Androgen receptor (AR) null male mice (AR L؊/Y ) revealed late-onset obesity, which was confirmed by computed tomography-based body composition analysis. AR L؊/Y mice were euphagic compared with the wild-type male (AR X/Y ) controls, but they were also less dynamic and consumed less oxygen. Transcript profiling indicated that AR L؊/Y mice had lower transcripts for the thermogenetic uncoupling protein 1, which was subsequently found to be ligand-dependently activated by AR. We also found enhanced secretion of adiponectin, which is insulin sensitizing, from adipose tissue and a relatively lower expression of peroxisome proliferatoractivated receptor-␥ in white adipose tissue in comparison to AR X/Y mice. Both factors might explain why the overall insulin sensitivity of AR L؊/Y mice remained intact, despite their apparent obesity. The results revealed that AR plays important roles in male metabolism by affecting the energy balance, and it is negative to both adiposity and insulin sensitivity. Diabetes 54:1000 -1008, 2005 T he etiology of obesity is extremely heterogeneous, in that it is the final result of interactions among genetic, environmental, and psychosocial factors. The androgen receptor (AR) gene may be one of these genetic factors. AR gene repeat variation was shown to be strongly associated with central obesity indexes in older adults (1). Testosterone is an important factor for determining body composition in males. Abdominal obesity is inversely correlated with serum testosterone levels in men but not in women (2). Steady increases in body fat mass accompany the age-dependent decrease in serum testosterone levels in men (3,4), leading to greater morbidity (5). Pathologically hypogonadal men also have a significantly higher fat mass (3,6), which is reversed by testosterone administration (7,8), whereas suppression of serum testosterone in healthy young men increased the percent fat mass and decreased lipid oxidation rates and resting energy expenditure (9).We generated an AR null (ARKO) mouse line, using a Cre-loxP system (10 -12), and found that male ARKO mice (AR LϪ/Y ) developed late-onset obesity, whereas neither heterozygous nor homozygous female ARKO mice were affected (10), suggesting a male-specific AR effect on adiposity.Herein we report the underlying mechanism of lateonset obesity in AR LϪ/Y mice. Despite a lack of hyperphagia, AR LϪ/Y mice had lower spontaneous activity and a decreased overall oxygen consumption ratio. We also observed a concomitant decrease in expression of the thermogenic uncoupling protein 1 (UCP-1). In addition, a unique lack of insulin resistance in AR LϪ/Y mice, despite the obese phenotype, suggests it was related to an enhanced secretion of adiponectin from adipose tissue. RESEARCH DESIGN AND METHODSAn ARKO mutant mouse line was established and maintained as described previously (10 -12). Heterozygous females were bred to wild-type males (C57BL/6NCrj; Charles River Japan, Tokyo, Japan) to produce ARKO male mice (AR LϪ/Y ) and heterozygous females. Their diet (CLEA rod...

As locally converted estrogen from testicular testosterone contributes to apparent androgen activity, the physiological significance of androgen receptor (AR) function in the beneficial effects of androgens on skeletal tissues has remained unclear. We show here that inactivation of AR in mice using a Cre-loxP system-mediated gene-targeting technique caused bone loss in males but not in females. Histomorphometric analyses of 8-week-old male AR knockout (ARKO) mice showed high bone turnover with increased bone resorption that resulted in reduced trabecular and cortical bone mass without affecting bone shape. Bone loss in orchidectomized male ARKO mice was only partially prevented by treatment with aromatizable testosterone. Analysis of primary osteoblasts and osteoclasts from ARKO mice revealed that AR function was required for the suppressive effects of androgens on osteoclastogenesis supporting activity of osteoblasts but not on osteoclasts. Furthermore, expression of the receptor activator of NF-B ligand (RANKL) gene, which encodes a major osteoclastogenesis inducer, was found to be up-regulated in osteoblasts from ARdeficient mice. Our results indicate that AR function is indispensable for male-type bone formation and remodeling.

Testicular testosterone produced during a critical perinatal period is thought to masculinize and defeminize the male brain from the inherent feminization program and induce male-typical behaviors in the adult. These actions of testosterone appear to be exerted not through its androgenic activity, but rather through its conversion by brain aromatase into estrogen, with the consequent activation of estrogen receptor (ER)-mediated signaling. Thus, the role of androgen receptor (AR) in perinatal brain masculinization underlying the expression of male-typical behaviors remains unclear because of the conversion of testosterone into estrogen in the brain. Here, we report a null AR mutation in mice generated by the Cre-loxP system. The AR-null mutation in males (AR L؊/Y ) resulted in the ablation of male-typical sexual and aggressive behaviors, whereas female AR-null homozygote (AR L؊/L؊ ) mice exhibited normal female sexual behaviors. Treatment with nonaromatizable androgen (5␣-dihydrotestosterone, DHT) was ineffective in restoring the impaired male sexual behaviors, but it partially rescued impaired male aggressive behaviors in AR L؊/Y mice. Impaired maletypical behaviors in ER␣ ؊/؊ mice were restored on DHT treatment. The role of AR function in brain masculinization at a limited perinatal stage was studied in AR L؊/L؊ mice. Perinatal DHT treatment of females led to adult females sensitive to both 17␤-estradiol and DHT in the induction of male-typical behaviors. However, this female brain masculinization was abolished by AR inactivation. Our results suggested that perinatal brain masculinization requires AR function and that expression of male-typical behaviors in adults is mediated by both AR-dependent and -independent androgen signaling.

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