Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity.
Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity.
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DOI：
10.1523/jneurosci.3806-12.2013
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发表时间：
2013-03-13
期刊：
影响因子：
--
通讯作者：
Krause EG
中科院分区：
文献类型：
--
作者：
de Kloet AD;Pati D;Wang L;Hiller H;Sumners C;Frazier CJ;Seeley RJ;Herman JP;Woods SC;Krause EG
Obesity is associated with increased levels of angiotensin-II (Ang-II), which activates angiotensin type-1a receptors (AT1a) to influence cardiovascular function and energy homeostasis. To test the hypothesis that specific AT1a within the brain control these processes, we utilized the Cre/lox system to delete AT1a from the paraventricular nucleus of the hypothalamus (PVN) of mice. PVN AT1a deletion did not affect body mass or adiposity when mice were maintained on standard chow. However, maintenance on a high-fat diet revealed a gene by environment interaction whereby mice lacking AT1a in the PVN had increased food intake and decreased energy expenditure that augmented body mass and adiposity relative to controls. Despite this increased adiposity, PVN AT1a deletion reduced systolic blood pressure, suggesting that this receptor population mediates the positive correlation between adiposity and blood pressure. Gene expression studies revealed that PVN AT1a deletion decreased hypothalamic expression of corticotrophin-releasing hormone and oxytocin, neuropeptides known to control food intake and sympathetic nervous system activity. Whole cell patch clamp recordings confirmed that PVN AT1a deletion eliminates responsiveness of PVN parvocellular neurons to Ang-II, and suggest that Ang-II responsiveness is increased in obese wild-type mice. Central inflammation is associated with metabolic and cardiovascular disorders and PVN AT1a deletion reduced indices of hypothalamic inflammation. Collectively, these studies demonstrate that PVN AT1a regulate energy balance during environmental challenges that promote metabolic and cardiovascular pathologies. The implication is that the elevated Ang-II that accompanies obesity serves as a negative feedback signal that activates PVN neurons to alleviate weight gain.
