Leeners Brigitte, Geary Nori, Tobler Philippe N, Asarian Lori
Division of Reproductive Endocrinology, University Hospital Zurich, Frauenklinikstr. 10, CH 8091 Zurich, Switzerland.
Center for Integrative Human Physiology (ZIHP), University of Zurich, 8057 Zurich, Switzerland.
Hum Reprod Update. 2017 May 1;23(3):300-321. doi: 10.1093/humupd/dmw045.
Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role.
We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE.
Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review.
We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates that one mechanism for the pre-ovulatory decrease in eating is a central action of estrogens to increase the satiating potency of the gastrointestinal hormone cholecystokinin. Another mechanism involves a decrease in the preference for sweet foods during the follicular phase. Genetic defects in brain α-melanocycte-stimulating hormone-melanocortin receptor (melanocortin 4 receptor, MC4R) signaling lead to a syndrome of overeating and obesity that is particularly pronounced in women and in female animals. The syndrome appears around puberty in mice with genetic deletions of MC4R, suggesting a role of ovarian hormones. Emerging functional brain-imaging data indicates that fluctuations in ovarian hormones affect eating by influencing striatal dopaminergic processing of flavor hedonics and lateral prefrontal cortex processing of cognitive inhibitory controls of eating. There is a dearth of research on the neuroendocrine control of eating after menopause. There is also comparatively little research on the effects of ovarian hormones on EE, although changes in ovarian hormone levels during the menstrual cycle do affect resting EE.
The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health.
肥胖是由能量摄入（即饮食）与能量消耗（EE）之间的失衡所致。在全球范围内，重度肥胖在女性中比在男性中更为普遍，而且肥胖的病理生理学以及由此产生的肥胖相关疾病风险在女性和男性中存在差异。其潜在机制在很大程度上尚不清楚。临床前和临床研究表明，卵巢激素可能起主要作用。
我们系统地回顾了关于卵巢激素对脂肪组织（AT）生理学以及通过能量摄入和EE对AT质量调节作用的临床和临床前文献。
使用与以下方面相关的关键词检索截至2016年1月在PubMed中索引的英文文章：（i）生殖激素，（ii）体重调节，以及（iii）中枢神经系统。我们旨在确定具有临床转化潜力的新兴研究热点，而非提供全面综述。
我们发现雌激素在女性肥胖的成因及后果中起主导作用。在肥胖方面，雌激素与AT基因协同作用，增加育龄女性臀股部皮下AT质量并减少中心AT质量，从而产生心脏代谢保护作用。绝经后雌激素丧失，独立于衰老因素，会增加总AT质量并减少瘦体重，因此对体重几乎没有净影响。绝经还会部分逆转女性具有保护作用的AT分布。这些影响可通过雌激素治疗得到抵消。在饮食方面，雌激素水平升高会在月经周期的卵泡期和围排卵期逐渐减少进食。孕激素水平与黄体期的进食有关，但似乎不存在因果关系。孕激素可能会增加黄体期的暴饮暴食以及由负面情绪状态刺激引起的进食。临床前研究表明，排卵前进食减少的一种机制是雌激素的中枢作用，可增加胃肠激素胆囊收缩素的饱腹感。另一种机制涉及卵泡期对甜食偏好的降低。大脑α-黑素细胞刺激激素-黑皮质素受体（黑皮质素4受体，MC4R）信号通路的基因缺陷会导致一种暴饮暴食和肥胖综合征，在女性和雌性动物中尤为明显。该综合征在MC4R基因缺失的小鼠青春期前后出现，提示卵巢激素的作用。新出现的功能性脑成像数据表明，卵巢激素的波动通过影响纹状体对味觉享乐主义的多巴胺能处理以及外侧前额叶皮质对进食的认知抑制控制处理来影响进食。关于绝经后进食的神经内分泌控制的研究较少。关于卵巢激素对EE影响的研究也相对较少，尽管月经周期中卵巢激素水平的变化确实会影响静息EE。
女性明显更大的肥胖负担使得了解卵巢激素对进食、EE和身体肥胖的多种影响成为紧迫的研究挑战。可以使用多种研究方式来研究女性中的这些影响，并且所综述的大多数机制在动物模型中是可探究的。因此，应加强关于卵巢激素在女性肥胖及其成因中作用的人体和转化研究，以获得更多可能最终转化为新型抗肥胖疗法从而改善女性健康的机制性见解。
