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Hypothalamic MC4R signaling pathways in sympathetic regulation of blood pressure

Award Number: R01HL182864
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Hypothalamic MC4R signaling pathways in sympathetic regulation of blood pressure - Project Summary / Abstract Evidence indicates that obesity-induced hypertension (HTN) is characterized by increased sympathetic activity, which may play a causal role in disease development. However, the underlying neural substrates responsible for the heightened sympathetic tone during obesity remain incompletely understood. Studies in both humans and rodents have implicated brain melanocortin 4 receptors (MC4Rs) signaling as a key determinant in this process, yet the neuroanatomical and intraneuronal signaling mechanisms through which MC4R does so remain unclear. Known as a Gαs-coupled receptor, MC4R activates membrane bound adenylyl cyclase (ADCYs) and increases cAMP production upon stimulation. Interestingly, recent literature suggests that MC4Rs are enriched in the primary cilium of hypothalamic neurons, where they overlap with the typical ciliary marker Adcy3, a member of the ADCY family whose loss of function results in severe obesity in both humans and rodents. MC4Rs are highly expressed in the hypothalamus, and despite the well-known role of the hypothalamus in regulating the sympathetic tone and blood pressure (BP), whether and how hypothalamic MC4R signaling pathways affect the sympathetic regulation of BP remain unknown. Our recent preliminary findings suggest that increasing the activity of MC4R-expressing neurons in distinct hypothalamic nuclei steadily increase BP, mice lacking Adcy3 in MC4R-expressing neurons develop obesity while maintaining normal to low BP, and Adcy3 gain-of-function in the hypothalamus elevates BP. Building on these compelling preliminary data and literature suggesting that signaling events at primary cilia are rapidly transmitted to the nucleus to alter transcriptomic landscape and neuronal activity, we hypothesize that MC4R signals through Adcy3 at the primary cilia of hypothalamic neurons to regulate sympathetic outflow and BP by altering neuronal activity. To test this hypothesis, we will pursue two specific aims. In Aim 1, we will determine the causal role of increased hypothalamic MC4R+ neuron activity in the development of obesity-induced sympathetic overdrive and HTN. In Aim 2, we will investigate if Adcy3 is a key mediator of MC4R signaling at the primary cilia of hypothalamic neurons for the sympathetic control of BP in obesity. The proposed research is expected to significantly advance our understanding of how MC4R-mediated signaling pathways regulate sympathetic activity and BP. It will also elucidate the largely unknown mechanisms by which ciliary cAMP signaling in hypothalamic neurons contributes to the sympathetic regulation of BP. Insights gained from this work may pave the way for developing novel therapeutic strategies to more effectively manage HTN in obese patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $638,245 )
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cardiovascular Diseases Research	000	1	8/7/2026	NEW	$638,245
														Subtotal = $638,245

Grand Total All Awards = $638,245

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Hypothalamic MC4R signaling pathways in sympathetic regulation of blood pressure

Award Number: R01HL182864

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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