Testosterone effects the expression of liver X receptor and targets of lipid and glucose metabolism in the testicular feminised mouse as a potential mechanism to improve insulin resistance

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 338-357-Steroid Hormone Actions
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-346
Daniel Marcus Kelly*1, Samia Akhtar1, Vakkat Muraleedharan2, Johnathan Brooke1, David McLaren1, Kevin s Channer3 and Thomas Hugh Jones4
1University of Sheffield, Sheffield, United Kingdom, 2Barnsley Hospital, Barnsley, United Kingdom, 3Sheffield Hallam University, Sheffield, United Kingdom, 4Barnsley District Gen Hosp, Barnsley S Yorkshire, United Kingdom
Symptomatic hypogonadism is common in obese men with type-2 diabetes (T2D) and metabolic syndrome (MetS), and is now an independent risk factor for cardiovascular disease.  Testosterone replacement (TRT) improves insulin resistance, glycaemic control and cholesterol in hypogonadal men. Liver X receptor (LXR) is a nuclear receptor which regulates lipid and glucose metabolism. LXR agonists protect against atherosclerosis but cause hepatic steatosis. We have previously shown that TRT protects against hepatic steatosis and atherosclerosis in high-fat diet-fed testicular feminized (Tfm) mice, which exhibit non-functional androgen receptors (AR) and low circulating testosterone levels. This study investigated LXR expression and key downstream targets involved in lipid and carbohydrate metabolism in liver, muscle and adipose tissue of Tfm mice.

Tfm mice were fed a high-cholesterol diet ad libitum for 28 weeks and received either physiological TRT or placebo and were compared to wild-type littermates. Liver, muscle, visceral adipose and subcutaneous adipose tissue mRNA and protein were analysed by qPCR and western blotting for LXR expression and downstream targets involved in lipid metabolism (Acetyl coA carboxylase, ACC; Fatty acid synthase, FAS; Lipoprotein lipase, LPL; Apolipoprotein E, ApoE; ATP-binding cassette transporters, ABC-A1, ABC-G5; Stearoyl-CoA desaturase-1, SCD1), glucose control (Glucose transporter4, GLUT4; Hexokinases, HK2, HK4; Phosphofructokinase, PFK) and master regulators of lipid and glucose metabolism (peroxisome proliferator-activated receptors, PPARα; PPARγ; Sterol regulatory element-binding proteins, Srebp-1; Srepb-2).

LXR was down-regulated in liver and subcutaneous adipose of Tfm mice compared to wild-type with TRT increasing LXR expression. LXR was not altered in muscle or visceral adipose. Downstream targets of LXR were altered in the liver (↑FAS, ↑ACC, ↓ApoE, ↓ABC-A1, ↓HK4, ↓PFK) muscle (↓HK2, ↓GLUT4, ↓PFK) and subcutaneous adipose (↓LPL, ↓ABC-A1, ↓ApoE, ↓HK2, ↓GLUT4, ↓Srebp-1, ↓Srebp-2) of Tfm mice. All other targets in alternate tissues were not affected. TRT in Tfm mice returned hepatic FAS, ACC, ApoE, ABC-A1, HK4; muscle GLUT4 and subcutaneous ApoE, HK2, Srebp-1, Srebp-2 to wild-type levels suggesting both AR-independent and dependent mechanisms.

Testosterone may act through LXR to influence carbohydrate and lipid metabolism as a mechanism to improve insulin resistance which is, in part, independent of the AR.

Disclosure: THJ: Researcher, Bayer Healthcare, Consultant, Bayer Healthcare, Speaker, Bayer Healthcare, Consultant, Eli Lilly & Company, Consultant, Pro Strakan, Researcher, Pro Strakan, Speaker, Pro Strakan, Consultant, Merck, Consultant, Clarus. Nothing to Disclose: DMK, SA, VM, JB, DM, KSC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NHS Foundation Trust, UK.