Late onset of obesity in male androgen receptor-deficient (AR KO) mice

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Abstract

An androgen receptor (AR) null mutant mice line was generated by means of a Cre-lox P system. The male (ARL−/Y) (KO) mice exhibited typical features of testicular feminization mutant (Tfm) disease in external reproductive organs with growth retardation. The growth curve of the male AR KO mice was similar to that of the wild-type female littermates until the 10th week of age, but thereafter a drastic increase in the growth was observed with development of obesity. Clear increase in the wet weights of white adipose tissues, but not of brown adipose tissue, was found in the 30-week-old male AR KO mice. However, no significant alteration in serum lipid parameters and food intake was observed. Thus, the present results suggest that AR may serve as a negative regulator of adipose development in adult males.

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Materials and methods

Animal conditions and food intake. AR KO mice were generated by targeting disruption of AR gene by means of a Cre-lox P system, as previously described [10], [11]. All mice were given a standard laboratory chow diet (4.4% w/w fat) and water ad libitum. The growth rates of male ARL−/Y and AR+/Y were monitored from the birth. Food intakes of ARL−/Y and AR+/Y mice were monitored for 12 weeks from the 12th week. For hormone treatments, a 60-day time-release pellet (Innovative Research of America)

Late onset of obesity of male AR KO mice

The AR floxed male (ARL3/Y) mice grew up normally with no overt abnormality in behaviors and metabolisms, and appeared completely normal in reproduction. Male AR floxed mice were then crossed with CMV-Cre transgenic mice [11] to generate female heterozygotes (AR+/L−) for further production of male AR KO(L−/Y) mice [10].

The male AR (ARL−/Y) KO mice exhibited growth retardation and the growth curve was indistinguishable from that of the wild-type female littermates up to the 10th week (Fig. 1A).

Discussion

We have succeeded in generating a null mutant mouse line by means of a Cre-lox P system [10], and the male AR KO (ARL−/Y) mice exhibited the typical features of Tfm syndrome [8], [9] including female-like outlook of external reproduction organs, degenerated testes, no ovary, and blunted vagina [10]. Male AR KO mice showed growth retardation, but the growth curve was similar to that of the wild-type female littermates up to the 8th week. However, thereafter obesity developed in the male AR KO

Acknowledgements

We thank I. Takada, M. Suzawa, and T. Imai for helpful discussions, R. Nakamura and H. Higuchi for manuscript preparation. This work was supported in part by the Human Frontier Science Program and a grant-in-aid for priority areas from the Ministry of Education, Science, Sports and Culture of Japan (S.K.).

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These authors contributed equally to this work.

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