Fibroblast Growth Factor-1 Improves Insulin Resistance via Repression of JNK-Mediated Inflammation

Abstract

Insulin resistance is associated with a greatly increased risk of type 2 diabetes. Administration of fibroblast growth factor-1 (FGF-1) resulted in a marked improvement in insulin sensitivity. However, the underlying molecular mechanism whereby FGF-1 represses insulin resistance remains largely unknown. Here, we sought to delineate the role of FGF-1 in insulin resistance with respect to its anti-inflammatory capability. In this study, we found that FGF-1 had positive effects on glucose intolerance, hepatic lipid accumulation, and insulin resistance, while it markedly repressed cytokine secretion (TNF-α and IL-6) in serum and reduced liver inflammation in diet-induced obesity (DIO) mice. Further, FGF-1 treatment significantly represses TNF-α-induced insulin resistance in vitro and in vivo. These results indicate that FGF-1 likely ameliorates insulin resistance via a mechanism that is independent of its glucose-lowering activity. Subsequent experiments demonstrated that FGF-1 ameliorated insulin resistance, and inflammation was accompanied by decreased c-Jun N-terminal kinase (JNK) signaling. In addition, it is likely that FGF-1 impedes JNK phosphorylation via blocking the transforming growth factor-β activated kinase 1 (TAK1) and TAK1 binding protein 1 (TAB1) interaction. These findings reveal that FGF-1 regulates insulin sensitivity and may represent an attractive therapeutic target for preventing the development of insulin resistance.

Cellular Mechanisms of FGF-Stimulated Tissue Repair

“…FGF1 or FGF2 administration decreased the inflammatory responses associated with acute pancreatitis in mice [ 136 ]. Furthermore, FGF1 administration decreased the secretion of TNFα and IL6 in a mouse model of diet-induced obesity [ 137 ], and this effect stemmed from the suppression of pro-inflammatory JNK signaling. One can suggest that the effects of FGFs on inflammation could depend on the dose and duration of recombinant FGF application, as well as on the specific tissue context.…”

Utilizing the ABC Transporter for Growth Factor Production by fleQ Deletion Mutant of Pseudomonas fluorescens

“…We only produced the beta-subunit of NGF because NGF is synthesized as a precursor, proNGF, which undergoes post-translational modification to generate the active form of NGF, βNGF [ 54 , 55 ]. FGF1 is involved in an array of physiological processes, including mammalian development, angiogenesis, wound healing, adipogenesis, and neurogenesis [ 56 , 57 , 58 , 59 ]. The administration of FGF1 resulted in improved insulin sensitivity, while also inhibiting hepatic lipid accumulation and attenuating increases in plasma glucose and insulin due to a high-fat diet [ 58 ].…”

“…FGF1 is involved in an array of physiological processes, including mammalian development, angiogenesis, wound healing, adipogenesis, and neurogenesis [ 56 , 57 , 58 , 59 ]. The administration of FGF1 resulted in improved insulin sensitivity, while also inhibiting hepatic lipid accumulation and attenuating increases in plasma glucose and insulin due to a high-fat diet [ 58 ]. TGFβ is a pleiotropic polypeptide involved in cell proliferation, migration, and differentiation during embryonic development, and it plays a vital role in tissue homeostasis in adults [ 60 ].…”

The Multiple Roles of Fibroblast Growth Factor in Diabetic Nephropathy

“…These processes are mediated by transforming growth factor β-activated kinase 1(TAK1)-TAK1 binding protein 1(TAB1). 63 However, it is not clear whether these pathways are the primary mechanisms with which FGF1 ameliorates DN.…”