Loss of fibroblast growth factor 21 action induces insulin resistance, pancreatic islet hyperplasia and dysfunction in mice

Fibroblast growth factor (FGF) 21 is an endocrine factor that normalizes glucose homeostasis and reduces insulin resistance in diabetes. Although the pancreas is an FGF21 target organ, its role in pancreatic islets remains obscure. This study aimed to elucidate the physiological role of FGF21 in pancreatic islets using FGF21-knockout (FGF21-KO) mice. Twenty-four-week-old male global FGF21-KO mice were used in this study. Glucose and insulin tolerance were assessed. Expression of genes and proteins related to islet function and underlying mechanisms were also examined. Islet morphology and insulin-secreting capacity were further evaluated. FGF21-KO mice exhibited insulin resistance while being normoglycemic, associated with increases in beta-cell proliferation and insulin synthesis, acting as compensatory responses. This phenotype probably results from enhanced growth hormone (GH) sensitivity in FGF21-KO mouse islets. In addition, ex vivo FGF21 treatment in normal C57BL/6J mouse islets reduced GH signaling, probably via upregulation of peroxisome proliferator-activated receptor gamma (PPAR gamma) and cytokine-inducible SH-2 containing (CIS) protein, whereas KO mouse islets displayed reduced PPAR gamma and CIS expression. FGF21 treatment also reversed GH-induced insulin expression, beta-cell proliferation and GH-impaired glucose-stimulated insulin secretion (GSIS) in islets. Furthermore, distorted islet morphology and impaired GSIS were observed in KO mice, suggestive of islet dysfunction, whereas the enhanced insulin expression and impaired GSIS in FGF21-KO mouse islets could be reversed by blockade of GH signaling. Our data indicate that FGF21 is important in the regulation of beta-cell proliferation and insulin synthesis, probably via modulation of GH signaling. These findings provide evidence that FGF21 is an obligatory metabolic regulator in pancreatic islets and shed new light onto the role of endogenous FGF21 in the pathogenesis of insulin resistance and islet dysfunction.