Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2010) 21 P354

SFEBES2009 Poster Presentations Steroids (37 abstracts)

Low testosterone and androgen receptor insensitivity results in decreased AMP-activated protein kinase activity (AMPK) in the liver in the testicular feminised (Tfm) mouse

Susana Igreja 1 , Joanne E Nettleship 2 , Richard D Jones 2 , Kevin S Channer 3 , T Hugh Jones 2 & Márta Korbonits 1


1Department for Endocrinology, Queen Mary University of London, London, UK; 2Academic Unit of Diabetes, Endocrinology and Metabolism, University of Sheffield, Sheffield, UK; 3Department of Cardiology, Royal Hallamshire Hospital, and Biomedical Research Centre, Sheffield Hallam University, Sheffield, UK.

There are controversial data on the beneficial/detrimental effects on the cardiovascular as well as on the metabolic system by the sex hormone testosterone. Recent data support the hypothesis that low levels of androgens are associated with adverse cardiovascular risk factors including an atherogenic lipid profile, obesity, insulin resistance and hypertension. AMPK is a sensor of energy balance at both the cellular and whole-body level. Once activated by low energy status, it switches on ATP-producing catabolic pathways and switches off ATP-consuming anabolic processes. Hormones are known to influence AMPK. The mechanism by which testosterone exerts its beneficial effects on both the cardiovascular system and the metabolic system are still unclear. We are hypothesising that testosterone produces its beneficial effects via AMPK activation. For this purpose we utilized the testicular feminized mouse (tfm) which have a non-functional androgen-receptor, low endogenous testosterone and reduced levels of 17-α-hydroxylase. All animal groups including XY-placebo, tfm-placebo, XY-castrate, tfm-sham operated and tfm-receiving physiological testosterone replacement were fed a cholesterol-enriched diet for 28 weeks. Serum levels of total cholesterol (TC) were elevated in the tfm-placebo mice compared to XY-placebo. No significant differences in TC were detected between tfm mice receiving testosterone replacement and tfm-placebo. However, the levels of high-density-lipoprotein-cholesterol were significantly raised in tfm mice receiving testosterone replacement compared to tfm-placebo mice. Liver, heart and abdominal fat tissues were collected to investigate the AMPK activity and mRNA expression of genes that are regulated by AMPK such as sterol regulatory element binding protein-1c (SREBP-1c, a transcription factor that regulates lipogenic genes) and phosphoenolpyruvate carboxykinase (PEPCK, a key enzyme in gluconeogenesis).

In the liver, AMPK activity was low in the testosterone-deficient animal groups (tfm-placebo, XY-castrate and tfm-sham operated animals). This effect was possibly mediated via the AR pathway, since AMPK activity was also decreased in tfm mice receiving physiological testosterone replacement. No significant changes on the AMPK activity were observed in the other tissues. Surprisingly, the mRNA expression of SREBP-1c and PEPCK was also decreased in the low testosterone animal groups. Taken together, reduced liver AMPK activity was found in testosterone deficient mice but lipogenic enzymes were also downregulated possibly due to lipid influx from the circulation or via alternative mechanisms.

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