Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin resistant mouse models-Association with liver and adipose tissue effects.

Xu, J., Stanislaus, S., Chinookoswong, N., Lau, Y.Y., Hager, T., Patel, J., Ge, H., Weiszmann, J., Lu, S.C., Graham, M., Busby, J., Hecht, R., Li, Y.S., Li, Y., Lindberg, R.A., Véniant, M.M.
Journal   Am J Physiol Endocrinol Metab.
Species  
Analytes Measured   Akt
Matrix Tested   Human hepatoma (HepG2) cell culture lysates, rat hepatoma (FAO) cell lysates, mouse tissue lysates
Year   2009
Volume  
Page Numbers  
Application   Phosphoproteins
Abstract
Recombinant FGF21 has anti-hyperglycemic, anti-hyperlipidemic, and anti-obesity effects in diabetic rodent and monkey models. Previous studies were confined to measuring steady state effects of FGF21 following subchronic or chronic administration. The current study focuses on the kinetics of biological actions of FGF21 following a single injection, and on the 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 (i.e., 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 hour after injection, and the maximal effects were sustained for more than 6 hours despite 1-2 hour half-life of FGF21. In DIO mice, FGF21 reduced fasting blood glucose and insulin levels, improved glucose tolerance and insulin sensitivity within 3 hours 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. Key words: Blood glucose, Insulin, FGF Signal transduction, Hepatic glucose production.

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