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Angiotensin AT1A receptors on leptin receptor–expressing cells control resting metabolism
Kristin E. Claflin, … , Kamal Rahmouni, Justin L. Grobe
Kristin E. Claflin, … , Kamal Rahmouni, Justin L. Grobe
Published March 6, 2017
Citation Information: J Clin Invest. 2017;127(4):1414-1424. https://doi.org/10.1172/JCI88641.
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Research Article Metabolism Neuroscience

Angiotensin AT1A receptors on leptin receptor–expressing cells control resting metabolism

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Abstract

Leptin contributes to the control of resting metabolic rate (RMR) and blood pressure (BP) through its actions in the arcuate nucleus (ARC). The renin-angiotensin system (RAS) and angiotensin AT1 receptors within the brain are also involved in the control of RMR and BP, but whether this regulation overlaps with leptin’s actions is unclear. Here, we have demonstrated the selective requirement of the AT1A receptor in leptin-mediated control of RMR. We observed that AT1A receptors colocalized with leptin receptors (LEPRs) in the ARC. Cellular coexpression of AT1A and LEPR was almost exclusive to the ARC and occurred primarily within neurons expressing agouti-related peptide (AgRP). Mice lacking the AT1A receptor specifically in LEPR-expressing cells failed to show an increase in RMR in response to a high-fat diet and deoxycorticosterone acetate–salt (DOCA-salt) treatments, but BP control remained intact. Accordingly, loss of RMR control was recapitulated in mice lacking AT1A in AgRP-expressing cells. We conclude that angiotensin activates divergent mechanisms to control BP and RMR and that the brain RAS functions as a major integrator for RMR control through its actions at leptin-sensitive AgRP cells of the ARC.

Authors

Kristin E. Claflin, Jeremy A. Sandgren, Allyn M. Lambertz, Benjamin J. Weidemann, Nicole K. Littlejohn, Colin M.L. Burnett, Nicole A. Pearson, Donald A. Morgan, Katherine N. Gibson-Corley, Kamal Rahmouni, Justin L. Grobe

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Figure 2

AT1A and LEPR colocalize within cells in the ARC.

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AT1A and LEPR colocalize within cells in the ARC.
(A) Representative pho...
(A) Representative photomicrographs of AT1A and LEPR expression in various brain regions including the ARC, lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), ventromedial hypothalamus (VMH), nucleus tractus solitarii (NTS), PVN, SFO, hippocampus, and cortex. Scale bars: 100 μm. (B) Primers for the detection of genetic recombination of the AT1a gene span the floxed region. Intact and recombined AT1afl/fl gene expression in the SFO, cortex, PVN, SON, and ARC of control and AT1ALepR-KO animals. (C) AT1A expression in peripheral tissues, including heart, kidney, liver, lung, BAT, perigonadal white adipose tissue (pgWAT), s.c. WAT (scWAT) and skeletal muscle of control and AT1ALepR-KO mice (n = 6/group). Data represent the mean ± SEM. *P < 0.05, by Tukey’s multiple comparisons procedure. (D) ARC p-STAT3 expression following i.p. PBS or leptin (1 μg/g) in control and AT1ALepR-KO mice after 2 weeks of HFD treatment (PBS-treated control mice; n = 3 leptin-treated control mice; PBS-treated AT1ALepR-KO mouse; n = 6 leptin-treated AT1ALepR-KO mice). Scale bars: 75 μm. Data represent the mean ± SEM. 3V, third ventricle.
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