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Melanocortin receptor-mediated effects on obesity are distributed over specific hypothalamic regions

International Journal of Obesity volume 35, pages 629–641 (2011)Cite this article

Subjects

Abstract

Objective:

Reduction of melanocortin signaling in the brain results in obesity. However, where in the brain reduced melanocortin signaling mediates this effect is poorly understood.

Design:

We determined the effects of long-term inhibition of melanocortin receptor activity in specific brain regions of the rat brain. Melanocortin signaling was inhibited by injection of a recombinant adeno-associated viral (rAAV) vector that overexpressed Agouti-related peptide (AgRP) into the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), the lateral hypothalamus (LH) or the accumbens shell (Acc).

Results:

Overexpression of AgRP in the rat PVN, VMH or LH increased bodyweight, the percentage of white adipose tissue, plasma leptin and insulin concentrations and food intake. Food intake was mainly increased because of an increase in meal size in the light and dark phases, after overexpression of AgRP in the PVN, LH or VMH. Overexpression of AgRP in the PVN or VMH reduced average body core temperature in the dark on day 40 post injection, whereas AgRP overexpression in the LH did not affect temperature. In addition, overexpression of AgRP in the PVN, LH or VMH did not significantly alter mRNA expression of AgRP, neuropeptide Y (NPY), pro-opiomelanocortin (POMC) or suppressor of cytokine signaling 3 (SOCS3) in the arcuate. Overexpression of AgRP in the Acc did not have any effect on the measured parameters.

Conclusions:

Reduction of melanocortin signaling in several hypothalamic regions increased meal size. However, there were brain area-specific effects on other parameters such as core temperature and plasma leptin concentrations. In a previous study, where NPY was overexpressed with an rAAV vector in the PVN and LH, meal frequency and meal size were increased respectively, whereas locomotor activity was reduced by NPY overexpression at both nuclei. Taken together, AgRP and NPY have complementary roles in energy balance.

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Acknowledgements

This work was performed in Utrecht, the Netherlands, and was supported by the Netherlands Organization for Scientific Research (NWO Grant No. 90339175).

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Authors and Affiliations

  1. Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, Utrecht University Medical Centre Utrecht, Utrecht, The Netherlands

    M W A de Backer, S E la Fleur, M A D Brans, A J van Rozen, M C M Luijendijk, M Merkestein, K M Garner, E M van der Zwaal & R A H Adan

  2. Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    S E la Fleur

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  1. M W A de Backer
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  2. S E la Fleur
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Correspondence to R A H Adan.

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de Backer, M., la Fleur, S., Brans, M. et al. Melanocortin receptor-mediated effects on obesity are distributed over specific hypothalamic regions. Int J Obes 35, 629–641 (2011). https://doi.org/10.1038/ijo.2010.169

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