OBESITY&HYPERTENSION · Identifying key neuronal pathways mediating melanocortin's effects on cardiovascular function
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2007-03-01 → 2009-02-28
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
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Results in brief
Final Activity Report Summary - OBESITY&HYPERTENSION (Identifying key neuronal pathways mediating melanocortin's effects on cardiovascular function)
Recent population statistics demonstrate drastically increased risk of cardiovascular death with obesity. To develop effective therapies, we need to understand the pathways regulating body weight homeostasis and cardiovascular function. Obesity results from an imbalance between energy intake and spending. Particular brain structures sense the body's energy status and through a sophisticated cascade of events, elicit an appropriate response to the body. Recent research has unravelled some of these pathways, but the exact mechanisms remain unclear. One of the central genes involved is the melanocortin-4-receptor (MC4R) and we aimed to define and detail its role in the regulation of obesity-induced cardiovascular disease. Data from these studies suggest that MC4Rs in a particular area of the hypothalamus, the paraventricular hypothalamus (PVH), are key contributors to melanocortin-mediated cardiovascular effects. Furthermore our results suggest that MC4Rs in the PVH may mediate their effects by increasing sympathetic tone onto the cardiovascular system. There is significant interest from the pharmaceutical industry to develop MC4R agonists as potential food intake reducing agents. However, side effects due to sympathetic activation after MC4R engagement are highly likely and our data help to understand where these effects are mediated.
Data: CORDIS, © European Union
Project objective
Population statistics demonstrate drastically increased risk of cardiovascular death with increasing body mass index. Given the current obesity epidemic our need to understand the central neuronal pathways regulating energy homeostasis and cardiovascular function could not be greater.This proposal aims to determine key neuronal pathways mediating melanocortin's autonomic effects on cardiovascular function. It combines molecular genetics and whole animal physiology to advance translational research in the development of effective therapies against obesity-induced hypertension. Recent evidence suggests that both obesity and essential hypertension are associated with increased sympathetic nerve activity. Increased sympatho-activation in obesity-associated hypertension has been linked to increases in central signalling via the melanocortin-4-receptor (MC4R).We hypothesize that the pressor actions of obesity are mediated via specific MC4Rs on central neurons regulating arterial blood pressure. We will investigate which subpopulation of MC4Rs mediates melanocortin's effects on cardiovascular function using functional genomics approaches, including an MC4R deficient mouse, in which a disrupted MC4R can be reactivated in specific CNS areas by the actions of Cre-recombinase. Using in vivo mouse telemetry we will thus determine the neuronal pathways involved in melanocortin-mediated regulation of cardiovascular function and define the MC4R¿s role in obesity-induced activation of the sympathetic nervous system.This proposal is absolutely consistent with the Sixth (and future 7th) Framework Programme, placing particular emphasis on functional genomics and the combat against major diseases such as hypertension. Furthermore, it brings significant skills in state-of-the-art generation of mouse models relevant to human disease, in combination with sophisticated physiological techniques to the European Research Area, thereby increasing its attractiveness to young researchers.
Original text from CORDIS.
Participants
- UNIVERSITY OF BRISTOL · BRISTOL, CLIFTONCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union