, Volume 62, Issue 8, pp 1463–1477 | Cite as

Androgens sensitise mice to glucocorticoid-induced insulin resistance and fat accumulation

  • Sylvia J. Gasparini
  • Michael M. Swarbrick
  • Sarah Kim
  • Lee J. Thai
  • Holger Henneicke
  • Lauryn L. Cavanagh
  • Jinwen Tu
  • Marie-Christin Weber
  • Hong Zhou
  • Markus J. SeibelEmail author



Chronic glucocorticoid therapy causes insulin resistance, dyslipidaemia, abnormal fat accumulation, loss of muscle mass and osteoporosis. Here we describe a hitherto unknown sexual dimorphism in the metabolic response to chronic glucocorticoid exposure in mice. This led us to investigate whether glucocorticoid-induced insulin resistance and obesity were dependent on sex hormones.


Male and female CD1 mice were treated for 4 weeks with supraphysiological doses (~250 μg/day) of corticosterone, the main glucocorticoid in rodents, or equivalent volume of vehicle (drinking water without corticosterone). To investigate the effects of sex hormones, a separate group of mice were either orchidectomised or ovariectomised prior to corticosterone treatment, with or without dihydrotestosterone replacement. Body composition was determined before and after corticosterone treatment, and insulin tolerance was assessed after 7 and 28 days of treatment. Adipocyte morphology was assessed in white and brown adipose tissues by immunohistochemistry, and fasting serum concentrations of NEFA, triacylglycerols, total cholesterol and free glycerol were measured using colorimetric assays. Obesity- and diabetes-related hormones were measured using multiplex assays, and RNA and protein expression in adipose tissues were measured by RT-PCR and immunoblotting, respectively.


Chronic corticosterone treatment led to insulin resistance, fasting hyperinsulinaemia, increased adiposity and dyslipidaemia in male, but not female mice. In males, orchidectomy improved baseline insulin sensitivity and attenuated corticosterone-induced insulin resistance, but did not prevent fat accumulation. In androgen-deficient mice (orchidectomised males, and intact and ovariectomised females) treated with dihydrotestosterone, corticosterone treatment led to insulin resistance and dyslipidaemia. In brown adipose tissue, androgens were required for corticosterone-induced intracellular lipid accumulation (‘whitening’), and dihydrotestosterone specifically exacerbated corticosterone-induced accumulation of white adipose tissue by increasing adipocyte hypertrophy. Androgens also suppressed circulating adiponectin concentrations, but corticosterone-induced insulin resistance did not involve additional suppression of adiponectin levels. In white adipose tissue, androgens were required for induction of the glucocorticoid target gene Gilz (also known as Tsc22d3) by corticosterone.


In mice, androgens potentiate the development of insulin resistance, fat accumulation and brown adipose tissue whitening following chronic glucocorticoid treatment.


Adipose tissue Androgens Glucocorticoid Insulin resistance 



Brown adipose tissue




Dual-energy x-ray absorptiometry


Gastric inhibitory peptide


Glucagon-like peptide-1


Orchidectomised mice


Ovariectomised mice


Plasminogen activator inhibitor-1


Polycystic ovary syndrome


Uncoupling protein-1


White adipose tissue



We would like to thank M. S. Cooper and D. Handelsman (ANZAC Research Institute, The University of Sydney, Australia) for thoughtful discussion and comments throughout this project. We thank M. Jiminez (ANZAC Research Institute) for providing the DHT implants, and J. Spaliviero (ANZAC Research Institute) and E. Karsten (Kolling Institute, The University of Sydney, Australia) for their expert technical assistance. This work has not previously been published, but was included in the PhD thesis of SJG. Some of the results have been presented at local and international conferences.

Contribution statement

All authors have made substantial contributions to conception and design, acquisition of data or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content, and have given final approval of the version to be published. SJG, MMS, HZ and MJS are guarantors of the work, accept full responsibility for the work and/or the conduct of the study, have access to the data, and controlled the decision to publish.


This study was supported by National Health and Medical Research Council (NHMRC) Project grant APP1086100 to MJS, MMS and HZ; the Australian government for Australian Postgraduate Award (SJG, SK); an International Postgraduate Research Scholarship (HH) and a research stipend from Humboldt University/ Charité University Medicine, Berlin (MCW). The study sponsors were not involved in the design of the study; the collection, analysis and interpretation of data; writing the report; or the decision to submit the report for publication.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2019_4887_MOESM1_ESM.pdf (575 kb)
ESM (PDF 574 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Sylvia J. Gasparini
    • 1
  • Michael M. Swarbrick
    • 1
  • Sarah Kim
    • 1
  • Lee J. Thai
    • 1
  • Holger Henneicke
    • 1
    • 2
    • 3
    • 4
  • Lauryn L. Cavanagh
    • 1
  • Jinwen Tu
    • 1
  • Marie-Christin Weber
    • 1
    • 5
  • Hong Zhou
    • 1
    • 6
  • Markus J. Seibel
    • 1
    • 6
    Email author
  1. 1.Bone Research Program, ANZAC Research InstituteThe University of SydneyConcordAustralia
  2. 2.Department of Medicine IIITechnische Universität Dresden Medical CenterDresdenGermany
  3. 3.Center for Healthy AgingTechnische Universität Dresden Medical CenterDresdenGermany
  4. 4.Center for Regenerative Therapies DresdenTechnische Universität DresdenDresdenGermany
  5. 5.Department of Rheumatology and Clinical ImmunologyCharité University HospitalBerlinGermany
  6. 6.Concord Medical SchoolThe University of SydneySydneyAustralia

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