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Melanocortin MC4R receptor is required for energy expenditure but not blood pressure effects of angiotensin II within the mouse brain. Physiol Genomics 2022 06 01;54(6):196-205

Date

04/28/2022

Pubmed ID

35476598

Pubmed Central ID

PMC9131927

DOI

10.1152/physiolgenomics.00015.2022

Scopus ID

2-s2.0-85131018208

Abstract

The brain renin-angiotensin system (RAS) is implicated in control of blood pressure (BP), fluid intake, and energy expenditure (EE). Angiotensin II (ANG II) within the arcuate nucleus of the hypothalamus contributes to control of resting metabolic rate (RMR) and thereby EE through its actions on Agouti-related peptide (AgRP) neurons, which also contribute to EE control by leptin. First, we determined that although leptin stimulates EE in control littermates, mice with transgenic activation of the brain RAS (sRA) exhibit increased EE and leptin has no additive effect to exaggerate EE in these mice. These findings led us to hypothesize that leptin and ANG II in the brain stimulate EE through a shared mechanism. Because AgRP signaling to the melanocortin MC4R receptor contributes to the metabolic effects of leptin, we performed a series of studies examining RMR, fluid intake, and BP responses to ANG II in mice rendered deficient for expression of MC4R via a transcriptional block (Mc4r-TB). These mice were resistant to stimulation of RMR in response to activation of the endogenous brain RAS via chronic deoxycorticosterone acetate (DOCA)-salt treatment, whereas fluid and electrolyte effects remained intact. These mice were also resistant to stimulation of RMR via acute intracerebroventricular (ICV) injection of ANG II, whereas BP responses to ICV ANG II remained intact. Collectively, these data demonstrate that the effects of ANG II within the brain to control RMR and EE are dependent on MC4R signaling, whereas fluid homeostasis and BP responses are independent of MC4R signaling.

Author List

Oliveira V, Riedl RA, Claflin KE, Mathieu NM, Ritter ML, Balapattabi K, Wackman KK, Reho JJ, Brozoski DT, Morgan DA, Cui H, Rahmouni K, Burnett CML, Nakagawa P, Sigmund CD, Morselli LL, Grobe JL

Authors

Justin L. Grobe PhD Associate Professor in the Physiology department at Medical College of Wisconsin
Lisa Morselli MD, PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Pablo Nakagawa PhD Assistant Professor in the Physiology department at Medical College of Wisconsin
John J. Reho Research Scientist II in the Physiology department at Medical College of Wisconsin
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Agouti-Related Protein
Angiotensin II
Animals
Blood Pressure
Brain
Energy Metabolism
Leptin
Melanocortins
Mice
Receptor, Melanocortin, Type 4