**Author details**

ARKO [51]. We are not yet able to explain this discrepancy, probably because change in

Next, we speculated that testosterone might increase mitochondrial activity to explain the increased basal metabolic rate. As shown in Fig. 5A, increased Cox4, a mitochondrial protein, as well as PGC1α, an up-stream regulator of mitochondrial biogenesis, was recognized in skeletal muscle isolated from testosterone-treated rats. Similar results were noted in mice [45]. In addition, treatment with testosterone up-regulates the expression levels of genes contribu‐ ting to mitochondrial biogenesis, such as nuclear respiratory factor-1 (NRF-1), NRF-2 and mitochondrial transcriptional factor A (Tfam), as well as mitochondrial DNA (mitDNA) in skeletal muscle [44]. Although DHEA and testosterone exhibit similar effects on adipocytes, administration of DHEA resulted in less increase in Cox4 than that of testosterone in skeletal muscle. This result was confirmed by the experiment showing that the testosterone-induced increase in mRNA of PGC1α and cytochrome C was greater than the DHEA-induced ones (Fig. 5C) in C2C12 myotubes. These results are consistent with data published by Sato *et al.* [41]. These differences in the response to DHEA and testosterone between adipocytes and myocytes may be attributable to differences in the efficacy of subcellular steroid converting enzymes. Although we did not assess the effect of androgens on total skeletal muscle volume, androgens have been reported to enhance the differentiation into skeletal muscle [53]. Therefore, the conclusion derived from our experiment should be further explored by increasing the whole skeletal muscle mass. In addition, we found that expression of PGC1α and mitochondrial genes

The results of our studies were summarized in Fig. 6. DHEA and testosterone equally sup‐ pressed proliferation of preadipocytes, differentiation of adipocytes and expression of PPARγ and its down-stream genes including adiponectin in adipocytes. Both DHEA and testosterone up-regulated PGC1α and mitochondrial biogenesis, more actively in the latter than the former in skeletal muscle. Which organ plays the main role in the androgens-induced reduction of adiposity remains an interesting problem. Our results suggest that reduced adiposity in testosterone-treated animals may be derived from decreased expression of PPARγ and suppressed differentiation into adipocytes. Moderate suppression of PPARγ activity by its antagonist HX531 resulted in decreased fat mass and increased oxygen con‐ sumption [56], and therefore androgen-induced reduction of PPARγ expression may be able

Whole body silencing of AR results in late-onset obesity [51, 56]. Recent technology has facilitated the generation of organ specific deletion of a gene. Adipocyte specific AR deficient mice showed identical body weight and adiposity with wild type at 20 wk of age in one study, although the authors did not show the data of older mice [57]. Since late obesity after 20 wk of age is the distinguishing feature in ARKO, this point is important. Conversely, mice lacking AR in the central nervous system develop late onset obesity and insulin resistance [59]. Although several investigations have reported that myocyte specific AR knockdown did not influence body weight and adiposity [60, 61], myocyte specific AR overexpression resulted in an increased metabolic rate and fat body mass [62]. These results suggest that skeletal muscle and brain might be responsible organs for androgen-induced reduction of adiposity. However,

locomotor activity may not occur in parallel with an androgen signal.

306 Treatment of Type 2 Diabetes

was reduced in skeletal muscle isolated from ARKO [45].

to influence systemic energy metabolism.

Kazuo Kajita1\*, Ichiro Mori1 , Masahiro1 , Takahide Ikeda1 , Hiroyuki Morita1 and Tatsuo Ishizuka2

\*Address all correspondence to: kkajita@gifu-u.ac.jp

1 Department of General Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Japan

2 Department of General Internal Medicine and Rheumatology, Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu, Japan

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