Aromatase catalyzes conversion of testosterone to estradiol and is expressed in a variety of tissues, including the brain. Suppression of aromatase adversely affects metabolism and physical activity behavior, but mechanisms remain uncertain. The hypothesis tested herein was that whole body aromatase deletion would cause gene expression changes in the nucleus accumbens (NAc), a brain regulating motivated behaviors such as physical activity, which is suppressed with loss of estradiol. Metabolic and behavioral assessments were performed in male and female wild-type (WT) and aromatase knockout (ArKO) mice. NAc-specific differentially expressed genes (DEGs) were identified with RNAseq, and associations between the measured phenotypic traits were determined. Female ArKO mice had greater percent body fat, reduced spontaneous physical activity (SPA), consumed less energy, and had lower relative resting energy expenditure (REE) than WT females. Such differences were not observed in ArKO males. However, in both sexes, a top DEG was Pts, a gene encoding an enzyme necessary for catecholamine (e.g., dopamine) biosynthesis. In comparing male and female WT mice, top DEGs were related to sexual development/fertility, immune regulation, obesity, dopamine signaling, and circadian regulation. SPA correlated strongly with Per3, a gene regulating circadian function, thermoregulation, and metabolism (r = -0.64, P = .002), which also correlated with adiposity (r = 0.54, P = .01). In conclusion, aromatase ablation leads to gene expression changes in NAc, which may in turn result in reduced SPA and related metabolic abnormalities. These findings may have significance to post-menopausal women and those treated with an aromatase inhibitor.

中文翻译：

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伏伏核基因表达的变化伴随着性别特异性抑制芳香化酶基因敲除小鼠的自发体力活动。

芳香酶催化睾丸激素转化为雌二醇，并在包括大脑在内的多种组织中表达。抑制芳香化酶会不利地影响新陈代谢和身体活动行为，但机制仍不确定。本文测试的假设是，整个身体的芳香酶缺失会导致伏隔核（NAc）的基因表达发生变化，伏隔核是大脑调节动机行为（例如体育活动）的过程，但雌二醇的丢失会抑制这种行为。在雄性和雌性野生型（WT）和芳香化酶敲除（ArKO）小鼠中进行了代谢和行为评估。用RNAseq鉴定NAc特异性差异表达基因（DEG），并确定所测表型性状之间的关联。雌性ArKO小鼠体内脂肪百分比更高，自发体力活动（SPA）减少，消耗的能量较少，并且相对静止的能量消耗（REE）低于野生雌性。在ArKO男性中未观察到此类差异。但是，在男女中，最高的DEG是Pts，Pts是编码儿茶酚胺（例如多巴胺）生物合成所必需的酶的基因。在比较雄性和雌性野生型小鼠时，最高的DEG与性发育/生育力，免疫调节，肥胖，多巴胺信号传导和昼夜节律调节有关。SPA与调节昼夜节律功能，体温调节和代谢的基因Per3密切相关（r = -0.64，P = .002），也与肥胖相关（r = 0.54，P = 0.01）。总之，消融芳香化酶可导致NAc基因表达发生变化，进而可能导致SPA降低和相关的代谢异常。