Ciglitazone-a human PPARγ agonist-disrupts dorsoventral patterning in zebrafish

Area of Science:

• Developmental Biology
• Molecular Endocrinology
• Zebrafish Embryogenesis

Background:

• Peroxisome proliferator-activated receptor γ (PPARγ) is crucial for lipid/glucose homeostasis and adipocyte differentiation.
• Its role in early embryonic development, particularly gastrulation and patterning, remains largely unexplored.
• Maternal pparγ transcripts are present early in zebrafish development, preceding zygotic transcription.

Purpose of the Study:

• To investigate the hypothesis that PPARγ regulates gastrulation and dorsoventral patterning in zebrafish embryos.
• To elucidate the mechanism of action of PPARγ agonists during early development.

Main Methods:

• Utilized ciglitazone, a PPARγ agonist, and a pparγ-specific morpholino for knockdown in zebrafish embryos.
• Assessed dorsoventral patterning and gastrulation defects following exposure.
• Performed mRNA-sequencing to analyze gene expression changes.

Main Results:

• Ciglitazone exposure from 4 hpf caused concentration-dependent ventralization without affecting epiboly.
• This ventralization was reversed by co-exposure with dorsomorphin, a BMP signaling inhibitor.
• PPARγ knockdown did not prevent ciglitazone-induced ventralization, indicating a PPARγ-independent effect.
• mRNA-sequencing indicated alterations in lipid and cholesterol metabolism.

Conclusions:

• PPARγ is not required for ciglitazone-induced ventralization or toxicity in zebrafish embryos.
• Ciglitazone exerts its effects through a novel, PPARγ-independent pathway during early development.
• This suggests a complex, uncharacterized mechanism underlying PPARγ agonist-induced phenotypes.