Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models--association with liver and adipose tissue effects.
Recombinant fibroblast growth factor (FGF)21 has antihyperglycemic, antihyperlipidemic, and antiobesity effects in diabetic rodent and monkey models. Previous studies were confined to measuring steady-state effects of FGF21 following subchronic or chronic administration. The present study focuses on the kinetics of biological actions of FGF21 following a single injection and on the associated physiological and cellular mechanisms underlying FGF21 actions. We show that FGF21 resulted in rapid decline of blood glucose levels and immediate improvement of glucose tolerance and insulin sensitivity in two animal models of insulin resistance (ob/ob and DIO mice). In ob/ob mice, FGF21 led to a 40-60% decrease in blood glucose, insulin, and amylin levels within 1 h after injection, and the maximal effects were sustained for more than 6 h despite the 1- to 2-h half-life of FGF21. In DIO mice, FGF21 reduced fasting blood glucose and insulin levels and improved glucose tolerance and insulin sensitivity within 3 h of treatment. The acute improvement of glucose metabolism was associated with a 30% reduction of hepatic glucose production and an increase in peripheral glucose turnover. FGF21 appeared to have no direct effect on ex vivo pancreatic islet insulin or glucagon secretion. However, it rapidly induced typical FGF signaling in liver and adipose tissues and in several hepatoma-derived cell lines and differentiated adipocytes. FGF21 was able to inhibit glucose release from H4IIE hepatoma cells and stimulate glucose uptake in 3T3-L1 adipocytes. We conclude that the acute glucose-lowering and insulin-sensitizing effects of FGF21 are potentially associated with its metabolic actions in liver and adipose tissues.
Xu
Jing
J
Amgen Inc., MS 29-1-A, One Amgen Center Dr., Thousand Oaks, CA 91320, USA. jingx@amgen.com
Stanislaus
Shanaka
S
Chinookoswong
Narumol
N
Lau
Yvonne Y
YY
Hager
Todd
T
Patel
Jennifer
J
Ge
Hongfei
H
Weiszmann
Jen
J
Lu
Shu-Chen
SC
Graham
Melissa
M
Busby
Jim
J
Hecht
Randy
R
Li
Yue-Sheng
YS
Li
Yang
Y
Lindberg
Richard
R
Véniant
Murielle M
MM
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005346:Fibroblast Growth Factors / Q000493:pharmacokinetics / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents; D007333:Insulin Resistance / Q000502:physiology*; D058228:Islet Amyloid Polypeptide / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology
D007004:Hypoglycemic Agents; D058228:Islet Amyloid Polypeptide; D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors