TY - JOUR
T1 - The arcuate nucleus
T2 - A site of synergism between Angiotensin II and leptin to increase sympathetic nerve activity and blood pressure in rats
AU - Shi, Zhigang
AU - Stornetta, Ruth L.
AU - Stornetta, Daniel S.
AU - Abbott, Stephen B.G.
AU - Brooks, Virginia L.
N1 - Funding Information:
The authors are grateful for the technical assistance provided by Jennifer Wong and Nicole Pelletier. NIH HL128181 (vlb), NIH HL028785 (rls), and NIH HL148004 (sbga).
Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2022/8/10
Y1 - 2022/8/10
N2 - The action of leptin in brain to increase sympathetic nerve activity (SNA) and blood pressure depends upon functional Angiotensin II (AngII) type 1a receptors (AT1aR); however, the sites and mechanism of interaction are unknown. Here we identify one site, the hypothalamic arcuate nucleus (ArcN), since prior local blockade of AT1aR in the ArcN with losartan or candesartan in anesthetized male rats essentially eliminated the sympathoexcitatory and pressor responses to ArcN leptin nanoinjections. Unlike mice, in male and female rats, AT1aR and LepR rarely co-localized, suggesting that this interdependence occurs indirectly, via a local interneuron or network of neurons. ArcN leptin increases SNA by activating pro-opiomelanocortin (POMC) inputs to the PVN, but this activation requires simultaneous suppression of tonic PVN Neuropeptide Y (NPY) sympathoinhibition. Because AngII-AT1aR inhibits ArcN NPY neurons, we propose that loss of AT1aR suppression of NPY blocks leptin-induced increases in SNA; in other words, ArcN-AngII-AT1aR is a gatekeeper for leptin-induced sympathoexcitation. With obesity, both leptin and AngII increase; therefore, the increased AT1aR activation could open the gate, allowing leptin (and insulin) to drive sympathoexcitation unabated, leading to hypertension.
AB - The action of leptin in brain to increase sympathetic nerve activity (SNA) and blood pressure depends upon functional Angiotensin II (AngII) type 1a receptors (AT1aR); however, the sites and mechanism of interaction are unknown. Here we identify one site, the hypothalamic arcuate nucleus (ArcN), since prior local blockade of AT1aR in the ArcN with losartan or candesartan in anesthetized male rats essentially eliminated the sympathoexcitatory and pressor responses to ArcN leptin nanoinjections. Unlike mice, in male and female rats, AT1aR and LepR rarely co-localized, suggesting that this interdependence occurs indirectly, via a local interneuron or network of neurons. ArcN leptin increases SNA by activating pro-opiomelanocortin (POMC) inputs to the PVN, but this activation requires simultaneous suppression of tonic PVN Neuropeptide Y (NPY) sympathoinhibition. Because AngII-AT1aR inhibits ArcN NPY neurons, we propose that loss of AT1aR suppression of NPY blocks leptin-induced increases in SNA; in other words, ArcN-AngII-AT1aR is a gatekeeper for leptin-induced sympathoexcitation. With obesity, both leptin and AngII increase; therefore, the increased AT1aR activation could open the gate, allowing leptin (and insulin) to drive sympathoexcitation unabated, leading to hypertension.
UR - http://www.scopus.com/inward/record.url?scp=85134307352&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85134307352&partnerID=8YFLogxK
U2 - 10.1016/j.neulet.2022.136773
DO - 10.1016/j.neulet.2022.136773
M3 - Article
C2 - 35809879
AN - SCOPUS:85134307352
SN - 0304-3940
VL - 785
JO - Neuroscience Letters
JF - Neuroscience Letters
M1 - 136773
ER -