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 1

GPR84 expression in BAT.

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GPR84 expression in BAT. (A) Expression of different FA receptors in met...
(A) Expression of different FA receptors in metabolic tissues in human samples from the GTEx database. vWAT, visceral WAT. (B) Expression of GPR84 in different metabolic tissues in human samples from the GTEx database. Bulk tissue gene expression level of GPR84 (Data Source: GTEx Analysis Release V8; ENSG00000139572.3). (C) GPR84 mRNA expression levels were measured by qPCR in different adipose tissues. n = 6–7/group. (D) Representative images of GPR84 IHC staining in different mouse adipose tissues. Data are representative of more than 5 images from at least 3 independent mouse cohorts. Scale bar: 50 μm. Data in bar graphs of the GPR84+ area are represented as means ± SEM. n = 4/group/cohort. (E) GPR84 and UCP1 mRNA expression were measured by qPCR in WT mouse BAT during cold exposure (CE). n = 3/each time point. (F) IHC images of GPR84 and UCP1 in BAT of WT mice exposed to cold and RT. Scale bars: 50 μm. Bar graph indicates quantification of the GPR84+ and UCP1+ areas analyzed by ImageJ from more than 3 images as means ± SEM from at least 3 independent mouse cohorts. n = 5–6/group/cohort. (G) GPR84 and UCP1 mRNA expression were measured by qPCR during brown adipocyte differentiation. Data are represented as means ± SEM of at least 3 independent experiments in triplicate. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, 2-tailed Student’s t test (F); 2-way ANOVA followed by Bonferroni’s multiple-comparison test (C and D). See also Supplemental Figure 1. Primer sequences are available in Supplemental Table 1.