GPR84-mediated signal transduction affects metabolic function by promoting brown adipocyte activity
Xue-Nan Sun, Yu A. An, Vivian A. Paschoal, Camila O. de Souza, May-yun Wang, Lavanya Vishvanath, Lorena M.A. Bueno, Ayanna S. Cobb, Joseph A. Nieto Carrion, Madison E. Ibe, Chao Li, Harrison A. Kidd, Shiuhwei Chen, Wenhong Li, Rana K. Gupta, Da Young Oh
Xue-Nan Sun, Yu A. An, Vivian A. Paschoal, Camila O. de Souza, May-yun Wang, Lavanya Vishvanath, Lorena M.A. Bueno, Ayanna S. Cobb, Joseph A. Nieto Carrion, Madison E. Ibe, Chao Li, Harrison A. Kidd, Shiuhwei Chen, Wenhong Li, Rana K. Gupta, Da Young Oh
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Research Article Cell biology Metabolism

GPR84-mediated signal transduction affects metabolic function by promoting brown adipocyte activity

Abstract

The G protein–coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, has garnered attention because of its potential involvement in a range of metabolic conditions. However, the precise mechanisms underlying this effect remain elusive. Our study has shed light on the pivotal role of GPR84, revealing its robust expression and functional significance within brown adipose tissue (BAT). Mice lacking GPR84 exhibited increased lipid accumulation in BAT, rendering them more susceptible to cold exposure and displaying reduced BAT activity compared with their WT counterparts. Our in vitro experiments with primary brown adipocytes from GPR84-KO mice revealed diminished expression of thermogenic genes and reduced O2 consumption. Furthermore, the application of the GPR84 agonist 6-n-octylaminouracil (6-OAU) counteracted these effects, effectively reinstating the brown adipocyte activity. These compelling in vivo and in vitro findings converge to highlight mitochondrial dysfunction as the primary cause of BAT anomalies in GPR84-KO mice. The activation of GPR84 induced an increase in intracellular Ca2+ levels, which intricately influenced mitochondrial respiration. By modulating mitochondrial Ca2+ levels and respiration, GPR84 acts as a potent molecule involved in BAT activity. These findings suggest that GPR84 is a potential therapeutic target for invigorating BAT and ameliorating metabolic disorders.

Authors

Xue-Nan Sun, Yu A. An, Vivian A. Paschoal, Camila O. de Souza, May-yun Wang, Lavanya Vishvanath, Lorena M.A. Bueno, Ayanna S. Cobb, Joseph A. Nieto Carrion, Madison E. Ibe, Chao Li, Harrison A. Kidd, Shiuhwei Chen, Wenhong Li, Rana K. Gupta, Da Young Oh

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Figure 5

GPR84 agonist 6-OAU promotes BAT activation in mice at cold exposure.

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GPR84 agonist 6-OAU promotes BAT activation in mice at cold exposure. (A...
(A) Experimental design for 6-OAU in vivo treatment using osmotic minipump implantation. (B) Body temperature of vehicle- (veh) and 6-OAU–treated mice during cold exposure. n = 10/group. (C) H&E staining of BAT from vehicle- and 6-OAU–treated mice 6 days after cold exposure. Images are representative of more than 10 images from at least 3 independent mouse cohorts. n = 4/group/cohort. Scale bar: 50 μm. (D) UCP1 staining in BAT from vehicle- and 6-OAU–treated mice at 6 days after cold exposure. Images are representative of more than 10 images from at least 3 independent mouse cohorts. n = 4/group/cohort. Western blotting analysis of UCP1 protein expression in BAT from vehicle- and 6-OAU–treated mice at 6 days after cold exposure. The scanned bar graphs are expressed as the mean ± SEM. n = 6/group. Scale bar: 50 μm. (E) Thermogenic gene mRNA levels in BAT of vehicle- and 6-OAU–treated mice at 6 days after cold exposure. Data are represented as means ± SEM of at least 3 independent experiments in triplicate. n = 6– 8/group. (F) OCR of BAT from vehicle- and 6-OAU–treated mice at 6 days after cold exposure. Data are represented as means ± SEM of at least 3 independent experiments in duplicate. n = 4/group. (G) Plasma levels of MCP1 were measured by ELISA (n = 5–6/group) in vehicle- and 6-OAU–treated mice, and inflammatory gene expression was measured by qPCR (n = 5–10/group) in BAT from vehicle- and 6-OAU–infused mice at 6 days after cold exposure. *P < 0.05; ****P < 0.0001, 2-tailed Student’s t test (D, E, and G); 2-way ANOVA was followed by Bonferroni’s multiple-comparison test (B and F).