CBBM Lecture "Cushing’s revisited: Cortisol metabolism and the obesity epidemic"

by Professor Jeremy Tomlinson,

Oxford Centre for Diabetes, Endocrinology and Metabolism,

University of Oxford

will take place on Tuesday, May 3, 2016 from 17:15 to 18:15 hours in CBBM, EG, Room 50/51.

Host: Prof. Hendrik Lehnert
Department of Internal Medicine I
Universität zu Lübeck


We are living the midst a global epidemic of metabolic disease with rapidly escalating rates of obesity, type 2 diabetes and insulin resistance. Patients with glucocorticoid excess, Cushing’s syndrome, develop a characteristic constellation of adverse metabolic features including central obesity, insulin resistance, proximal muscle wasting, hypertension and non-alcoholic fatty liver disease (NAFLD). However, in simple obesity, circulating glucocorticoid levels are not elevated. At a tissue-specific level, notably in adipose, liver and muscle, the availability of glucocorticoid (cortisol in humans) to bind and activate the glucocorticoid receptor (GR) is controlled by a series of enzymes that either activate or inactivate cortisol; 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active cortisol from inactive cortisone and thus amplifies local glucocorticoid signalling. Conversely, the A-ring reductases (5α-reductase type 1 and 2 and 5β-reductase) clear cortisol to inactive metabolites and limit GR activation. Adopting a truly translational, bench-to-bedside approach, my work has defined the role of pre-receptor glucocorticoid metabolism within key target tissues upon the development of global metabolic phenotype.

Using in vitro cell systems including primary cultures of adipose, liver and muscle, we have characterized the action of glucocorticoids upon insulin action and lipid metabolism. We have identified a novel mechanism by which glucocorticoids cause insulin resistance in skeletal muscle through serine phosphorylation of insulin receptor substrate 1. Furthermore, there is tissue specificity of response; we have challenged the dogma that glucocorticoids cause insulin resistance in all tissues and demonstrated insulin sensitization both in vitro and in translational clinical studies selectively in human adipose tissue.

Our translation approach has been exemplified by a series of studies that have demonstrated the beneficial impact of therapeutic inhibition of 11β-HSD1 to limit glucocorticoid availability in vitro, in animal models and in dedicated clinical studies. Most recently, based upon observations in a patient with Cushing’s disease without a clinical phenotype, we have identified a novel role for 11β-HSD1 in controlling the response to exogenous glucocorticoid excess raising the potential for therapeutic inhibition of 11β-HSD1 may not only as a treatment for Cushing’s disease, but as an approach to the treatment of iatrogenic glucocorticoid excess to limit adverse metabolic effects.

The A-ring reductases provide an additional layer of complexity. We have shown in cross-sectional and intervention clinical studies that 5α-reductase activity is dysregulated in metabolic disease including obesity and NAFLD and have postulated that this represents a compensatory mechanism to protect the liver form the adverse effects of cortisol. Endorsing this hypothesis, using rodent models we have shown that 5α-reductase knock out mice develop hepatic steatosis. Importantly, preliminary data from parallel translational studies suggest that specific inhibition of 5α-reductase type 1 may lead to hepatic steatosis and impaired adipose tissue function. This has important clinical implications bearing in mind the widespread use of 5α-reductase inhibitors in the treatment of prostatic disease.


Professor Jeremy Tomlinson graduated from the University of Oxford Medical School in 1995, having previously completed his undergraduate degree at the University of Cambridge. He embarked upon a career in Diabetes and Endocrinology and secured an MRC Clinical Training Fellowship in 2000 and obtained his PhD from University of Birmingham studying steroid metabolism and human obesity in 2003. Subsequently he obtained fellowships from the Wellcome Trust and most recently an MRC senior clinical fellowship investigating the pathogenesis of human obesity and insulin resistance. He is a professor of Metabolic Endocrinology and consultant endocrinologist based in the Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford. His research investigates the pathogenesis of human obesity, insulin resistance and non-alcoholic fatty liver disease. His work has focussed on glucocorticoid action and metabolism and in particular the role of the pre-receptor metabolizing enzymes to regulate metabolic function.