Molecular determinants of FGF-21 activity-synergy and cross-talk with PPARgamma signaling.
Fibroblast growth factor (FGF)-21 is a novel regulator of insulin-independent glucose transport in 3T3-L1 adipocytes and has glucose and triglyceride lowering effects in rodent models of diabetes. The precise mechanisms whereby FGF-21 regulates metabolism remain to be determined. Here we describe the early signaling events triggered by FGF-21 treatment of 3T3-L1 adipocytes and reveal a functional interplay between FGF-21 and peroxisome proliferator-activated receptor gamma (PPARgamma) pathways that leads to a marked stimulation of glucose transport. While the early actions of FGF-21 on 3T3-L1 adipocytes involve rapid accumulation of intracellular calcium and phosphorylation of Akt, GSK-3, p70(S6K), SHP-2, MEK1/2, and Stat3, continuous treatment for 72 h induces an increase in PPARgamma protein expression. Moreover, chronic activation of the PPARgamma pathway in 3T3-L1 adipocytes with the PPARgamma agonist and anti-diabetic agent, rosiglitazone (BRL 49653), enhances FGF-21 action to induce tyrosine phosphorylation of FGF receptor-2. Strikingly, treatment of cells with FGF-21 and rosiglitazone in combination leads to a pronounced increase in expression of the GLUT1 glucose transporter and a marked synergy in stimulation of glucose transport. Together these results reveal a novel synergy between two regulators of glucose homeostasis, FGF-21 and PPARgamma, and further define FGF-21 mechanism of action.
Moyers
Julie S
JS
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Shiyanova
Tatiyana L
TL
Mehrbod
Farrokh
F
Dunbar
James D
JD
Noblitt
Timothy W
TW
Otto
Keith A
KA
Reifel-Miller
Anne
A
Kharitonenkov
Alexei
A
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D020239:Receptor Cross-Talk; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D051272:Glucose Transporter Type 1; D007004:Hypoglycemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D047495:PPAR gamma; D011994:Recombinant Proteins; C495678:Slc2a1 protein, mouse; D045162:Thiazolidinediones; C414620:fibroblast growth factor 21; D000077154:Rosiglitazone; D005346:Fibroblast Growth Factors; D051497:Receptor, Fibroblast Growth Factor, Type 2; D005947:Glucose