Androgen Receptor Null Male Mice Develop Late-Onset Obesity Caused by Decreased Energy Expenditure and Lipolytic Activity but Show Normal Insulin Sensitivity With High Adiponectin Secretion

Abstract

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...

Conditional Inactivation of Androgen Receptor Gene in the Nervous System: Effects on Male Behavioral and Neuroendocrine Responses

“…Another consequence of central AR gene invalidation was the alteration of the sexually dimorphic somatotropic axis. A transient decrease in body weight was described in ubiquitous ARKO mice, but it was reversed since 12 weeks of age due to the increased adipose tissue mass and decreased lipolytic activity Fan et al, 2005). In AR NesCre males, growth retardation was persistent until 20 -30 weeks of age.…”

Response of the adipose tissue transcriptome to dihydrotestosterone in mice

“…Triglycerides in retroperitoneal and mesenteric adipose tissue increase after castration in rats but decrease when animals are treated with testosterone (25). Additionally, androgen receptor knockout mice develop late onset obesity through reduced adipose tissue lipolysis in animals of both sexes (16,42). These findings suggest that androgens may be key steroids in the modulation of fat accumulation and distribution in both humans and rodent models.…”

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

“…Accordingly, in vitro studies demonstrated that androgens inhibit adipogenic differentiation of mouse or human preadipocytes through an AR-mediated pathway (Singh et al 2006, Gupta et al 2008. By contrast, studies on the relationship between the androgen-AR system and insulin sensitivity produced conflicting results, showing both negative (Sato et al 2003, Fan et al 2005 and positive (Lin et al 2005) effects.…”

“…The results from ARKO models revealed that AR plays an important role in male metabolism, by affecting the energy balance and lipolysis (Sato et al 2003, Fan et al 2005. A negative effect of AR activation on visceral adiposity has been clearly demonstrated in ARKO mice (Yanase et al 2008).…”