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Melanocortin 4 receptor agonists activate obesity-related hypertension
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A cellular correlation between melanocortin 4 receptor agonists and their role in obesity-associated hypertension has been identified, according to data published in Cell.
“Obesity is a major risk factor for cardiovascular disease, with recent statistics showing that obese adults are three to four times more likely to develop high blood pressure,” study researcher Nina Balthasar, PhD, from the school of physiology and pharmacology at the University of Bristol, United Kingdom, said in a press release. “In order to curb the escalating incidence of obesity and obesity-related diseases, a primary prevention goal must be to understand the physiological processes underlying our vulnerability to weight gain — knowledge that is central to the development of novel, effective therapies.”
Melanocortin 4 receptors (MC4Rs) are responsible for regulating energy and glucose homeostasis within the central nervous system (CNS). The molecule’s mutation or loss in human and animal models has caused notable obesity with type 2 diabetes, according to researchers.
“Our data illustrate the complexity of the CNS pathways governing the body’s metabolic balance and highlight the challenges ahead for the development of safe therapies,” Balthasar said in the release.
Based on their study on mice, the researchers wrote that MC4R agonists inhibit parasympathetic preganglionic neurons in the brainstem. However, MC4R agonists also activate sympathetic preganglionic neurons in the spinal cord. Thus, deletion of MC4Rs in cholinergic neurons led to elevations in insulin. Further data indicate the re-expression of MC4Rs repaired obesity-related hypertension in null mice.
The researchers said these findings demonstrate that regulation of the autonomic nervous system by MC4R mediation and the regulation of insulin levels play an important part in obesity-induced hypertension.
Disclosure: This study was supported by the American Diabetes Association, American Heart Association, British Heart Foundation, Lister Institute of Preventive Medicine, and National Institutes of Health. The researchers report no relevant financial disclosures.
Perspective
Back to TopLawrence R. Krakoff, MD
The sympathetic nervous system regulates metabolic and cardiovascular function through several mechanisms. Central melanocortin (MC) pathways linked to energy metabolism may regulate blood pressure in human obesity-hypertension via sympathetic activation. MC-4R loss of function mutations are associated with human obesity without hypertension and with lower norepinephrine excretion compared to controls. Rodent models lacking MC 4 receptors have a similar pattern; obesity with lower blood pressures. MC-4 agonists increase blood pressure; MC-4 antagonists have the opposite effect.
Sohn et al extend knowledge of MC's role by characterizing MC 4 receptors in brainstem and spinal cord nuclei that regulate parasympathetic or sympathetic tone. Restoration of deficient MC 4 receptors in these nuclei (re-expression) increases blood pressure. Does this portend development of an effective MC 4 receptor antagonist to treat obesity hypertension in those without MC-4 mutations? Caution is suggested, as the other effects of MC 4 inhibition at other sites will need careful definition.
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