Role of muscarinic acetylcholine receptors in glucose and energy homeostasis

全身M3 mAChR KO小鼠的代谢研究表明，M3受体的缺乏始终与食物摄入减少和能量消耗增加相关（Gautam等人，细胞代谢4，363-375，2006）。我们证明，这种能量消耗的增加是由于基础和总耗氧量的升高，与运动活动，体温和交感神经张力增加有关。此外，全身M3受体KO小鼠受到保护，免受不同形式的实验和遗传诱导的肥胖和肥胖相关疾病的影响。 M3受体存在于许多外周组织中，包括腺体和平滑肌组织以及CNS的大部分区域。因此，为了深入了解全身M3受体KO小鼠所显示的惊人代谢表型的机制，我们开始使用Cre/LoxP技术来产生仅在特定组织或细胞类型中缺乏M3受体的突变小鼠。 肝脏在维持正常的葡萄糖和能量平衡中起着关键作用。我们最近证明，M3受体亚型是小鼠肝脏（肝细胞）表达的唯一mAChR。为了评估这些肝脏M3受体在体内调节葡萄糖和能量稳态中的生理作用，我们采用Cre/loxP技术来产生仅在肝细胞中缺乏M3受体的突变小鼠。此外，为了研究通过肝脏M3受体增强信号传导的代谢效应，我们还产生了在肝细胞中选择性过表达这种受体亚型的突变小鼠。目前正在对这些动物进行表型分析。 能量平衡和食物摄入被认为是在下丘脑的调节中心的严格控制之下。在下丘脑中发现的许多细胞类型中，已知含有POMC和AGRP的神经元在调节食欲和能量稳态中起关键作用。我们证明，基本上所有的POMC和AGRP含有神经元表达M3 mAChR。因此，我们开始使用Cre/loxP技术来产生仅在含有POMC和AGRP的神经元中缺乏M3受体的突变小鼠。这些突变动物的表型分析应该揭示下丘脑M3受体在调节能量稳态和食物摄入中的作用。 这些研究很可能会导致识别用于治疗肥胖症和相关代谢紊乱的新的药理学靶点。

Metabolic studies with whole body M3 mAChR KO mice showed that the lack of M3 receptors is consistently associated with reduced food intake and increased energy expenditure (Gautam et al., Cell Metab. 4, 363-375, 2006). We demonstrated that this increase in energy expenditure is due to an elevated rate in basal and total oxygen consumption, associated with increased locomotor activity, body temperature, and sympathetic tone. Moreover, the whole body M3 receptor KO mice were protected against different forms of experimentally- and genetically-induced obesity and obesity-associated disorders. The M3 receptor is found in many peripheral tissues, including glands and smooth muscle tissues, and most areas of the CNS. Therefore, to gain insight into the mechanisms underlying the striking metabolic phenotypes displayed by the whole body M3 receptor KO mice, we started to use Cre/LoxP technology to generate mutant mice that lack M3 receptors only in specific tissues or cell types. The liver plays a key role in maintaining normal glucose and energy homeostasis. We recently demonstrated that the M3 receptor subtype is the only mAChR expressed by the mouse liver (hepatocytes). To assess the physiological role of these liver M3 receptors in regulating glucose and energy homeostasis in vivo, we employed Cre/loxP technology to generate mutant mice lacking M3 receptors in hepatocytes only. Moreover, to study the metabolic effects of enhanced signaling through liver M3 receptors, we also generated mutant mice selectively overexpressing this receptor subtype in hepatocytes. The phenotypic analysis of these animals is currently ongoing. Energy homeostasis and food intake are known to be under the strict control of regulatory centers in the hypothalamus. Among the many cell types found in the hypothalamus, the POMC- and AGRP-containing neurons are known to play key roles in regulating appetite and energy homeostasis. We demonstrated that essentially all POMC- and AGRP-containing neurons express M3 mAChRs. We therefore started to use Cre/loxP technology to generate mutant mice lacking M3 receptors in POMC- and AGRP-containing neurons only. Phenotypic analysis of these mutant animals should shed new light on the roles of hypothalamic M3 receptors in the regulation of energy homeostasis and food intake. It is likely that these studies will lead to the identification of novel pharmacologic targets for the treatment of obesity and associated metabolic disorders.