title: Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse.
abstract: Testosterone deficiency is commonly associated with obesity, metabolic syndrome, type 2 diabetes and their clinical consequences-hepatic steatosis and atherosclerosis. The testicular feminised mouse (non-functional androgen receptor and low testosterone) develops fatty liver and aortic lipid streaks on a high-fat diet, whereas androgen-replete XY littermate controls do not. Testosterone treatment ameliorates these effects, although the underlying mechanisms remain unknown. We compared the influence of testosterone on the expression of regulatory targets of glucose, cholesterol and lipid metabolism in muscle, liver, abdominal subcutaneous and visceral adipose tissue. Testicular feminised mice displayed significantly reduced GLUT4 in muscle and glycolytic enzymes in muscle, liver and abdominal subcutaneous but not visceral adipose tissue. Lipoprotein lipase required for fatty acid uptake was only reduced in subcutaneous adipose tissue; enzymes of fatty acid synthesis were increased in liver and subcutaneous tissue. Stearoyl-CoA desaturase-1 that catalyses oleic acid synthesis and is associated with insulin resistance was increased in visceral adipose tissue and cholesterol efflux components (ABCA1, apoE) were decreased in subcutaneous and liver tissue. Master regulator nuclear receptors involved in metabolism-Liver X receptor expression was suppressed in all tissues except visceral adipose tissue, whereas PPARγ was lower in abdominal subcutaneous and visceral adipose tissue and PPARα only in abdominal subcutaneous. Testosterone treatment improved the expression (androgen receptor independent) of some targets but not all. These exploratory data suggest that androgen deficiency may reduce the buffering capability for glucose uptake and utilisation in abdominal subcutaneous and muscle and fatty acids in abdominal subcutaneous. This would lead to an overspill and uptake of excess glucose and triglycerides into visceral adipose tissue, liver and arterial walls.
authors.affiliation: Department of Oncology and Metabolism, Medical School, The University of Sheffield, Sheffield, UK. daniel.kelly@shu.ac.uk.|Biomolecular Research Centre, Sheffield Hallam University, Sheffield, UK. daniel.kelly@shu.ac.uk.
authors.forename: Daniel M
authors.identifier: http://orcid.org/0000-0002-7463-0692
authors.initials: DM
authors.lastname: Kelly
authors.affiliation: Department of Oncology and Metabolism, Medical School, The University of Sheffield, Sheffield, UK.
authors.forename: Samia
authors.initials: S
authors.lastname: Akhtar
authors.affiliation: Biomolecular Research Centre, Sheffield Hallam University, Sheffield, UK.|Present address: Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Queensland 4229, Australia.
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Sellers
authors.affiliation: Department of Oncology and Metabolism, Medical School, The University of Sheffield, Sheffield, UK.|Centre for Diabetes and Endocrinology, Barnsley Hospital NHS Foundation Trust, Barnsley, UK.
authors.forename: Vakkat
authors.initials: V
authors.lastname: Muraleedharan
authors.affiliation: Department of Cardiology, Royal Hallamshire Hospital, Sheffield, UK.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Channer
authors.affiliation: Centre for Diabetes and Endocrinology, Barnsley Hospital NHS Foundation Trust, Barnsley, UK.|Department of Cardiology, Royal Hallamshire Hospital, Sheffield, UK.
authors.forename: T Hugh
authors.initials: TH
authors.lastname: Jones
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D013739:Testosterone / Q000097:blood / Q000494:pharmacology*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; C497388:Srebf1 protein, mouse; C497391:Srebf2 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013739:Testosterone; D005947:Glucose
keywords: Adipose tissue; Androgen receptor; Metabolism; Testosterone; Type 2 diabetes