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 2

Phenotypes of GPR84-KO mice in young versus old mice.

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Phenotypes of GPR84-KO mice in young versus old mice. (A) Body weights (...
(A) Body weights (BW) of different ages of WT and GPR84-KO mice at RT. Data are represented as means ± SEM from at least 2 independent cohorts. n = 8–13/group/cohort. (B) Insulin tolerance test of WT and GPR84-KO mice on normal chow diet at different ages. n = 10/group. (C) H&E staining in BAT of WT and GPR84-KO mice at different ages at RT. Scale bar: 50 μm. (D) UCP1 staining and quantification of UCP1+ area in BAT of WT and GPR84-KO mice of different ages at RT. Scale bar: 50 μm. Data are representative images from at least 3 independent mouse cohorts. n = 6/group/cohort. (E and F) Thermogenic gene expression (E) and FA metabolism–related gene expression (F) were measured by qPCR in BAT from WT and GPR84-KO mice at different ages. n = 4–5/group for 3 months old; n = 9–10/group for 13 month old. (G and H) OCR was measured in BAT from WT and GPR84-KO mice at different ages. Data are represented as means ± SEM of at least 3 independent experiments in duplicate. n = 3–6/group. All data are represented as means ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001, 2-tailed Student’s t test (A, D, E, and F); 2-way ANOVA followed by Bonferroni’s multiple-comparison test (B, G, and H). See also Supplemental Figures 1 and 2.