GPR92 activation in islet macrophages controls β cell function in a diet-induced obesity model
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
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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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 2

Lack of GPR92 expression leads to glucose intolerance via reduced insulin secretion induced by IMs.

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Lack of GPR92 expression leads to glucose intolerance via reduced insuli...
(A) GTT in WT or KO mice on a NCD or a HFD and their respective AUCs. Glucose 1.5 g/kg injected i.p., n = 9–20/group. (B) GSIS in WT or KO mice on a NCD or a HFD. Oral gavage of glucose at 1.5 g/kg, n = 12–23/group. (C) Immunofluorescence of the pancreas. Insulin (green), glucagon (red) and DAPI (blue). Scale bars: 20 μm. (D) Islet size (μm2) and (E) histogram of frequency of islets per size, calculated from IF stained islets in C, n = 20–40 islets from 5 mice/group. (F) Percentage of insulin+ and glucagon+ cells in islets IF, n = 20–40 islets/group. (G) Gene expression of growth factors in islets, n = 3–5/group. (H) GSIS of the islets of WT or KO mice on a NCD (left panel) or a HFD (right panel) cultured in vitro with clodronate or control liposome (7 mg/mL) for 24 hours, n = 5–8/group. See Supplemental Table 1 for primer sequences. Fold change normalized by Rpl19 expression of WT-NCD. Data and images are representative of at least 3 independent experiments. 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.