FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes

Thomas Laeger,Christian Baumeier,Josefine Würfel,Ilka Wilhelmi,Annette Schürmann,Anne Kamitz

doi:10.1007/s00125-017-4389-x

Abstract

Aims/hypothesisFibroblast growth factor 21 (FGF21) is considered to be a promising therapeutic candidate for the treatment of type 2 diabetes. However, as FGF21 levels are elevated in obese and diabetic conditions we aimed to test if exogenous FGF21 is sufficient to prevent diabetes and beta cell loss in New Zealand obese (NZO) mice, a model for polygenetic obesity and type 2 diabetes.MethodsMale NZO mice were treated with a specific dietary regimen that leads to the onset of diabetes within 1 week. Mice were treated subcutaneously with PBS or FGF21 to assess changes in glucose homeostasis, energy expenditure, food intake and other metabolic endpoints.ResultsFGF21 treatment prevented islet destruction and the onset of hyperglycaemia, and improved glucose clearance. FGF21 increased energy expenditure by inducing browning in subcutaneous white adipose tissue. However, as a result of a compensatory increased food intake, body fat did not decrease in response to FGF21 treatment, but exhibited elevated Glut4 expression.Conclusions/interpretationFGF21 prevents the onset of diet-induced diabetes, without changing body fat mass. Beneficial effects are mediated via white adipose tissue browning and elevated thermogenesis. Furthermore, these data indicate that obesity does not induce FGF21 resistance in NZO mice.

Highlights

IntroductionType 2 diabetes mellitus is a complex disease characterised by insufficient secretion of insulin from pancreatic beta cells (beta cell failure) in the setting of insulin resistance
Electronic supplementary material The online version of this article contains peer-reviewed but unedited supplementary material, which is available to authorised users.Type 2 diabetes mellitus is a complex disease characterised by insufficient secretion of insulin from pancreatic beta cells in the setting of insulin resistance
Hyperglycaemic mice showed a significant increase in hepatic Fgf21 mRNA expression compared with normoglycaemic mice on the −CH diet (p < 0.05; electronic supplementary material (ESM) Fig. 1c) and Klb mRNA expression was significantly decreased in brown adipose tissue (BAT), but not affected in liver, gonadal WAT (gWAT) or subcutaneous WAT (sWAT) (p < 0.05; ESM Fig. 1d, e)

Summary

Introduction

Type 2 diabetes mellitus is a complex disease characterised by insufficient secretion of insulin from pancreatic beta cells (beta cell failure) in the setting of insulin resistance. Before the onset of type 2 diabetes beta cells start to proliferate and increase the biosynthesis and secretion of insulin to compensate for peripheral insulin resistance and glucose intolerance [1]. Due to a decline in the secretory rate and a decrease in beta cell mass, impaired insulin secretion fails to compensate, resulting in hyperglycaemia, beta cell destruction and type 2 diabetes. Causes of beta cell loss are chronic hyperglycaemia (glucotoxicity) and chronically elevated. Current research efforts are focused on new strategies to improve insulin sensitivity and protect beta cells against glucolipotoxicity

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