Zinc finger protein 407 overexpression upregulates PPAR target gene expression and improves glucose homeostasis in mice

Alyssa Charrier, Li Wang, Erin Stephenson, Siddharth V. Ghanta, Chih Wei Ko, Colleen M. Croniger, Dave Bridges, David A. Buchner

Research output: Contribution to journalArticle

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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 PPAR_ 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, PPARγ, PPARγ, and PPARγ. 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.

Original languageEnglish (US)
Pages (from-to)E869-E880
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume311
Issue number5
DOIs
StatePublished - Nov 1 2016

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Peroxisome Proliferator-Activated Receptors
Zinc Fingers
Homeostasis
Up-Regulation
Gene Expression
Glucose
Proteins
Metabolic Diseases
Myocardium
Genes
Adipogenesis
Messenger RNA
Facilitative Glucose Transport Proteins
High Fat Diet
Gene Expression Profiling
Cytoplasmic and Nuclear Receptors
Lipid Metabolism
Transgenic Mice
Body Weight
RNA

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Zinc finger protein 407 overexpression upregulates PPAR target gene expression and improves glucose homeostasis in mice. / Charrier, Alyssa; Wang, Li; Stephenson, Erin; Ghanta, Siddharth V.; Ko, Chih Wei; Croniger, Colleen M.; Bridges, Dave; Buchner, David A.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 311, No. 5, 01.11.2016, p. E869-E880.

Research output: Contribution to journalArticle

Charrier, Alyssa ; Wang, Li ; Stephenson, Erin ; Ghanta, Siddharth V. ; Ko, Chih Wei ; Croniger, Colleen M. ; Bridges, Dave ; Buchner, David A. / Zinc finger protein 407 overexpression upregulates PPAR target gene expression and improves glucose homeostasis in mice. In: American Journal of Physiology - Endocrinology and Metabolism. 2016 ; Vol. 311, No. 5. pp. E869-E880.
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