inflammation and increased insulin secretion in WT mice, but not in GPR92-KO mice. Thus, our study suggests that GPR92 can be a potential target to alleviate β cell dysfunction via the inhibition of islet inflammation associated with the progression of diabetes.

Authors

Camila O. de Souza, Vivian A. Paschoal, Xuenan Sun, Lavanya Vishvanath, Qianbin Zhang, Mengle Shao, Toshiharu Onodera, Shiuhwei Chen, Nolwenn Joffin, Lorena M.A. Bueno, Rana K. Gupta, Da Young Oh

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Figure 4

GPR92 activation promotes antiinflammatory responses and improves β cell function.

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GPR92 activation promotes antiinflammatory responses and improves β cell...
(A) Peritoneal Macrophages (pMacs) from WT and KO mice cultured in vitro with or without FPP (10 μM) for 1 hour and then treated with LPS (1 ng/mL) for 15 minutes to detect JNK phosphorylation. The top panel is a representative image of 3 independent experiments, and the bar graph (bottom panel) shows fold induction over basal after normalization for total JNK. (B) Gene expression of proinflammatory mediators, Tnfa, Mcp1, and Il6 in the islets from WT and KO mice cultured in vitro with (+) or without (–) FPP (100 μM) for 24 hours and then treated with LPS (+) (1 ng/mL) or PBS (–) for 2 hours, n = 5–6/group. (C and D) GSIS of WT islets cultured in vitro with conditioned medium (CM) obtained from WT or KO (C) pMacs or (D) IMs previously incubated with or without FPP (100 μM) for 24 hours. The islets were cultured with CM diluted to 1:5 to reflect the macrophage/β cell ratio in HFD-mice islets, (C) n = 9–10/group, (D) n = 4–6/group. The insulin secreted in the GSIS (ng/mL) was normalized by the islets total insulin (ng/mL) and then multiplied by 100. (E and F) Insulin secretion (ng/mL/min) of perfused pancreas from WT versus KO on a (E) NCD or (F) HFD. Pancreas was perfused with a basal glucose concentration (2.8 or 5 mmol/L) for 35 minutes, FPP (20 μM) was added to the perfusate during 10–25 minutes, and arginine (10 μM) from 35–45 minutes, n = 3/group. The bar graph shows the incremental AUC values of insulin secretion during FPP infusion. (G) GTT in WT mice on a HFD treated with FPP (0.1 mg/kg, i.p.) or saline (vehicle) for 1 week, and respective AUC, n = 4–11/group. (H) GSIS in WT mice on HFD treated with FPP or saline (vehicle) for 1 week, n = 4–11/group. All data are expressed as mean ± SEM. ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05 by 2-way ANOVA with Bonferroni’s post hoc.