GPR146 acts as modulator in adipocyte differentiation and homeostasis influencing lipid metabolism in vitro and in vivo

Aims In our human MAINTAIN study, we observed a significant increase in adipose tissue expression of G protein-coupled receptor 146 (GPR146) over the three months weight reduction interval. Furthermore, adipose GPR146 expression correlated negatively with BMI and positively with insulin sensitivity before weight loss, and increased adipose GPR146 expression is associated with enhanced insulin-mediated suppression of fatty acid release before and after weight loss. Metabolic investigation of our Gpr146-deficient mouse line (GPR146-KO) revealed a lean, adipose tissue-emphasizing phenotype that is protected from diet-induced obesity. Therefore, we investigated the role of GPR146 during adipocyte differentiation and its role in the modulation of lipid metabolism.

Methods: We studied murine 3T3-L1 cells in which Gpr146 was genetically deleted by CRISPR/Cas9 editing during differentiation into adipocytes. Furthermore, we isolated primary progenitor cells from adipose tissue of GPR146-deficient mice and differentiated them ex vivo. During differentiation, we investigated the expression profile of adipocyte differentiation marker and the storage of lipid droplets. Moreover, we examined mitochondrial respiration of adipose tissue-derived cells in response to lipid stimulation. Finally, we analyzed the lipogenic and lipolytic capacity of adipose tissue of GPR146-KO mice and their lipid metabolism regarding uptake and release.

Results: Further analysis of the MAINTAIN data revealed a prediction of adipose GPR146 expression for body weight regain. During in vitro adipocyte differentiation, we observed a significant upregulation of GPR146 expression throughout the differentiation process. In GPR146-deficient 3T3 cells, the differentiation was nearly abolished and virtually no lipid accumulation was found. Other differentiation marker such as Cd36, Fabp4 and Plin1 were also downregulated due to GPR146 deficiency, which could be substantially reversed by stimulation via beta-adrenergic receptors. In vivo, we observed lower plasma triglycerides and cholesterol levels in GPR146-KO. Plasma cholesterol levels could be restored via isoprenaline-treatment of mice. Upon lipid challenge, reduced triglyceride and free fatty acid concentration were reduced in plasma. Lipid release from adipocytes was reduced under basal conditions but elevated under stimulation.

Conclusion: Our results indicate that GPR146 plays a significant role in adipocyte differentiation and modifies functionality and homeostasis of adipose tissue. GPR146 not only affects lipid uptake into circulation and (adipose) tissue but also adjusts lipid release from adipose tissue, thereby modulating lipid metabolism.

Publikationsverlauf

Artikel online veröffentlicht:
18. April 2024