GPR84-Mediated Signal Transduction Promotes Brown Adipocyte Function

G protein-coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, may be involved in various metabolic conditions but the mechanism remains unclear. We found that GPR84 is highly expressed and functions in brown adipose tissue (BAT). GPR84 knockout mice exhibited increased adiposity and vulnerability to cold exposure after aging, along with an increased BAT lipid content and decreased BAT activation compared to wild-type control mice. In vitro, primary brown adipocytes from GPR84 knockout mice showed reduced expression of thermogenic genes and lower O2 consumption. The GPR84 agonist 6-OAU reversed these effects and restored brown adipocyte activation. In vivo and in vitro results showed that BAT defects in GPR84 knockout mice were attributed to mitochondrial dysfunction. GPR84 activation greatly affected intracellular calcium efflux, further influencing mitochondrial respiration. GPR84 activates BAT by controlling the mitochondrial calcium content and respiration, suggesting a therapeutic target for activating BAT and treating metabolic diseases. HIGHLIGHTSO_LIHigh expression of GPR84 in brown adipocytes is induced by cold stimulation. C_LIO_LIAged GPR84 knockout mice exhibit brown adipose tissue defects under cold exposure. C_LIO_LIGPR84 knockout mice show reduced mitochondrial function of brown adipocytes. C_LIO_LIGPR84 activation improves brown adipocyte functions. C_LI