G12 Activation Alone Doesn’t Affect WAT Browning or Glucose Homeostasis, but Combined Activation Shows Promising Results
A new study has found that the activation of G12 signaling alone does not have a significant impact on white-adipose tissue (WAT) browning, glucose homeostasis, or brown-adipose tissue (BAT) activation. However, when combined with the activation of G protein-coupled receptor (GPCR) β3AR through the administration of the β3AR-selective agonist CL316,243, promising results were observed.
The study, conducted on mice, involved the use of chemogenetic G12 activation to examine its effects on WAT browning and glucose homeostasis. Daily intraperitoneal injections of the compound CNO were given to both control mice and mice with adipo-G12D (genetically modified) mice for five days prior to tissue collection. However, analysis showed that there were no significant differences in the expression of thermogenic and adipogenic genes in WAT or BAT between the two genotypes. Additionally, there were no morphological changes observed in both types of adipose tissue. Furthermore, glucose tolerance remained unchanged in both groups, regardless of whether they were fed a regular chow or a high-fat diet.
Despite these findings, researchers decided to investigate the potential synergistic effects of G12 activation combined with β3AR stimulation through the administration of CL316,243. Both groups of mice were given daily injections of CL316,243 and CNO for five days and then evaluated for WAT browning. The results showed a significant upregulation of key thermogenic genes in the inguinal WAT of adipo-GD mice, but not in adipogenic genes. Western blotting confirmed increased protein levels of UCP1, a marker of brown and beige adipocytes, in the adipo-GD mice. Histological analysis also revealed increased numbers of multilocular cells, which are characteristic of beige adipocytes. However, the synergistic effects of CNO and CL316,243 on thermogenic gene expression and histology in BAT were minimal.
To further understand the pathways affected by G12 activation, researchers performed RNA-seq transcriptome analysis using samples from inguinal WAT. The analysis revealed that the upregulated genes in adipo-GD mice were involved in oxidative phosphorylation, adipogenesis, and fatty acid metabolism pathways, which are crucial for the development of beige adipocytes. Conversely, downregulated gene sets were associated with the inflammatory response, such as interferon-α response and TNF-α signaling via NF-κB, which are involved in adipocyte dysfunction, including insulin resistance.
Overall, this study highlights that G12 activation alone does not significantly impact WAT browning, BAT activation, or whole-body glucose homeostasis. However, when combined with β3AR stimulation, positive effects on WAT browning were observed. These findings provide valuable insights into the complex mechanisms underlying adipose tissue function and may have implications for the development of targeted therapies for metabolic disorders such as obesity and diabetes. Further research is necessary to fully understand the potential therapeutic applications of these findings.
