Angiotensin AT1A receptors on leptin receptor–expressing cells control resting metabolism
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
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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Research Article Metabolism Neuroscience

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

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 3

AT1ALepR-KO mice exhibit impaired responses to an HFD and leptin.

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AT1ALepR-KO mice exhibit impaired responses to an HFD and leptin. (A–D) ...
(A–D) Body mass (A) (n = 28 chow-fed control mice; n = 35 HFD-fed control mice; n = 26 chow-fed AT1ALepR-KO mice; n = 31 HFD-fed AT1ALepR-KO mice); fat mass (B) (n = 28 chow-fed control mice; n = 35 HFD-fed control mice; n = 26 chow-fed AT1ALepR-KO mice; n = 31 HFD-fed AT1ALepR-KO mice); home cage food intake (C) (n = 12 chow-fed control mice; n = 29 HFD-fed control mice; n = 15 chow-fed AT1ALepR-KO mice; n = 14 HFD-fed AT1ALepR-KO mice); and digestive efficiency (D) (n = 5/group) of control and AT1ALepR-KO mice on a chow diet or after 5 weeks of 45% HFD treatment. (E) Physical activity of control and AT1ALepR-KO mice on a chow diet (n = 10 control mice; n = 9 AT1ALepR-KO mice). (F and G) ANCOVA-adjusted RMR (F) (n = 13 chow-fed control mice; n = 22 HFD-fed control mice; n = 15 chow-fed AT1ALepR-KO mice; n = 12 HFD-fed AT1ALepR-KO mice) and BAT Ucp1 expression (G) (n = 4 chow-fed control mice; n = 4 HFD-fed control mice; n = 5 chow-fed AT1ALepR-KO mice; n = 8 HFD-fed AT1ALepR-KO mice) in control and AT1ALepR-KO mice on a chow diet or after 2 weeks of HFD treatment. (H) Changes in BAT SNA following i.v. administration of leptin (60 μg) in control and AT1ALepR-KO mice (n = 6 control mice; n = 5 AT1ALepR-KO mice). RVI, rectified/integrated voltage. Data represent the mean ± SEM. *P < 0.05, by Tukey’s multiple comparisons procedure.