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Published on: September 11, 2018
Melanocortin-4 receptors activate sympathetic preganglionic neurons and elevate blood pressure via TRPV1
Sang Hyeon Ju1, Hyeonju Yun2, Youjin Oh2
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, South Korea.
Abstract:
Melanocortin-4 receptors (MC4Rs) expressed by the central nervous system are essential regulators of energy homeostasis, and Mc4r mutation is the most common cause of human monogenic obesity. Notably, patients with obesity carrying Mc4r mutations are protected against obesity-induced hypertension, and MC4R agonists elevate blood pressure (BP). Although increased sympathetic tone by MC4Rs is suggested to underlie this phenotype, the detailed mechanisms remain unclear. Here, we investigate how MC4Rs regulate the sympathetic preganglionic neurons and find that MC4Rs activate these neurons via the protein kinase A-dependent activation of the transient receptor potential vanilloid 1 (TRPV1) channel. Importantly, we demonstrate that the inhibition of TRPV1 prevents MC4R-induced elevation of BP but does not affect MC4R-induced anorexia. We further show that TRPV1 is responsible for MC4R-dependent activation of the sympathetic preganglionic neurons by high-fat diet. Together, our results provide insight into how MC4Rs regulate sympathetic function.
Insights
Melanocortin-4 receptors (MC4Rs) regulate blood pressure by activating sympathetic neurons. This activation involves the TRPV1 channel, which is crucial for MC4R-induced blood pressure increases but not appetite control.
Area of Science:
- Neuroendocrinology
- Cardiovascular Physiology
- Metabolic Regulation
Background:
- Melanocortin-4 receptors (MC4Rs) in the central nervous system are key regulators of energy balance.
- MC4R mutations are a primary genetic cause of obesity, yet paradoxically, these individuals are protected from obesity-related hypertension.
- MC4R agonists increase blood pressure, suggesting a role in sympathetic nervous system regulation, though mechanisms are not fully understood.
Purpose of the Study:
- To elucidate the precise mechanisms by which MC4Rs modulate sympathetic preganglionic neurons.
- To investigate the role of the transient receptor potential vanilloid 1 (TRPV1) channel in MC4R-mediated cardiovascular and appetite regulation.
Main Methods:
- Investigated MC4R regulation of sympathetic preganglionic neurons.
- Utilized protein kinase A (PKA) pathway analysis.
- Examined the effects of TRPV1 channel inhibition on MC4R-induced physiological responses and sympathetic neuron activation, including in the context of a high-fat diet.
Main Results:
- MC4Rs activate sympathetic preganglionic neurons through PKA-dependent TRPV1 channel activation.
- TRPV1 inhibition blocked MC4R-induced blood pressure elevation but did not impact MC4R-mediated anorexia.
- TRPV1 mediates MC4R-dependent sympathetic activation in response to a high-fat diet.
Conclusions:
- MC4Rs regulate sympathetic nervous system activity and blood pressure via TRPV1 channels.
- TRPV1 is a critical downstream mediator of MC4R's cardiovascular effects, distinct from its role in appetite control.
- These findings offer novel insights into the neurobiological links between MC4R signaling, sympathetic function, and metabolic homeostasis.
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