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Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet

Z. Michailidou^*, R. N. Carter^*, E. Marshall^*, H. G. Sutherland, D. G. Brownstein^*, E. Owen^*, K. Cockett^*, V. Kelly^*, L. Ramage^*, E. A. S. Al-Dujaili, M. Ross^*, I. Maraki^*, K. Newton, M. C. Holmes^*, J. R. Seckl^*, N. M. Morton^*, C. J. Kenyon^* and K. E. Chapman^*,1

^* Centre for Cardiovascular Sciences, Queen’s Medical Research, Institute, University of Edinburgh, Edinburgh, UK;

Medical Research Council Human Genetics Unit, Edinburgh, UK; and

Queen Margaret University, Musselburgh, East Lothian, UK

¹Correspondence: Endocrinology Unit, Centre for Cardiovascular Sciences, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. E-mail: karen.chapman{at}ed.ac.uk

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR^βgeo/+ mice were generated from embryonic stem (ES) cells with a gene trap integration of a β-galactosidase-neomycin phosphotransferase (βgeo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GR^βgeo/+ mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin-aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GR^βgeo/+ mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GR^βgeo/+ mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet.—Michailidou, Z., Carter, R. N., Marshall, E., Sutherland, H. G., Brownstein, D. G., Owen, E., Cockett, K., Kelly, V., Ramage, L., Al-Dujaili, E. A. S., Ross, M., Maraki, I., Newton, K., Holmes, M. C., Seckl, J. R., Morton, N. M., Kenyon, C. J., Chapman, K. E. Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet.

Key Words: HPA axis • diet-induced obesity • NR3C1 • glucose and lipid homeostasis