GPR84-mediated signal transduction affects metabolic function by promoting brown adipocyte activity
Xue-Nan Sun, … , Rana K. Gupta, Da Young Oh
Xue-Nan Sun, … , Rana K. Gupta, Da Young Oh
Published October 19, 2023
Citation Information: J Clin Invest. 2023;133(24):e168992. https://doi.org/10.1172/JCI168992.
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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 4

GPR84 stimulation promotes brown adipocyte function.

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GPR84 stimulation promotes brown adipocyte function. (A) Thermogenic gen...
(A) Thermogenic genes were measured by qPCR in fully differentiated brown adipocytes from WT and GPR84-KO mice. Data are represented as means ± SEM of at least 3 independent experiments. n = 9/group. (B) Images of Oil Red O staining in WT and KO brown adipocytes with or without GPR84 agonist 6-OAU treatment. Image is a representative image from 3 independent experiments. n = 5/group. Scale bar: 50 μm. (C) Ucp1, Cidea, and Pgc1α mRNA levels in WT and KO brown adipocytes with or without 6-OAU treatment. Data are represented as mean ± SEM of 2 independent experiments. n = 6/group. (D) OCR was measured in WT and KO brown adipocytes. Cells were pretreated with or without 6-OAU for 30 minutes before OCR was measured by a Seahorse X24 analyzer. Data are represented as means ± SEM of at least 3 independent experiments in duplicate. n = 5/group. (E) WT and GPR84-KO brown adipocytes were incubated with the calcium-sensitive dye Fluo-4 AM for 1 hour at RT, followed by live-cell imaging with a confocal laser-scanning microscope and stimulation with 6-OAU (50 μM). Data are representative images from more than 3 independent experiments. n = 6–10/group. Scale bar: 50 μm. (F) WT brown adipocytes were pretreated with 6-OAU (50 μM) for 1 hour, followed by treatment with BAPTA-AM for 30 minutes, and then OCR was measured. (G) Brown adipocytes were pretreated with 6-OAU (50 μM) for 1 hour and treated with Ru360 for 1 hour, and then OCR was measured. Data and images are representative of at least 3 independent experiments in duplicate. n = 5/group. **P < 0.01; ***P < 0.001; ****P < 0.0001, 2-tailed Student’s t test (A–C); 2-way ANOVA followed by Bonferroni’s multiple-comparison test (D, F, and G). See also Supplemental Figure 5.