Diabetologia

pp 1–11

c-Abl inhibition mitigates diet-induced obesity through improving insulin sensitivity of subcutaneous fat in mice

Article

DOI: 10.1007/s00125-016-4202-2

Cite this article as:
Wu, R., Sun, J., Wang, J. et al. Diabetologia (2017). doi:10.1007/s00125-016-4202-2

Abstract

Aims/hypothesis

High-energy diets are among the main causes of the global epidemic of metabolic disorders, including obesity and type 2 diabetes. The mechanisms of high-energy-diet-induced metabolic disorders are complex and largely unknown. The non-receptor tyrosine kinase c-Abl plays an important role in adipogenesis in vitro but its role in vivo in the regulation of metabolism is still elusive. Hence, we sought to address the role of c-Abl in diet-induced obesity and obesity-associated insulin resistance.

Methods

The expression of c-Abl in different fat tissues from obese humans or mice fed a high-fat diet (HFD) were first analysed by western blotting and quantitative PCR. We employed conditional deletion of the c-Abl gene (also known as Abl1) in adipose tissue using Fabp4-Cre and 6-week-old mice were fed with either a chow diet (CD) or an HFD. Age-matched wild-type mice were treated with the c-Abl inhibitor nilotinib or with vehicle and exposed to either CD or HFD, followed by analysis of body mass, fat mass, glucose and insulin tolerance. Histological staining, ELISA and biochemical analysis were used to clarify details of changes in physiology and molecular signalling.

Results

c-Abl was highly expressed in subcutaneous fat from obese humans and HFD-induced obese mice. Conditional knockout of c-Abl in adipose tissue improved insulin sensitivity and mitigated HFD-induced body mass gain, hyperglycaemia and hyperinsulinaemia. Consistently, treatment with nilotinib significantly reduced fat mass and improved insulin sensitivity in HFD-fed mice. Further biochemical analyses suggested that c-Abl inhibition improved whole-body insulin sensitivity by reducing HFD-triggered insulin resistance and increasing adiponectin in subcutaneous fat.

Conclusions/interpretation

Our findings define a new biological role for c-Abl in the regulation of diet-induced obesity through improving insulin sensitivity of subcutaneous fat. This suggests it may become a novel therapeutic target in the treatment of metabolic disorders.

Keywords

Adiponectinc-AblInsulin resistanceNilotinibObesity

Abbreviations

BAT

Brown adipose tissue

CD

Chow diet

cKO

Conditional knockout

CML

Chronic myelogenous leukaemia

ER

Endoplasmic reticulum

eWAT

Epidymal white adipose tissue

GLM

General linear model

HFD

High-fat diet

ITT

Insulin tolerance test

JNK

c-Jun amino-terminal kinase

PDGFR

Platelet-derived growth factor receptor

PI3K

Phosphatidylinositol 3-kinase

RBP-4

Retinol-binding protein 4

sWAT

Subcutaneous white adipose tissue

WT

Wild-type

Supplementary material

125_2016_4202_MOESM1_ESM.pdf (591 kb)
ESM(PDF 590 kb)

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Rong Wu
    • 1
    • 2
  • Jian-guang Sun
    • 1
    • 3
  • Ji-qiu Wang
    • 4
  • Binhua Li
    • 5
  • Qingsong Liu
    • 5
  • Guang Ning
    • 4
  • Wanzhu Jin
    • 6
  • Zengqiang Yuan
    • 1
    • 2
    • 7
  1. 1.State Key Laboratory of Brain and Cognitive SciencesInstitute of Biophysics, Chinese Academy of SciencesBeijingChina
  2. 2.College of Life SciencesUniversity of Chinese Academy of SciencesBeijingChina
  3. 3.Sino-Danish Center Neuroscience ProgramUniversity of Chinese Academy of SciencesBeijingChina
  4. 4.Ruijin Hospital Affiliated to Shanghai Jiaotong University School of MedicineShanghaiChina
  5. 5.High Magnetic Field LaboratoryChinese Academy of SciencesHefeiChina
  6. 6.Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of SciencesBeijingChina
  7. 7.Center of Alzheimerʼs Disease, Beijing Institute for Brain DisordersBeijingChina