FGF21 Is an Exocrine Pancreas Secretagogue

Abstract

Summary The metabolic stress hormone FGF21 is highly expressed in exocrine pancreas, where its levels are increased by refeeding and chemically-induced pancreatitis. However, its function in the exocrine pancreas remains unknown. Here, we show that FGF21 stimulates digestive enzyme secretion from pancreatic acinar cells through an autocrine/paracrine mechanism that requires signaling through a tyrosine kinase receptor complex composed of an FGF receptor and β-Klotho. Mice lacking FGF21 accumulate zymogen granules and are susceptible to pancreatic ER stress, an effect that is reversed by administration of recombinant FGF21. Mice carrying an acinar cell-specific deletion of β-Klotho also accumulate zymogen granules, but are refractory to FGF21-stimulated secretion. Like the classical post-prandial secretagogue, cholecystokinin (CCK), FGF21 triggers intracellular calcium release via PLC-IP3R signaling. However, unlike CCK, FGF21 does not induce protein synthesis, thereby preventing protein accumulation. Thus, pancreatic FGF21 is a digestive enzyme secretagogue whose physiologic function is to maintain acinar cell proteostasis.

Pancreatic fibroblast growth factor 21 protects against type 2 diabetes in mice by promoting insulin expression and secretion in a PI3K/Akt signaling‐dependent manner

“…37 Furthermore, exogenous administration of FGF21 can improve islet transplant success as well as protect islets from glucolipotoxicity and cytokine-induced apoptosis. 23,25 A recent study has suggested that FGF21 is highly expressed in exocrine pancreas and functions as an exocrine pancreas secretagogue, 38 which is not consistent with our findings that the majority of pancreatic FGF21 is synthesized in the islets of C57/BL6 mice at the basal state. Furthermore, another report stated that FGF21 23 is highly expressed in pancreatic islets, supporting out data, and pancreatic islet and liver may be major sources of systemic FGF21 since chemical ablation of pancreatic β-cells by streptozotocin and liver-specific FGF21 KO both result in a dramatic reduction in circulating FGF21.…”

Fibroblast growth factor 21 in chronic kidney disease

“…FGF21 might be considered an exocrine pancreas secretagogue which stimulates digestive enzyme secretion from acinar cells through an autocrine/paracrine mechanism that requires FGFR and β-klotho. FGF21 −/− mice accumulate zymogen granules and are susceptible to pancreatic endoplasmic reticulum (ER) stress, an effect that was reversed by administration of rFGF21 [71]. FGF21 also exerts protective actions in pancreatic islets.…”

FGF21-receptor agonists: an emerging therapeutic class for obesity-related diseases

“…Finally, FGF21 was recently described as a secretagogue of digestive enzymes by acting directly on the FGFR/KLB receptor complex expressed in pancreatic acinar cells [64]. The specific FGFRs mediating this effect is unknown; however, anti-FGFR1/KLB agonist antibody induces ERK phosphorylation in pancreatic acinar cells in mice, thus FGFR1 is likely involved [27].…”

“…For example, anti-drug antibodies against a mutant FGF21 have the potential to cross-react and neutralize the endogenous FGF21 protein leading to autoimmune FGF21-deficiencies. FGF21 deficient mice are viable, but exhibit a heightened pathology when acute pancreatitis or non-alcoholic steatohepatitis is experimentally induced [64], [75], [76], [77]. Thus, the immunogenicity of each FGF21-analog should be carefully monitored during clinical studies.…”