Elsevier

Molecular Metabolism

Volume 12, June 2018, Pages 76-88
Molecular Metabolism

Original Article
Neuraminidase 1 activates insulin receptor and reverses insulin resistance in obese mice

https://doi.org/10.1016/j.molmet.2018.03.017Get rights and content
Under a Creative Commons license
open access

Highlights

  • Desialylation of insulin receptor by NEU1 induces formation of its active dimer leading to insulin signaling.

  • Overexpression of NEU1 in palmitate-treated HepG2 cells restores insulin signaling.

  • Acute treatment with Ambroxol reverses insulin resistance and glycemia in high-fat diet mouse model.

  • Ambroxol effect is mediated through NEU1 induction.

  • Pharmacological modulation of NEU1 activity may be potentially explored for treatment of insulin resistance.

Abstract

Objectives

Neuraminidase 1 (NEU1) cleaves terminal sialic acids of glycoconjugates during lysosomal catabolism. It also modulates the structure and activity of cellular surface receptors affecting diverse pathways. Previously we demonstrated that NEU1 activates the insulin receptor (IR) and that NEU1-deficient CathAS190A-Neo mice (hypomorph of the NEU1 activator protein, cathepsin A/CathA) on a high-fat diet (HFD) develop hyperglycaemia and insulin resistance faster than wild-type animals. The major objective of the current work was to reveal the molecular mechanism by which NEU1 desialylation activates the IR and to test if increase of NEU1 activity in insulin target tissues reverses insulin resistance and glucose intolerance.

Methods

To test if desialylation causes a conformational change in the IR dimer we measured interaction between the receptor subunits by Bioluminescence Resonance Energy Transfer in the HEK293T cells either overexpressing NEU1 or treated with the NEU1 inhibitor. The influence of NEU1 overexpression on insulin resistance was studied in vitro in palmitate-treated HepG2 cells transduced with NEU1-expressing lentivirus and in vivo in C57Bl6 mice treated with HFD and either pharmacological inducer of NEU1, Ambroxol or NEU1-expressing adenovirus. NEU1-deficient CathAS190A-Neo mice were used as a control.

Results

By desialylation of IR, NEU1 induced formation of its active dimer leading to insulin signaling. Overexpression of NEU1 in palmitate-treated HepG2 cells restored insulin signaling, suggesting that increased NEU1 levels may reverse insulin resistance. Five-day treatment of glycemic C57Bl6 mice receiving HFD with the activator of the lysosomal gene network, Ambroxol, increased NEU1 expression and activity in muscle tissue, normalized fasting glucose levels, and improved physiological and molecular responses to glucose and insulin. Ambroxol did not improve insulin sensitivity in obese insulin-resistant CathAS190A-Neo mice indicating that the Ambroxol effect is mediated through NEU1 induction. Sustained increase of liver NEU1 activity through adenovirus-based gene transfer failed to attenuate insulin resistance most probably due to negative feedback regulation of IR expression.

Conclusion

Together our results demonstrate that increase of NEU1 activity in insulin target tissues reverses insulin resistance and glucose intolerance suggesting that a pharmacological modulation of NEU1 activity may be potentially explored for restoring insulin sensitivity and resolving hyperglycemia associated with T2DM.

Keywords

Neuraminidase 1
Ambroxol
Insulin resistance
Insulin signaling

Abbreviations

NEU1
neuraminidase 1
HFD
high-fat diet
IR
insulin receptor
T2DM
type 2 diabetes mellitus
AV
adenovirus
LV
lentivrus
BRET
bioluminescence resonance energy transfer
DANA
2,3-dehydro-2-deoxy-N-acetylneuraminic acid
IGTT
intraperitoneal glucose tolerance test
ITT
insulin tolerance test
PA
palmitate, Ambroxol, trans-4-(2-Amino-3,5-dibromobenzylamino)cyclohexanol
TFEB
transcription factor EB
PNA
peanut agglutinin

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