Insig-1 "brakes" lipogenesis in adipocytes and inhibits differentiation of preadipocytes.
We have examined gene expression in the fat tissue of normal mice at the onset of diet-induced obesity. Insulin-induced gene 1 (insig-1) mRNA rose progressively with a high-fat diet and declined on a restricted diet. Because insig-1 binds sterol regulatory element-binding protein cleavage-activating protein in the endoplasmic reticulum, thereby blocking proteolytic processing required for sterol regulatory element-binding protein activation, we tested its influence on lipogenesis. In differentiating 3T3-L1 cells, insig-1 and -2 rose in parallel with aP2 mRNA during differentiation. The mRNA of the lipogenic transcription factor, carbohydrate response element-binding protein, was undetectable in undifferentiated 3T3-L1 preadipocytes but rose dramatically during differentiation in 25 mM, but not in 5 mM, glucose. Transfection of mouse or human insig-1 into 3T3-L1 preadipocytes completely prevented oil red O staining and blocked upregulation of aP2, peroxisome proliferator-activated receptor gamma2, and carbohydrate response element-binding protein, while reducing down-regulation of preadipocyte factor 1. The results suggest that insig-1 expression restricts lipogenesis in mature adipocytes and blocks differentiation in preadipocytes.
Li
Jinping
J
Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center and Veterans Affairs Medical Center, Dallas, TX 75390, USA.
Takaishi
Kiyosumi
K
Cook
William
W
McCorkle
Sara Kay
SK
Unger
Roger H
RH
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015152:Blotting, Northern; D002135:Calcium-Binding Proteins; D050260:Carbohydrate Metabolism; D002454:Cell Differentiation; D002455:Cell Division; D004396:Coloring Agents / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004032:Diet; D015536:Down-Regulation; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000235:genetics; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation
D001391:Azo Compounds; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002135:Calcium-Binding Proteins; D004396:Coloring Agents; C512941:DLK1 protein, human; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C512925:Dlk1 protein, mouse; C512923:Dlk1 protein, rat; C108626:INSIG1 protein, human; C491574:Insig1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C442825:Mlxipl protein, rat; D011506:Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014157:Transcription Factors; C011049:oil red O; D005947:Glucose