Zinc Finger Protein 407 Overexpression Upregulates PPAR Target Gene Expression and Improves Glucose Homeostasis in Mice

Am J Physiol Endocrinol Metab. 2016 Nov 1;311(5):E869-E880. doi: 10.1152/ajpendo.00234.2016. Epub 2016 Sep 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • DNA-Binding Proteins / genetics*
  • Diet, High-Fat
  • Gene Expression Profiling
  • Glucose / metabolism
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism*
  • Homeostasis / genetics
  • Insulin / metabolism
  • Insulin Resistance / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism
  • Myocardium / metabolism
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • PPAR delta / genetics
  • PPAR delta / metabolism
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Peroxisome Proliferator-Activated Receptors / genetics*
  • Peroxisome Proliferator-Activated Receptors / metabolism
  • Protein Processing, Post-Translational / genetics
  • RNA, Messenger / metabolism
  • Transcription Factors / genetics

Substances

  • Blood Glucose
  • DNA-Binding Proteins
  • Glucose Transporter Type 4
  • Insulin
  • PPAR alpha
  • PPAR delta
  • PPAR gamma
  • Peroxisome Proliferator-Activated Receptors
  • RNA, Messenger
  • Slc2a4 protein, mouse
  • Transcription Factors
  • ZNF407 protein, mouse
  • Glucose