Young Colin N, Morgan Donald A, Butler Scott D, Rahmouni Kamal, Gurley Susan B, Coffman Thomas M, Mark Allyn L, Davisson Robin L
Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.
Department of Pharmacology, University of Iowa, Iowa City, IA, 52242, USA.
Mol Metab. 2015 Jan 31;4(4):337-43. doi: 10.1016/j.molmet.2015.01.007. eCollection 2015 Apr.
Elevations in brain angiotensin-II cause increased energy expenditure and a lean phenotype. Interestingly, the metabolic effects of increased brain angiotensin-II mimic the actions of leptin, suggesting an interaction between the two systems. Here we demonstrate that angiotensin-type 1a receptors (AT1aR) in the subfornical organ (SFO), a forebrain structure emerging as an integrative metabolic center, play a key role in the body weight-reducing effects of leptin via brown adipose tissue (BAT) thermogenesis.
Cre/LoxP technology coupled with targeted viral delivery to the SFO in a mouse line bearing a conditional allele of the Agtr1a gene was utilized to determine the interaction between leptin and SFO AT1aR in metabolic regulation.
Selective deletion of AT1aR in the SFO attenuated leptin-induced weight loss independent of changes in food intake or locomotor activity. This was associated with diminished leptin-induced increases in core body temperature, blunted upregulation of BAT thermogenic markers, and abolishment of leptin-mediated sympathetic activation to BAT.
These data identify a novel interaction between angiotensin-II and leptin in the control of BAT thermogenesis and body weight, and highlight a previously unrecognized role for the forebrain SFO in metabolic regulation.
脑内血管紧张素 II 水平升高会导致能量消耗增加和瘦体型。有趣的是，脑内血管紧张素 II 增加所产生的代谢效应类似于瘦素的作用，提示这两个系统之间存在相互作用。在此，我们证明，穹窿下器（SFO）中的 1a 型血管紧张素受体（AT1aR），作为一个新兴的整合代谢中心的前脑结构，通过棕色脂肪组织（BAT）产热在瘦素的体重减轻效应中起关键作用。
利用 Cre/LoxP 技术并结合向携带 Agtr1a 基因条件等位基因的小鼠品系的 SFO 进行靶向病毒递送，以确定瘦素与 SFO AT1aR 在代谢调节中的相互作用。
SFO 中 AT1aR 的选择性缺失减弱了瘦素诱导的体重减轻，这与食物摄入量或运动活动的变化无关。这与瘦素诱导的核心体温升高减弱、BAT 产热标志物上调减弱以及瘦素介导的对 BAT 的交感神经激活消失有关。
这些数据确定了血管紧张素 II 与瘦素在控制 BAT 产热和体重方面的一种新的相互作用，并突出了前脑 SFO 在代谢调节中以前未被认识的作用。
