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Séminaire - Brian R Walker'Brain to body and back again; peripheral control of the human HPA axis'

Abstract :

Elevated plasma cortisol predicts features of metabolic syndrome such as insulin resistance and hypertension,
and subsequent risk of cardiovascular disease. Conversely, lower plasma cortisol predicts mortality in critical illness, including after myocardial infarction. The basis for such dysregulation of the HPA axis has been sought in the "central" control of the axis, including in receptor mediated negative feedback. However, recent data highlight several alternative mechanisms affecting HPA axis function, including those which operate in "peripheral" organs, affecting cortisol biosynthesis, plasma protein binding, and clearance/regeneration.

Using stable isotope tracers we have quantified substantial tissue-specific effects on the circulating pool of cortisol in humans from peripheral metabolism, including from regeneration of cortisol by 11beta-HSD1 and its inactivation by 11beta-HSD2 and A-ring reductases. Much of the physiological variation in plasma cortisol after meals can be attributed to insulin-mediated changes in cortisol metabolism rather than altered adrenal secretion. Impaired cortisol clearance appears to underlie the down-regulation of the HPA axis in critical illness, with consequent "relative adrenal insufficiency", while exaggerated cortisol clearance may explain a hyper-responsive HPA axis in PCOS and obesity.

In humans, circulating glucocorticoids include corticosterone as well as cortisol. Tissue-specific sensitivity to glucocorticoids may be achieved by differential transmembrane transport of cortisol and corticosterone, allowing corticosterone to play a greater role in the brain and in HPA axis negative feedback. Adrenal secretion of corticosterone is disproportionately low in subjects with metabolic syndrome, potentially explaining impaired negative feedback and hence their elevated cortisol.

An international consortium, the CORtisol NETwork (CORNET), has undertaken hypothesis free genome wide association studies to identify predictors of plasma cortisol. None of the candidate genes known to influence central control of the HPA axis were implicated, but a locus has been identified where sequence variation appears to influence plasma cortisol through regulation of protein binding.

These and other research strands highlight the complexity of control of glucocorticoid action, but also suggest therapeutic avenues which might lower glucocorticoid action without compromising the HPA axis stress response.

Scientific focus :

Brian Walker obtained his medical training in Edinburgh and Glasgow and held a MRC Training Fellowship followed by a BHF Senior Fellowship from 1996-2006. He is now Professor of Endocrinology and Head of the 170-strong University/BHF Centre for Cardiovascular Science at the University of Edinburgh. His research over the last 25 years has spanned rodent models, experimental medicine, drug discovery, and epidemiology to demonstrate the contributions of endogenous cortisol and exogenous glucocorticoids to cardiovascular disease risk, discover novel determinants of tissue glucocorticoid action, and target these with new drugs. He has edited 3 editions of Davidson’s Principles and Practice of Medicine, co-directs the Edinburgh Clinical Academic Track (ECAT) programme, and chairs the Wellcome Trust Clinical Interview Committee. He has supervised >40 PhD students and published >200 original papers which have attracted >12,000 citations.