Mark Nixon

DR

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Biography

My research is centred on unravelling the mechanisms that control glucocorticoid action in adipose tissue, how these mechanisms are dysregulated in obesity and diabetes, and how we can target these pathways to provide greater therapeutic options for patients.

Glucocorticoids are steroid hormones released by the adrenal gland in response to stress (physiological or psychological). These stress hormones play keys roles in regulating energy homeostasis and immune function. Due to their potent anti-inflammatory effects, glucocorticoids are a mainstay of treatment for inflammatory conditions. However, their use is limited due to the adverse effects they cause when taken in high doses over long periods of time. People on long-term glucocorticoid treatment often suffer from excess weight gain, skin thinning and bone weakness. These symptoms are also present in people suffering from Cushing's syndrome, in which a tumor inside the body causes excess release of glucocorticoids.

My research has focused on the discovery of novel mechanisms that control intracellular glucocorticoid action, and how these are dysregulated in obesity and the metabolic syndrome. I have demonstrated that 5α-reduced glucocorticoid metabolites retain agonist activity at the glucocorticoid receptor, but with a dissociated profile compared to the parent glucocorticoid. In human adipocytes I have shown that intracellular glucocorticoid regeneration by 11β-HSD1 is reduced by anti-inflammatory salicylate, and demonstrated in vivo in mice that this reduction is essential for the insulin-sensitising effects of salicylate in obesity. 

My postdoctoral work focused on the export of glucocorticoids from adipocytes by ATP-binding cassette (ABC) transporters. Our recently published work in Science Translational Medicine demonstrated that the two endogenously produced glucocorticoids (cortisol and corticosterone) are differentially exported from adipose tissue as a result of tissue-specific expression of ABCC1, demonstrating increased adipose sensitivity to cortisol over corticosterone. This export pathway could potentially be exploited to allow clinicians to use corticosterone instead of cortisol as a safer glucocorticoid replacement therapy.

Recently I have been awarded a British Heart Foundation Intermediate Research fellowship to investigate a potential role for CBG cleavage in enhancing GC delivery to adipose tissue. CBG (SERPINA6) is synthesised in the liver. In the plasma, CBG binds 80-85% of GCs with high affinity. Traditionally, only unbound hormone is considered to be available to diffuse into tissues. However, contrary to the popular opinion that the primary role of CBG is to bind GCs, thus rendering them unavailable, accumulating evidence points to an active role for CBG in GC release and delivery to tissues.

My research in a nutshell

Glucocorticoid excess, particularly in adipose tissue, drives increased cardiovascular disease risk, including visceral obesity, hyperglycemia, dyslipidemia, and hypertension. Thus, efforts to reduce glucocorticoid action in adipose tissue as a treatment for cardiometabolic disease have both scientific and clinical merit. Our research is focused on the delivery mechanism through which glucocorticoids are ‘targeted’ to metabolic tissues, with the aims of not only advancing our understanding of glucocorticoid action in cardiometabolic disease, but identifying novel pathways to limit adverse glucocorticoid exposure.

Education/Academic qualification

Diabetes and Endocrinology, Doctor of Philosophy (PhD), University of Edinburgh

Sep 2007Sep 2010

Award Date: 10 May 2011

Immunology, Bachelor of Science, University of Edinburgh

Sep 2002Jul 2006

Award Date: 20 Jul 2007

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