Role for dusp4 in modulating PPARγ activity by covalent modification in adipocytes (1037.12)

Abstract

Peroxisome proliferator‐activated receptor gamma (PPARγ) is a ligand‐activated transcription factor that plays a prominent role in adipocyte differentiation and insulin sensitivity with aberrant activity linked to obesity and type 2 diabetes. Recent studies have highlighted covalent modification of PPARγ, including phosphorylation, sumoylation and ubiquitylation, as an important mechanisms modulating biological outcome. Phosphorylation of PPARγ by mitogen‐activated protein kinases (MAPKs; ERK, JNK) inhibits transcriptional activity while mice with targeted mutation against the single MAPK‐consensus recognition site are protected against diet‐induced insulin resistance. Others have also shown MAPK‐dependent phosphorylation of PPARγ as an obligatory step in sumoylation‐dependent inhibition of activity. As MAPK activity is modulated by kinases and phosphatases, the objective of this study was to investigate a role for MAPK‐specific phosphatases in modulating PPARγ activity through covalent modification. We examined the expression profile of the 10 known MAPK‐specific phosphatases, collectively referred to as dual‐specificity phosphatases (DUSPs), in insulin‐responsive tissues of genetic‐ and diet‐induced obese mice. We observed that dusp4 was significantly more abundant in white adipose tissue relative to liver, skeletal muscle, and heart in lean mice and that this phosphatase was induced during early stages of obesity and repressed during later stages correlating with the onset of obesity‐induced inflammation. The expression profile of dusp4 was further shown to correlate precisely with PPARγ during differentiation of 3T3‐L1 and F442A adipocytes. Loss‐of‐function studies are underway to support our working model that dusp4 plays a role in modulating biological outcome of PPARγ activity through covalent modification involving phosphorylation by MAPK.Grant Funding Source: Support by NIH‐NIDDK (R15‐DK082799)