Our aim is to understand the role of natural steroid hormones in the control of fat mass and risk of diabetes. We aim to trial and develop interventions targeting steroid hormone action that have the potential to deliver significant benefit to patients
Our research group
The research groups runs a truly translational program of research with the aim of understanding the molecular mechanisms by which glucocorticoids modulate metabolic phenotype including lipid and carbohydrate metabolism as well as insulin signalling and action in liver, adipose tissue and muscle. The group uses in vitro cell culture models, generates and characterizes rodent models and translates these finding through to state-of-the-art metabolic clinical studies in healthy and obese individuals and those with type 2 diabetes and non-alcoholic fatty liver disease.
Using a similar translational approach with in vitro, rodent and clinical components, the group explores the role of pre-receptor regulation of glucocorticoid hormone action through manipulation(genetic and pharmacological) of expression and activity of the enzymes 11β-hydroxysteroid dehydrogenase and the A-ring reductases (5α-reductase and 5β-reductase) that have the ability to increase or decrease local glucocorticoid availability.
In vitro models of key metabolic target tissues (adipose, liver, muscle) using primary cultures and cell lines to determine the role of A-ring reductases and 11β-hydroxysteroid dehydrogenase in the control lipid and carbohydrate metabolism.
Generation and phenotyping of mouse models including global knock out of A-ring reductases, liver specific knock-out of 11β-hydroxysteroid dehydrogenase type1, liver specific transgenic over-expression of A-ring reductase and in vivo knock down of 5 β-reductase.
Translational clinical research program including
Prospective analysis of steroid metabolism and risk of development of impaired glucose tolerance and type 2 diabetes – BPODS cohort
Metabolic characterization of patients before and after 5α-reductase inhibition and in patients with inactivating mutations in 5α-reductase
Progression and treatment of non-alcoholic fatty liver disease
Lavery GG, Zielinska AE, Gathercole LL, Hughes B, Semjonous N, Guest P, Saqib K, Sherlock M, Reynolds G, Morgan SA, Tomlinson JW , Walker EA, Rabbitt EH, Stewart PM. Lack of Significant Metabolic Abnormalities in Mice with Liver-Specific Disruption of 11β-Hydroxysteroid Dehydrogenase Type 1. Endocrinology. 2012 153(7):3236-48
Gathercole LL, Morgan SA, Bujalska IJ, Hauton D, Stewart PM and Tomlinson JW . Depot specific regulation of lipid homeostasis in human adipose tissue. PLoS One. 2011 6(10):e26223
Sinclair AJ, Walker EA, Burdon MA, van Beek AP, Kema IP, Hughes BA, Murray PI, Nightingale PG, Stewart PM, Rauz S, Tomlinson JW . Cerebrospinal fluid corticosteroid levels and cortisol metabolism in patients with Idiopathic Intracranial Hypertension: a link between 11β-HSD1 and intracranial pressure regulation? J Clin Endocrinol Metab. 2010 95(12):5348-56
Morgan SA, Sherlock M, Gathercole LL, Lavery GG, Lenaghan C, Bujalska IJ, Laber D, Yu A, Convey G, Hegyi K, Sethi JK, Stewart PM, Smith DM, Tomlinson JW. 11b-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle. Diabetes 2009 58(11):2506-15
Tomlinson JW , Finney J, Gay C, Hughes BA, Hughes SV, Stewart PM. Impaired glucose tolerance and insulin resistance are associated with increased adipose 11β-hydroxysteroid dehydrogenase type 1 expression and elevated hepatic 5α-reductase activity. Diabetes 2008 57(10):2652-60
Dr Jeremy Tomlinson