Abstract

Background: Islet autophagy plays a role in glucose/lipid metabolism in type 2 diabetes mellitus. Meanwhile, fibroblast growth factor 21 (FGF21) has been found to regulate insulin sensitivity and glucose homeostasis. Whether FGF21 induces islet autophagy, remains to be elucidated. This study aimed to explore the physiological roles and signaling pathways involved in FGF21-stimulated islet autophagy under glucolipotoxic conditions. Methods: C57/BL6J mice were fed a standard diet or high-fat diet (HFD) for 12 weeks, and islets were isolated from normal and FGF21 knockout (KO) mice. Isolated islets and INS-1E cells were exposed to normal and high-concentration glucose and palmitic acid with/without FGF21 or AMPK inhibitor compound C. Real-time PCR, Western blot and immunohistochemistry/transmission electron microscopy were performed for the expression of targeted genes/proteins. Results: HFD-treated mice showed increases in fasting plasma glucose, body weight and impaired glucose tolerance; islet protein expression of FGF21 was induced after HFD treatment. Protein expression levels of FGF21 and LC3-II (autophagy marker) were induced in mouse islets treated with high concentrations of palmitic acid and glucose, while phosphorylation of AMPK was reduced, compared with controls. In addition, induction of LC3-II protein expression was reduced in islets isolated from FGF21 KO mice. Furthermore, exogenous administration of FGF21 diminished phosphorylation of AMPK and stimulated protein expression of LC3-II. Consistently, compound C significantly induced increased expression of LC3-II protein. Conclusions: Our data indicate that glucolipotoxicity-induced FGF21 activation mediates islet autophagy via AMPK inhibition, and further consolidate the evidence for the FGF21/analog being a pharmacotherapeutic target for obesity and its related T2DM.

Highlights

  • It is estimated over 400 million people are suffering from diabetes worldwide, with type 2 diabetes mellitus (T2DM) being the predominant form, which accounts for >90% of all cases [1]

  • Exposure of islets and INS-1E cell β-cells to diabetic conditions attenuates fibroblast growth factor 21 (FGF21) responsivity, as evidenced by reductions in extracellular mitogen-activated protein kinase 1 and 2 (ERK1/2) phosphorylation, Protein kinase B (PKB) signaling, and FGF21 target gene expression [6,7]

  • We demonstrated that weight gain, glucose intolerance and insulin resistance in high-fat diet (HFD)-f3e.dDmisicuescsoiuolnd be reversed by an application of the FGF21 mimetic CVX343

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Summary

Introduction

It is estimated over 400 million people are suffering from diabetes worldwide, with type 2 diabetes mellitus (T2DM) being the predominant form, which accounts for >90% of all cases [1]. Extensive studies confirmed the beneficial role of FGF21 in insulin sensitivity and glucose homeostasis in liver and adipose tissues, less attention has been paid to glucolipotoxicity-induced pancreatic β-cell dysfunction [7]. In this regard, FGF21 knockout (KO) mice exhibited abnormal islet morphology, islet dysfunction, and impaired GSIS due to a dysregulation of growth hormone signaling [9]. Protein expression levels of FGF21 and LC3-II (autophagy marker) were induced in mouse islets treated with high concentrations of palmitic acid and glucose, while phosphorylation of AMPK was reduced, compared with controls. Conclusions: Our data indicate that glucolipotoxicity-induced FGF21 activation mediates islet autophagy via AMPK inhibition, and further consolidate the evidence for the FGF21/analog being a pharmacotherapeutic target for obesity and its related T2DM

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