Unconjugated
Background/objectives: Signaling mediators of PPAR? influence pathways involved in adipogenesis, lipid storage, inflammation, energy-related processes, and glucose utilization. Recent research indicates that PPAR? coregulators, recruited or released during ligand binding, govern specific gene pathways. It was recently discovered that Gaq, a heterotrimeric G protein subunit, also signals to PPAR? and may significantly affect adipogenesis and glucose sensitivity.
Methods: To explore Gaq's role in adipocytes, we generated CRISPR-mediated Gaq (Gnaq) knockout (Gnaq KO) and scramble control cells from 3T3-L1 preadipocytes.
Results: The absence of Gaq resulted in increased lipid accumulation and elevated serine 273 (but not serine 112) phosphorylation of PPAR?. Gaq deficiency also decreased mitochondrial abundance and respiration in response to PPAR? ligands such as rosiglitazone, pioglitazone, and troglitazone. RNA sequencing comparing differentiated Gnaq KO and control adipocytes identified over 800 differentially expressed genes, including those associated with enhanced lipid metabolism and reduced inflammation. Corresponding PamGene kinome profiling showed increased serine/threonine kinase activity and decreased phosphotyrosine kinase signaling in Gnaq KO adipocytes.
Conclusions: These findings support Gaq as a regulator of adipocyte function, linking kinase signaling pathways to PPAR?-mediated transcription. This research provides mechanistic insights into targeting Gaq as a potential treatment for individuals with obesity and metabolic disorders.
