IGF-I downregulates resistin gene expression and protein secretion.
Resistin (Rstn) is known as an adipocyte-specific secretory factor that can cause insulin resistance and decrease adipocyte differentiation. Conversely, based on various studies, insulin-like growth factors (IGFs) can improve insulin resistance and stimulate adipocyte adipogenesis. Whether IGFs exert their effects through the control of Rstn's production or modulation of Rstn's action is unknown. This study was designed to examine the influence and the signaling of IGF-I on Rstn gene expression and protein secretion by 3T3-L1 adipocytes. We found that IGF-I suppressed Rstn mRNA expression and protein release in dose- and time-dependent manners. The IC50 of IGF-I was approximately 1 nM for a range of 6-10 h of treatment. Treatment with cycloheximide, but not with actinomycin D, prevented IGF-I-suppressed Rstn mRNA expression, suggesting that IGF-I destabilizes Rstn mRNA and that IGF-I's effect requires new protein, but not mRNA, synthesis. Pretreatment with IGF-I receptor (IGF-IR) antibody blocked IGF-I-altered IGF-IR activity and Rstn mRNA levels. Neither PD-98059, SB-203580, nor LY-294002 changed the IGF-I-decreased levels of Rstn mRNA, but they inhibited IGF-I-stimulated activities of MEK1, p38 MAPK, and phosphoinositide 3-kinase, respectively. However, SB-203580 antagonized the IGF-I-decreased Rstn protein release. These data demonstrate that IGF-I downregulates Rstn gene expression via IGF-IR-dependent and MEK1-, p38 MAPK-, and phosphoinositide 3-kinase-independent pathways and likely modifies the distribution of Rstn protein between the intracellular and extracellular compartments via a p38 MAPK-dependent pathway. Decreases in Rstn production and secretion induced by IGF-I may be related to the mechanism by which IGF-I modulates body weight and diabetes in animals.
Chen
Yen-Hang
YH
Department of Life Science, College of Science, National Central University, Chung-Li City, Taoyuan, Taiwan.
Hung
Pei-Fang
PF
Kao
Yung-Hsi
YH
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006729:Hormones, Ectopic / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D052243:Resistin; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D006729:Hormones, Ectopic; D052243:Resistin; C499623:Retn protein, mouse; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases