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The Journal of Neuroscience, November 10, 2004, 24(45):10176-10181; doi:10.1523/JNEUROSCI.3442-04.2004

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Neurobiology of Disease
Induction of Brain Region-Specific Forms of Obesity by Agouti

Martien J. H. Kas,¹ Birgitte Tiesjema,¹ Gertjan van Dijk,² Keith M. Garner,¹ Gregory S. Barsh,³ Olivier Ter Brake,⁴ Joost Verhaagen,⁴ and Roger A. H. Adan¹

¹Rudolf Magnus Institute of Neuroscience, Department of Pharmacology and Anatomy, University Medical Centre Utrecht, 3584 CG Utrecht, The Netherlands, ²Division of Neuroendocrinology, Department of Animal Physiology, University of Groningen, 9750 AA Haren, The Netherlands, ³Department of Pediatrics and Genetics, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, and ⁴Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, 1105 AZ Amsterdam, The Netherlands

Disruption of melanocortin (MC) signaling, such as by ectopic Agouti overexpression, leads to an obesity syndrome with hyperphagia, obesity, and accelerated body weight gain during high-fat diet. To investigate where in the brain disruption of MC signaling results in obesity, long-term Agouti expression was induced after local injections of recombinant adeno-associated viral particles in selected brain nuclei of adult rats. Agouti expression in the paraventricular nucleus, a hypothalamic region with a high density of MC receptors, induced acute onset hyperphagia and rapid weight gain that persisted for at least 6 weeks. In contrast, obesity and hyperphagia developed with a 3 week delay when Agouti was expressed in the dorsal medial hypothalamus. Agouti expression in the lateral hypothalamus (LH) did not affect food intake and body weight during regular diet, despite the presence of MC receptors in this region. However, during exposure to a high-fat diet, animals with Agouti expression in the LH exhibited a marked increase in body weight. Here we show that the LH is important for the protection against diet-induced obesity by controlling caloric intake during consumption of a high-fat diet. Together, this study provides evidence that different aspects of the Agouti-induced obesity syndrome, such as hyperphagia and diet responsiveness, are mediated by distinct brain regions and opens challenging opportunities for further understanding of pathophysiological processes in the development of the obesity syndrome.

Key words: melanocortin; obesity; lateral hypothalamus; dorsal medial hypothalamus; paraventricular nucleus; high-fat diet

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Received June 29, 2004; revised September 28, 2004; accepted September 28, 2004.

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