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Zinc finger protein 407 overexpression upregulates PPAR target gene expression and improves glucose homeostasis in
Alyssa Charrier1, Li Wang1, Erin J Stephenson2
1Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio.
Abstract:
The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors is central to the pathophysiology and treatment of metabolic disease through the receptors' ability to regulate the expression of genes involved in glucose homeostasis, adipogenesis, and lipid metabolism. However, the mechanism by which PPAR is regulated remains incompletely understood. We generated a transgenic mouse strain (ZFP-TG) that overexpressed Zfp407 primarily in muscle and heart. Transcriptome analysis by RNA-Seq identified 1,300 differentially expressed genes in the muscle of ZFP-TG mice, among which PPAR target genes were significantly enriched. Among the physiologically important PPARγ target genes, Glucose transporter (Glut)-4 mRNA and protein levels were increased in heart and muscle. The increase in Glut4 and other transcriptional effects of Zfp407 overexpression together decreased body weight and lowered plasma glucose, insulin, and HOMA-IR scores relative to control littermates. When placed on high-fat diet, ZFP-TG mice remained more glucose tolerant than their wild-type counterparts. Cell-based assays demonstrated that Zfp407 synergistically increased the transcriptional activity of all PPAR subtypes, PPARα, PPARγ, and PPARδ. The increased PPAR activity was not associated with increased PPAR mRNA or protein levels, suggesting that Zfp407 posttranslationally regulates PPAR activity. Collectively, these results demonstrate that Zfp407 overexpression improved glucose homeostasis. Thus, Zfp407 represents a new drug target for treating metabolic disease.
Insights
Zfp407 overexpression in mice improved glucose homeostasis by enhancing peroxisome proliferator-activated receptor (PPAR) activity. This suggests Zfp407 as a potential therapeutic target for metabolic diseases.
Area of Science:
- Metabolic disease research
- Nuclear receptor signaling
- Gene regulation
Background:
- Peroxisome proliferator-activated receptor (PPAR) is crucial for metabolic disease pathophysiology and treatment.
- PPAR regulates genes in glucose homeostasis, adipogenesis, and lipid metabolism.
- Mechanisms regulating PPAR activity are not fully understood.
Purpose of the Study:
- To investigate the role of Zfp407 in regulating PPAR activity and its impact on metabolic homeostasis.
- To determine if Zfp407 overexpression affects glucose metabolism and body weight.
Main Methods:
- Generated Zfp407-overexpressing transgenic mice (ZFP-TG) primarily in muscle and heart.
- Performed transcriptome analysis using RNA-Seq to identify differentially expressed genes.
- Conducted cell-based assays to assess Zfp407's effect on PPAR transcriptional activity.
Main Results:
- Zfp407 overexpression significantly enriched PPAR target genes in mouse muscle.
- Increased Glucose transporter (Glut)-4 mRNA and protein levels in heart and muscle of ZFP-TG mice.
- ZFP-TG mice exhibited decreased body weight, lower plasma glucose, insulin, HOMA-IR, and improved glucose tolerance on a high-fat diet.
- Zfp407 synergistically increased transcriptional activity of PPARα, PPARγ, and PPARδ without altering PPAR expression levels, indicating posttranslational regulation.
Conclusions:
- Zfp407 overexpression improves glucose homeostasis and metabolic parameters.
- Zfp407 acts as a posttranslational regulator of PPAR activity.
- Zfp407 represents a novel therapeutic target for metabolic diseases like diabetes.
