Increased adiposity in DNA binding-dependent androgen receptor knockout male mice associated with decreased voluntary activity and not insulin resistance

Rana, Kesha; Fam, Barbara C; Clarke, Michele V; Pang, Tammy P S; Zajac, Jeffrey D; MacLean, Helen E.

doi:10.1152/ajpendo.00584.2010

Cited by 64 publications

(83 citation statements)

References 62 publications

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“…Our finding is consistent with studies in men with experimentally induced hypogonadism (26) and in mice lacking the androgen receptor (29), which also showed that the effects of testosterone on body composition and glucose metabolism can be dissociated. In our study, this dissociation may have occurred because testosterone treatment did not decrease visceral adipose tissue (Table 3), 2 The P value refers to overall significance of the change between groups during follow-up.…”

Section: Discussionsupporting

confidence: 92%

Effect of Testosterone Treatment on Glucose Metabolism in Men With Type 2 Diabetes: A Randomized Controlled Trial

et al. 2014

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OBJECTIVETo determine whether testosterone therapy improves glucose metabolism in men with type 2 diabetes (T2D) and lowered testosterone. RESEARCH DESIGN AND METHODSWe conducted a randomized, double-blind, parallel, placebo-controlled trial in 88 men with T2D, aged 35-70 years with an HbA 1c £8.5% (69 mmol/mol), and a total testosterone level, measured by immunoassay, of £12.0 nmol/L (346 ng/dL). Participants were randomly assigned to 40 weeks of intramuscular testosterone undecanoate (n = 45) or matching placebo (n = 43). All study subjects were included in the primary analysis. Seven men assigned to testosterone and six men receiving placebo did not complete the study. Main outcome measures were insulin resistance by homeostatic model assessment (HOMA-IR, primary outcome) and glycemic control by HbA 1c (secondary outcome). CONCLUSIONSTestosterone therapy does not improve glucose metabolism or visceral adiposity in obese men with moderately controlled T2D and modest reductions in circulating testosterone levels typical for men with T2D.Observational studies consistently show that 30-50% of men with type 2 diabetes (T2D) have lowered circulating testosterone levels, relative to references based on healthy young men (1-3). This association is independent of age and obesity (4,5), and low testosterone levels in men with T2D are independently associated with insulin resistance (3). However, it is not known whether low testosterone levels are a cause or a consequence of T2D or its associated clinical features. Several lines of evidence lend support to the hypothesis that testosterone treatment decreases insulin resistance. Experimental evidence, reviewed in Grossmann

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Section: Discussionsupporting

confidence: 92%

Effect of Testosterone Treatment on Glucose Metabolism in Men With Type 2 Diabetes: A Randomized Controlled Trial

et al. 2014

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“…However, studies that have reported thresholds for both fat mass and insulin sensitivity suggest that the testosterone level required to prevent fat accumulation may be higher than the level below which insulin resistance increases (Table 3). Studies in men with experimentally induced hypogonadism (Singh et al 2002) and in male mice lacking a functional androgen receptor either globally (Rana et al 2011) or selectively in fat (McInnes et al 2012) also show that effects of testosterone on body composition and glucose metabolism can be dissociated. In part, this may be due to the fact that the effects of testosterone therapy on visceral adiposity, the fat compartment most closely associated with insulin resistance, have been inconsistent: the (2013a)) showed that testosterone therapy does not reduce visceral fat.…”

Section: Effect On Lipidsmentioning

confidence: 99%

“…In rodent models, there is evidence that testosterone may increase the metabolic rate via androgen receptor-dependent actions on skeletal muscle (Fernando et al 2010). Mice lacking the androgen receptor have decreased physical activity, which may, at least in part, be responsible for their sarcopaenic obesity (Rana et al 2011). Data from human studies are less clear, as RCTs of testosterone therapy have, to date, not measured changes in physical activity carefully.…”

Section: End Organ Deficits Of Androgen Deficiencymentioning

confidence: 99%

“…One important caveat remains: the strongest evidence that low testosterone is the cause rather than consequence of insulin resistance comes from men with prostate cancer (Grossmann & Zajac 2011a) or biochemical castration, and from mice lacking the androgen receptor. How findings with such extreme manipulations of sex steroids (Yialamas et al 2007, Hamilton et al 2011, Rana et al 2011 apply to the majority of men with diabetes who only have modest reductions in testosterone is therefore not known.…”

Section: End Organ Deficits Of Androgen Deficiencymentioning

confidence: 99%

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Testosterone and glucose metabolism in men: current concepts and controversies

Grossmann¹

2013

Journal of Endocrinology

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A wealth of observational studies show that low testosterone is associated with insulin resistance and with an increased risk of diabetes and the metabolic syndrome. Experimental studies have identified potential mechanisms by which low testosterone may lead to insulin resistance. Visceral adipose tissue is an important intermediate in this relationship. Actions of testosterone or its metabolite oestradiol on other tissues such as muscle, liver, bone or the brain, and body composition-independent effects may also play a role. However, definitive evidence from randomised controlled trials (RCTs) to clarify whether the association of low testosterone with disordered glucose metabolism is causative is currently lacking. It therefore remains possible that this association is due to reverse causation, or simply originates by association with common health and lifestyle factors. RCTs of testosterone therapy in men with or without diabetes consistently show modest metabolically favourable changes in body composition. Despite this, testosterone effects on glucose metabolism have been inconsistent. Recent evidence suggests that the hypothalamic-pituitary-testicular axis suppression in the majority of obese men with metabolic disorders is functional, and may be, at least in part, reversible with weight loss. Until further evidence is available, lifestyle measures with emphasis on weight reduction, treatment of comorbidities and optimisation of diabetic control should remain the first-line treatment in these men. Such measures, if successful, may be sufficient to normalise testosterone levels in men with metabolic disorders, who typically have only modest reductions in circulating testosterone levels.

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“…Based on our previous observation of increased adiposity and serum adiponectin in global AR knockout mice (Rana et al 2011), we determined the serum levels Figure 6 Serum (a) adiponectin (mg/ml) and (b) glucose (mmol/l) in wild-type (WT) and mOBL-ARKOs at 6 and 12 weeks of age.…”

Section: Discussionmentioning

confidence: 99%

Identification of gene pathways altered by deletion of the androgen receptor specifically in mineralizing osteoblasts and osteocytes in mice

Russell¹,

Clarke²,

Skinner³

et al. 2012

Journal of Molecular Endocrinology

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Androgens play a key role in skeletal growth and maintenance in males and can mediate their actions, at least in part, via the androgen receptor (AR) in osteoblasts. To investigate the mechanisms by which androgens exert their effects via the AR in mineralizing osteoblasts and osteocytes, we identified gene targets/pathways regulated by the AR using targeted gene expression and microarray approaches on bone isolated from mice in which the AR is specifically deleted in mineralizing osteoblasts and osteocytes (mOBL-ARKOs). Gene ontology mining indicated a number of biological processes to be affected in the bones of mOBL-ARKOs including skeletal and muscular system development and carbohydrate metabolism. All genes identified to have altered expression in the bones of mOBL-ARKOs were confirmed by Q-PCR for their androgen responsiveness in an androgen deprivation and replacement mouse model. The osteoblast genes Col1a1 and Bglap and the osteoclast genes Ctsk and RANKL (Tnfs11) were upregulated in the bones of mOBLARKOs, consistent with the increased matrix synthesis, mineralization, and bone resorption observed previously in these mice. Of significant interest, we identified genes involved in carbohydrate metabolism (adiponectin and Dpp4) and in growth and development (GH, Tgfb (Tgfb2), Wnt4) as potential targets of androgen action via the AR in mineralizing osteoblasts.

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Increased adiposity in DNA binding-dependent androgen receptor knockout male mice associated with decreased voluntary activity and not insulin resistance

Cited by 64 publications

References 62 publications

Effect of Testosterone Treatment on Glucose Metabolism in Men With Type 2 Diabetes: A Randomized Controlled Trial

Effect of Testosterone Treatment on Glucose Metabolism in Men With Type 2 Diabetes: A Randomized Controlled Trial

Testosterone and glucose metabolism in men: current concepts and controversies

Identification of gene pathways altered by deletion of the androgen receptor specifically in mineralizing osteoblasts and osteocytes in mice

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