Abstract
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 (PPARγ) and cytokine-inducible SH-2 containing (CIS) protein, whereas KO mouse islets displayed reduced PPARγ 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.
Highlights
Fibroblast growth factor (FGF) 21 is an endocrine factor that belongs to the FGF family
It is known that both FGF21 and Growth hormone (GH) are involved in the determination of insulin sensitivity and/or resistance, whether FGF21 modulates metabolic parameters via its interaction with GH has not been investigated
In light of these findings and of the knowledge gap identified, this study aimed to elucidate the role of FGF21 in islet function and in the pathogenesis of Type 2 diabetes mellitus (T2DM) and, in particular, to identify the role of GH signaling via the use of FGF21-knockout (KO) mice
Summary
Fibroblast growth factor (FGF) 21 is an endocrine factor that belongs to the FGF family. (JAK2) is phosphorylated and activated; it in turn phosphorylates members of the signal transducers and activators of transcription proteins (STAT), mainly 5A and 5B, leading to their nuclear translocation to regulate target genes transcription.[9] Several molecules have been identified to modulate GH signaling, including suppressors of cytokine signaling (SOCS), cytokine-inducible SH-2 containing (CIS) protein,[11,12] and peroxisome proliferator-activated receptor gamma (PPARγ),[13] which directly inhibit phosphorylation or transcriptional activity of JAK and STAT. FGF21 expression directly or indirectly, suggesting a negative feedback loop that prevents excessive GH signaling.[27,28] it is known that both FGF21 and GH are involved in the determination of insulin sensitivity and/or resistance, whether FGF21 modulates metabolic parameters via its interaction with GH has not been investigated. It is well recognized that islet dysfunction has a critical role in controlling the progression of T2DM; the physiological role of FGF21 and the functional correlate between FGF21 and GH in the islets has not been explored
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