Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates lipid/glucose homeostasis and adipocyte differentiation. While the role of PPARγ in adipogenesis and diabetes has been extensively studied, little is known about PPARγ function during early embryonic development. Within zebrafish, maternally-loaded pparγ transcripts are present within the first 6 h post-fertilization (hpf), and de novo transcription of zygotic pparγ commences at ~48 hpf. Since maternal pparγ transcripts are elevated during a critical window of cell fate specification, the objective of this study was to test the hypothesis that PPARγ regulates gastrulation and dorsoventral patterning during zebrafish embryogenesis. To accomplish this objective, we relied on (1) ciglitazone as a potent PPARγ agonist and (2) a splice-blocking, pparγ-specific morpholino to knockdown pparγ. We found that initiation of ciglitazone—a potent human PPARγ agonist—exposure by 4 hpf resulted in concentration-dependent effects on dorsoventral patterning in the absence of epiboly defects during gastrulation, leading to ventralized embryos by 24 hpf. Interestingly, ciglitazone-induced ventralization was reversed by co-exposure with dorsomorphin, a bone morphogenetic protein signaling inhibitor that induces strong dorsalization within zebrafish embryos. Moreover, mRNA-sequencing revealed that lipid- and cholesterol-related processes were affected by exposure to ciglitazone. However, pparγ knockdown did not block ciglitazone-induced ventralization, suggesting that PPARγ is not required for dorsoventral patterning nor involved in ciglitazone-induced toxicity within zebrafish embryos. Our findings point to a novel, PPARγ-independent mechanism of action and phenotype following ciglitazone exposure during early embryonic development.
Highlights
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that, upon activation by endogenous or exogenous ligands, heterodimerizes with retinoid X receptor and binds to PPAR response elements in order to regulate transcription of genes such as adipocyte fatty acid binding protein (A-FABP/aP2) and cytochrome P450 4B1 (CYP4B1)How to cite this article Cheng V, Dasgupta S, Reddam A, Volz DC. 2019
Zebrafish and mammalian PPARs are highly conserved As expected, when comparing protein sequences of PPARs from human, mouse, rat, and zebrafish, we found that zebrafish PPARa (a/b), PPARδ (a/b), and Peroxisome proliferator-activated receptor γ (PPARγ) are closely related to mammalian PPARa, PPARδ, and PPARγ, respectively (Fig. 1A)
When comparing ligand binding pocket amino acid residues involved with rosiglitazone binding to human PPARγ (Sheu et al, 2005), we found that eight out of 13 residues that interact with thiazolidinediones are conserved between humans and zebrafish (Fig. S3)
Summary
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that, upon activation by endogenous (e.g., fatty acids, prostaglandins) or exogenous (e.g., thiazolidinediones) ligands, heterodimerizes with retinoid X receptor and binds to PPAR response elements in order to regulate transcription of genes such as adipocyte fatty acid binding protein (A-FABP/aP2) and cytochrome P450 4B1 (CYP4B1)How to cite this article Cheng V, Dasgupta S, Reddam A, Volz DC. 2019. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that, upon activation by endogenous (e.g., fatty acids, prostaglandins) or exogenous (e.g., thiazolidinediones) ligands, heterodimerizes with retinoid X receptor and binds to PPAR response elements in order to regulate transcription of genes such as adipocyte fatty acid binding protein (A-FABP/aP2) and cytochrome P450 4B1 (CYP4B1). PPARγ plays a central role in lipid/glucose homeostasis, adipocyte differentiation, proliferation, and immune response (Chawla et al, 1994; Tontonoz, Hu & Spiegelman, 1994; Ricote et al, 1998; Martin et al, 1998). As a mediator of adipogenesis, PPARγ plays a role in the progression of pathological diseases such as obesity, diabetes, atherosclerosis, cancer, and chronic inflammation (Vidal-Puig et al, 1996; Tontonoz et al, 1997; Gilroy et al, 1999). PPARγ agonists (e.g., rosiglitazone and pioglitazone) have been used for nearly 20 years for treatment of type II diabetes mellitus (Lehmann et al, 1995; Martens et al, 2002)
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