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

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.

In Vivo ZIMIR Imaging of Mouse Pancreatic Islet Cells Shows Oscillatory Insulin Secretion.

Appropriate insulin secretion is essential for maintaining euglycemia, and impairment or loss of insulin release represents a causal event leading to diabetes. There have been extensive efforts of studying insulin secretion and its regulation using a variety of biological preparations, yet it remains challenging to monitor the dynamics of insulin secretion at the cellular level in the intact pancreas of living animals, where islet cells are supplied with physiological blood circulation and oxygenation, nerve innervation, and tissue support of surrounding exocrine cells. Herein we presented our pilot efforts of ZIMIR imaging in pancreatic islet cells in a living mouse. The imaging tracked insulin/Zn2+ release of individual islet ß-cells in the intact pancreas with high spatiotemporal resolution, revealing a rhythmic secretion activity that appeared to be synchronized among islet ß-cells. To facilitate probe delivery to islet cells, we also developed a chemogenetic approach by expressing the HaloTag protein on the cell surface. Finally, we demonstrated the application of a fluorescent granule zinc indicator, ZIGIR, as a selective and efficient islet cell marker in living animals through systemic delivery. We expect future optimization and integration of these approaches would enable longitudinal tracking of beta cell mass and function in vivo by optical imaging.