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

Abstract

Fibroblast growth factor 21 (FGF21) is important in glucose, lipid homeostasis and insulin sensitivity. However, it remains unknown whether FGF21 is involved in insulin expression and secretion that are dysregulated in type 2 diabetes mellitus (T2DM). In this study, we found that FGF21 was down‐regulated in pancreatic islets of db/db mice, a mouse model of T2DM, along with decreased insulin expression, suggesting the possible involvement of FGF21 in maintaining insulin homeostasis and islet β‐cell function. Importantly, FGF21 knockout exacerbated palmitate‐induced islet β‐cell failure and suppression of glucose‐stimulated insulin secretion (GSIS). Pancreatic FGF21 overexpression significantly increased insulin expression, enhanced GSIS, improved islet morphology and reduced β‐cell apoptosis in db/db mice. Mechanistically, FGF21 promoted expression of insulin gene transcription factors and soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) proteins, the major regulators of insulin secretion, as well as activating phosphatidylinositol 3‐kinase (PI3K)/Akt signaling in islets of db/db mice. In addition, pharmaceutical inhibition of PI3K/Akt signaling effectively suppressed FGF21‐induced expression of insulin gene transcription factors and SNARE proteins, suggesting an essential role of PI3K/Akt signaling in FGF21‐induced insulin expression and secretion. Taken together, our results demonstrate a protective role of pancreatic FGF21 in T2DM mice through inducing PI3K/Akt signaling‐dependent insulin expression and secretion.

CRISPR-mediated BMP9 ablation promotes liver steatosis via the down-regulation of PPARα expression

“…Insulin receptor signaling proteins (like p-IR and p-Akt) were greatly activated as BMP9 and FGF21 were rescued ( fig. S4E), which was consistent with a previous study (37). These data show a marked glycemia recovery after AAV-BMP9 administration.…”

FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases

“…FGF21 also improves β cell homeostasis by promoting autophagy and resistance to ER stress ( 259 , 260 ). In obese or diabetic mice, FGF21 restores the insulin secretion capacity of β cells in vivo ( 261 ) via several pathways: first, by activating AMPK signaling and autophagy ( 262 ); second, by reducing the accumulation of lipotoxic lipids in the pancreas by upregulating expression of CPT1 (which facilitates oxidation of long-chain fatty acids) and downregulating the expression of lipogenic genes SREBF1 and FASN ( 263 ); third, by restoring the expression of core pancreatic genes including PDX1, INS (insulin), and MafA ( 264 ); and finally, by reducing immune cell infiltration and activation within islets ( 190 ).…”

Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats

“…Interestingly, we identified six potential bivalent genes, Acod1, Fgf21, Serpina11, Cdh16, Lrrc27, and Lrrc66, whose alterations in bivalency and expression levels may contribute to IUGR phenotypes observed in adult islets. Although the roles of Serpina11, Cdh16, Lrrc27, and Lrrc66 in regulating islet function remain unclear, Acod1 is known to be important in modulating the immune system and mitochondrial function [116][117][118], and Fgf21 can protect against type 2 diabetes in mice by increasing insulin expression and secretion [119,122]. However, whether these genes are truly bivalent will need to be determined.…”

“…Fgf21 protects against inflammation and islet hyperplasia induced by a high-fat diet [121]. It also protects against type 2 diabetes in mice by increasing insulin expression and secretion [122]. Loss of Fgf21 induces insulin resistance and islet dysfunction in mice [123].…”