Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show that cyclic GMP–selective phosphodiesterase 9A inhibition (PDE9-I) in both male and ovariectomized female mice suppresses preestablished severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat; stimulates mitochondrial activity in brown and white fat; and improves CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis in a PPARα-dependent manner and increased mitochondrial respiration in both adipocytes and myocytes. PPARα upregulation was required to achieve the lipolytic, antiobesity, and metabolic effects of PDE9-I. All these PDE9-I–induced changes were not observed in obese/CMS nonovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was reoriented away from fat metabolism–regulating genes when stimulated in the presence of coactivated estrogen receptor-α, and this may underlie the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.

中文翻译：

---

抑制 9 型磷酸二酯酶可减少小鼠的肥胖和心脏代谢综合征

伴有心脏代谢综合征 (CMS) 的中心性肥胖是全球人类疾病的主要致病因素，因此需要有效的治疗方法。在这里，我们表明环 GMP 选择性磷酸二酯酶 9A 抑制 (PDE9-I) 在雄性和切除卵巢的雌性小鼠中抑制预先建立的严重饮食诱导的肥胖/CMS，有或没有叠加轻度心脏压力负荷。PDE9-I 减少全身、腹股沟、肝脏和心肌脂肪；刺激棕色和白色脂肪中的线粒体活动；并改善 CMS，而不会显着改变活动或食物摄入量。PDE9 定位于线粒体，其体外抑制以 PPAR α依赖性方式刺激脂肪分解，并增加脂肪细胞和肌细胞中的线粒体呼吸。PPARα _上调是实现 PDE9-I 的脂肪分解、抗肥胖和代谢作用所必需的。所有这些 PDE9-I 诱导的变化都没有在肥胖/CMS 非卵巢切除的女性中观察到，表明强烈的性别二态性。我们发现，当在共激活的雌激素受体-α存在的情况下受到刺激时，PPAR α染色质结合被重新定位，远离脂肪代谢调节基因，这可能是二态性的基础。鉴于 PDE9-I 已经在人体中研究包括心力衰竭在内的适应症，这些发现具有转化相关性，并且对肥胖/CMS 的疗效将提高其治疗效用。