(436) Assessing the Impact of Tirzepatide Exposure on Human Fetal Neural Stem Cells.

Glucagon-like peptide-1 receptor (GLP-1R) agonists are now commonly used for weight loss and diabetes management. Semaglutide (Ozempic/Wegovy) targets GLP-1R, whereas tirzepatide (Mounjaro/Zepbound) is a dual receptor agonist that also activates glucose-dependent insulinotropic receptor (GIPR). The actions of these drugs on brain development remain poorly understood despite fetal exposures occurring. Previously we modeled the effects of semaglutide on neurodevelopment by exposing human fetal neural stem cells (NSCs) in vitro and observed no obvious changes. Due to differences between these drugs, we hypothesize that tirzepatide may alter development and examined its effects on NSC programming and inflammatory responses.

Study Design:

Commercially available fetal NSCs were exposed to a physiological concentration of tirzepatide or the vehicle. In parallel they were given PBS as a control or Interleukin-1 beta (IL-1B) to stimulate inflammatory responses. Cells were harvested 24-hours post exposure (n=5-6 per condition) and examined for gene expression. 

Results:

The expression of genes related to stem cell programming (NESTIN, SOX2) and neural differentiation (TUBBIII, GFAP) was not different with tirzepatide exposure and/or IL-1B (Figure 1A). Tirzepatide alone significantly lowered the expression of TNF but did not impact the upregulation of proinflammatory genes by IL-1B (Figure 1B). GLP-1R was significantly downregulated with IL-1B irrespective of tirzepatide exposure, whereas GIPR did not change.

Conclusion:

There was a significant downregulation of TNF with tirzepatide, not previously observed with semaglutide. No other changes in NSC programming were observed. TNF is essential not only for inflammation but also developmental processes. Lower levels of TNF may alter NSC proliferation and survival during normal brain formation. The downregulation of GLP1R with inflammatory stimulation may disrupt metabolic signaling within the developing brain. Further research is warranted to validate the clinical significance of these findings in exposed pregnancies.