Journal article
Loss of MRAP2 in MC4R neurons protect from obesity-associated autonomic and cardiovascular dysfunctions
Cardiovascular research, Vol.121(12), pp.1929-1940
10/24/2025
DOI: 10.1093/cvr/cvaf067
PMCID: PMC12551390
PMID: 40244925
Appears in UI Libraries Support Open Access
Abstract
The melanocortin receptor accessory protein 2 (MRAP2), which is abundantly expressed in the brain including the hypothalamus, has emerged as a key regulator of melanocortin-4 receptor (MC4R) activity. We sought to delineate the physiological significance of MRAP2 in MC4R neurons, with a particular focus on autonomic and cardiovascular functions.
Selective deletion of MRAP2 in MC4R neurons causes obesity that was associated with hyperphagia and impairment in glucose homeostasis and insulin sensitivity. MC4R agonist Melatonan II (MTII)-induced anorectic effects were blunted in mice lacking MRAP2 in MC4R neurons, whereas Celastrol retained its efficacy in reducing food intake and body weight. MRAP2 deletion also reduced baseline sympathetic nerve activity (SNA), particularly the SNA subserving the kidney. This was associated with reduced innervation of the kidney. In addition, MTII-induced increases in renal and brown adipose tissue (BAT) SNA as well as hepatic vagal nerve activity were significantly attenuated in MC4R neuron MRAP2-deficient mice. Anatomical tracing revealed that MC4R neurons projecting to BAT and kidneys were localized to specific brain nuclei including the paraventricular nucleus of the hypothalamus, providing anatomical substrate for MRAP2 regulation of sympathetic outflow. Although loss of MRAP2 in MC4R neurons did not affect arterial pressure, it caused a significant decrease in heart rate and baroreflex sensitivity. Finally, MRAP2 deficiency in MC4R neurons attenuated MTII-induced increase in arterial pressure and heart rate.
These findings demonstrate that in addition to its role in energy balance and glucose homeostasis MRAP2 in MC4R neurons is crucial for cardiovascular autonomic regulation and is required for the development of obesity-associated hypertension and autonomic dysfunction.
Details
- Title: Subtitle
- Loss of MRAP2 in MC4R neurons protect from obesity-associated autonomic and cardiovascular dysfunctions
- Creators
- Deng Fu Guo - Iowa City Veterans Affairs Health Care System, Iowa City, IA, USAPaul A Williams - University of IowaAlexis Olson - University of IowaDonald A Morgan - Iowa City Veterans Affairs Health Care System, Iowa City, IA, USAHussein Herz - University of IowaJon Resch - University of IowaDeniz Atasoy - Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USAHarald M Stauss - Department of Biomedical Sciences, Burrell College of Osteopathic Medicine, Las Cruces, NM, USAJulien A Sebag - University of IowaKamal Rahmouni - Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
- Resource Type
- Journal article
- Publication Details
- Cardiovascular research, Vol.121(12), pp.1929-1940
- DOI
- 10.1093/cvr/cvaf067
- PMID
- 40244925
- PMCID
- PMC12551390
- NLM abbreviation
- Cardiovasc Res
- ISSN
- 1755-3245
- eISSN
- 1755-3245
- Publisher
- Oxford University Press
- Grant note
- US Department of Health and Human Services National Institutes of Health: R01 HL162773, R01 HL172944 US Department of Veterans Affairs: I01 BX004249, IK6 BX006040 University of Iowa Fraternal Order of Eagles Diabetes Research CentreUniversity of Iowa Office of the Vice President for ResearchCarver College of Medicine
This work was supported by US Department of Health and Human Services National Institutes of Health (R01 HL162773 and R01 HL172944), US Department of Veterans Affairs (I01 BX004249 and IK6 BX006040), and the University of Iowa Fraternal Order of Eagles Diabetes Research Centre to K.R. The University of Iowa Central Microscopy Research Facility used for confocal imaging is a core resource supported by the University of Iowa Office of the Vice President for Research and the Carver College of Medicine.
- Language
- English
- Electronic publication date
- 04/17/2025
- Date published
- 10/24/2025
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9984810950702771
Metrics
51 Record Views