Androgens sensitise mice to glucocorticoid-induced insulin resistance and fat accumulation
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.
KeywordsAdipose tissue Androgens Glucocorticoid Insulin resistance
Brown adipose tissue
Dual-energy x-ray absorptiometry
Gastric inhibitory peptide
Plasminogen activator inhibitor-1
Polycystic ovary syndrome
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.
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.
- 12.Strack AM, Bradbury MJ, Dallman MF (1995) Corticosterone decreases nonshivering thermogenesis and increases lipid storage in brown adipose tissue. Am J Phys 268:R183–R191Google Scholar
- 17.Wright AS, Thomas LN, Douglas RC, Lazier CB, Rittmaster RS (1996) Relative potency of testosterone and dihydrotestosterone in preventing atrophy and apoptosis in the prostate of the castrated rat. J Clin Invest 98(11):2558–2563. https://doi.org/10.1172/JCI119074 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Spaanderman DCE, Nixon M, Buurstede JC et al (2018) Androgens modulate glucocorticoid receptor activity in adipose tissue and liver. J Endocrinol 240(1):51–63Google Scholar
- 24.Shen Y, Roh HC, Kumari M, Rosen ED (2017) Adipocyte glucocorticoid receptor is important in lipolysis and insulin resistance due to exogenous steroids, but not insulin resistance caused by high fat feeding. Mol Metab 6(10):1150–1160. https://doi.org/10.1016/j.molmet.2017.06.013 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Monjo M, Rodriguez AM, Palou A, Roca P (2003) Direct effects of testosterone, 17 beta-estradiol, and progesterone on adrenergic regulation in cultured brown adipocytes: potential mechanism for gender-dependent thermogenesis. Endocrinology 144(11):4923–4930. https://doi.org/10.1210/en.2003-0537 CrossRefPubMedGoogle Scholar
- 40.Protzek AO, Rezende LF, Costa-Junior JM et al (2016) Hyperinsulinemia caused by dexamethasone treatment is associated with reduced insulin clearance and lower hepatic activity of insulin-degrading enzyme. J Steroid Biochem Mol Biol 155:1–8. https://doi.org/10.1016/j.jsbmb.2015.09.020 CrossRefPubMedGoogle Scholar
- 43.Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS (2015) Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev 36(5):487–525. https://doi.org/10.1210/er.2015-1018 CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Korhonen S, Hippelainen M, Vanhala M, Heinonen S, Niskanen L (2003) The androgenic sex hormone profile is an essential feature of metabolic syndrome in premenopausal women: a controlled community-based study. Fertil Steril 79(6):1327–1334. https://doi.org/10.1016/S0015-0282(03)00347-9 CrossRefPubMedGoogle Scholar
- 46.Ganie MA, Khurana ML, Nisar S et al (2013) Improved efficacy of low-dose spironolactone and metformin combination than either drug alone in the management of women with polycystic ovary syndrome (PCOS): a six-month, open-label randomized study. J Clin Endocrinol Metab 98(9):3599–3607. https://doi.org/10.1210/jc.2013-1040 CrossRefPubMedGoogle Scholar
- 49.Ohlsson C, Hammarstedt A, Vandenput L et al (2017) Increased adipose tissue aromatase activity improves insulin sensitivity and reduces adipose tissue inflammation in male mice. Am J Physiol Endocrinol Metab 313(4):E450–E462. https://doi.org/10.1152/ajpendo.00093.2017 CrossRefPubMedPubMedCentralGoogle Scholar