The effects of chronic testosterone administration on body weight, food intake, and adipose tissue are changed by estrogen treatment in female rats.

In females, estrogens play pivotal roles in preventing excess body weight (BW) gain. On the other hand, the roles of androgens in female BW, appetite, and energy metabolism have not been fully examined. We hypothesized that androgens' effects on food intake (FI) and BW regulation change according to the estrogens' levels. To evaluate this hypothesis, the effects of chronic testosterone administration in ovariectomized (OVX) female rats with or without estradiol supplementation were examined in this study. Chronic testosterone administration decreased BW, FI, white adipose tissue (WAT) weight, and adipocyte size in OVX rats, whereas it increased BW, WAT weight, and adipocyte size in OVX with estradiol-administered rats. In addition, chronic testosterone administration increased hypothalamic CYP19a1 mRNA levels in OVX rats, whereas it did not alter CYP19a1 mRNA levels in OVX with estradiol-administered rats, indicating that conversion of testosterone to estrogens in the hypothalamus may be activated in testosterone-administered OVX rats. Furthermore, chronic testosterone administration decreased hypothalamic TNF-α mRNA levels in OVX rats, whereas it increased hypothalamic IL-1β mRNA levels in OVX with estradiol-administered rats. On the other hand, IL-1β and TNF-α mRNA levels in visceral and subcutaneous WAT and liver were not changed by chronic testosterone administration in both groups. These data indicate that the effects of chronic testosterone administration on BW, FI, WAT weight, and adipocyte size were changed by estradiol treatment in female rats. Testosterone has facilitative effects on BW gain, FI, and adiposity under the estradiol-supplemented condition, whereas it has inhibitory effects in the non-supplemented condition. Differences in the responses of hypothalamic factors, such as aromatase and inflammatory cytokines, to testosterone might underlie these opposite effects.

Iwasa T ，Matsuzaki T ，Yano K ，Yanagihara R ，Tungalagsuvd A ，Munkhzaya M ，Mayila Y ，Kuwahara A ，Irahara M ... -  《-》

Effects of chronic testosterone administration on body weight and food intake differ among pre-pubertal, gonadal-intact, and ovariectomized female rats.

In females, estrogens play pivotal roles in preventing excessive body weight gain. On the other hand, the roles of androgen in female appetite and body weight regulation have not been fully studied. In this study, whether the roles of androgen in the regulation of body weight and appetite were different among ages and/or the estrogen milieu in females was evaluated. Body weight gain and food intake were increased by chronic testosterone administration in pre-pubertal and gonadal-intact female rats, but not in ovariectomized female rats. Testosterone administration also affected the serum leptin level and adipose leptin gene expression levels differently in each experimental condition. Hypothalamic mRNA levels of ERα, which plays pivotal roles in regulation of body weight and metabolism, were decreased by chronic testosterone administration in pre-pubertal and gonadal-intact female rats, but not in ovariectomized female rats. These results indicate that the effects of testosterone on body weight and appetite differed among ages and/or estrogen milieu in female rats, and that attenuation of estrogens' actions on the hypothalamus might be partly involved in the androgen-induced increases of body weight gain and food intake in females.

Iwasa T ，Matsuzaki T ，Tungalagsuvd A ，Munkhzaya M ，Yiliyasi M ，Kato T ，Kuwahara A ，Irahara M ... -  《-》

Effects of chronic testosterone administration on the degree of preference for a high-fat diet and body weight in gonadal-intact and ovariectomized female rats.

Energy balance and reproductive functions are closely linked in some species. The sex hormones (estrogens and androgens) are involved in the regulation of appetite, metabolism, body weight (BW), and body composition in mammals. Previously, we showed that the effects of testosterone on BW, appetite, and fat weight were markedly affected by alterations to the gonadal hormonal milieu. In this study, we examined whether testosterone administration changes food preferences and whether these effects of testosterone depend on gonadal status in female rats. We also evaluated the underlying mechanisms responsible for these effects, focusing on hypothalamic inflammation and endoplasmic reticulum (ER) stress. In gonadal-intact (sham) female rats, chronic testosterone administration promoted a preference for a high-fat diet (HFD) and increased BW gain, fat weight, and adipocyte size, whereas no such effects were observed in ovariectomized (OVX) rats. Testosterone administration increased hypothalamic interleukin-1 mRNA expression in the sham rats, but not the OVX rats. On the contrary, testosterone administration decreased the hypothalamic mRNA levels of ER stress-response genes in the OVX rats, but not the sham rats. These testosterone-induced alterations in OVX rats might represent a regulatory mechanism for preventing hypothalamic inflammation and the overconsumption of a HFD. In conclusion, testosterone's effects on food preferences and the subsequent changes were affected by gonadal status. Testosterone-induced changes in hypothalamic inflammatory cytokine production and ER stress might be related to these findings.

Iwasa T ，Matsuzaki T ，Yano K ，Yiliyasi M ，Kuwahara A ，Matsui S ，Irahara M ... -  《-》

Regulation of UCP1, UCP2, and UCP3 mRNA expression in brown adipose tissue, white adipose tissue, and skeletal muscle in rats by estrogen.

The effects of ovariectomy (OVX) and estrogen substitution on body weight, body composition, food intake, weight gain, and expression of uncoupling proteins (UCPs) in brown adipose tissue (BAT), white adipose tissue (WAT), and skeletal muscle were studied in four groups of rats: (1) Sham-operated rats (N = 8), (2) ovariectomized rats (OVX - E) (N = 8), (3) estrogen-treated OVX rats (OVX + E) (N = 8), and (4) OVX rats on energy restriction (OVX - E + D) (N = 8). OVX was associated with an increase in food intake and body weight gain during a 5-week study period compared to sham-operated rats. The estrogen-substituted rats had a significantly lower food intake and weight gain during the 5 weeks compared to the sham-operated group. However, we also included a nontreated OVX group that was allowed to eat only enough chow to match the weight gain of the sham-operated group. To match the weight gain in the two groups, the OVX group had to consume 16% less chow than the sham-operated group. In BAT, the UCP1 expression was significantly lower in estrogen-deficient rats compared to either intact rats or estrogen-substituted rats, whereas UCP2 and UCP3 mRNA expression was similar in BAT from all four groups. In WAT, both estrogen-deficient groups had significantly lower UCP2 mRNA expression compared to the control rats and estrogen-treated rats; In contrast, the UCP3 mRNA expression in WAT was similar in all four groups. Finally, in skeletal muscle the OVX group on mild energy restriction had reduced UCP3 mRNA expression compared to control, OVX, and estrogen-treated rats. In contrast, the UCP2 mRNA expression in skeletal muscle was similar in all four groups. Thus, the findings that estrogen deficiency is followed by reduced UCP1 expression in BAT and reduced UCP2 expression in WAT in association with weight gain probably caused by a decrease in energy expenditure might indicate that UCPs play a role for the estrogen-mediated changes in body weight and energy expenditure.

Pedersen SB ，Bruun JM ，Kristensen K ，Richelsen B ... -  《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》

The Effects of Testosterone on Hypothalamic and Serum Oxytocin Levels Are Affected by the Estrogen Milieu in Female Rats.

Arata M ，Tamura K ，Aoki H ，Noguchi H ，Takeda A ，Minato S ，Yamamoto S ，Kinouchi R ，Yoshida K ，Yamamoto Y ，Kaji T ，Iwasa T ... -  《Nutrients》