Abstract
Insulin-induced gene 1 (INSIG-1) is a key regulator in the processing of the sterol regulatory element-binding proteins (SREBPs). We demonstrated that Insig-1 is regulated by peroxisome proliferator-activated receptor gamma (PPARgamma) providing a link between insulin sensitization/glucose homeostasis and lipid homeostasis. Insig-1 was identified as a PPARgamma target gene using microarray analysis of mRNA from the white adipose tissue of diabetic (db/db) animals treated with PPARgamma agonists. Insig-1 was induced in subcutaneous (9-fold) and epididymal (4-fold) fat pads from db/db mice treated for 8 days with the PPARgamma agonist rosiglitazone (30 mg/kg/day). This in vivo response was confirmed in differentiated C3H10T1/2 adipocytes treated with rosiglitazone. To elucidate the molecular mechanisms regulating INSIG-1 expression, we cloned and characterized the human INSIG-1 promoter. Co-expression of PPARgamma and RXRalpha transactivated the INSIG-1 promoter in the presence of PPARgamma agonists. This induction was attenuated when a dominant negative PPARgamma construct was transfected into cells. Furthermore, a PPARgamma antagonist repressed the transactivation of the INSIG-1 promoter-reporter construct. Truncations of the promoter resulted in the identification of a PPAR response element that mediated the regulation of the promoter. We demonstrated with recombinant proteins that the PPARgamma/RXRalpha heterodimer binds directly to this PPAR response element. In addition to regulation by PPARgamma/RXRalpha, we demonstrated that the INSIG-1 promoter is regulated by transcriptionally active SREBP. The sterol response element was identified 380 base pairs upstream of the transcriptional start site. These findings suggest that the regulation of Insig-1 by PPARgamma agonists could in turn regulate SREBP processing and thus couple insulin sensitizers with the regulation of lipid homeostasis.
Highlights
Ligands of the peroxisome proliferator-activated receptor ␥ (PPAR␥)1 promote adipogenesis, stimulate glucose disposal in skeletal muscle, and depress glucose production from the liver [1,2,3]
Insulin-induced gene 1 (INSIG-1) Is Induced by a PPAR␥ Agonist in Adipose Tissue of db/db Mice—We originally identified INSIG-1 mRNA in microarray experiments as being increased compared with vehicle-treated animals in epididymal fat from db/db mice 6 h following a single dose of either the RXR agonist LG268 or the PPAR␥ agonist rosiglitazone (Incyte Genomics)
We demonstrated that insulininduced gene 1 (Insig-1) mRNA levels are induced by PPAR␥ agonists in a diabetic mouse model
Summary
PPAR␥ angiopoietin-related protein, fasting induced adipose factor, angiopoietin-like 4. When the INSIG-1 protein is overexpressed in cultured cells, it tethers the SCAP1⁄7SREBP complex in the endoplasmic reticulum and prevents translocation to the Golgi. This blocks SREBP maturation to nSREBP and reduces SREBP-dependent transcription [16]. The PPAR␥ ligand rosiglitazone induces endogenous Insig-1 in adipose tissue of db/db mice and in differentiated adipocytes in vitro. These data further implicate PPAR␥ as a central player in adipose tissue homeostasis
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