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Open Access Highly Accessed Research article

Reducing hypothalamic AGRP by RNA interference increases metabolic rate and decreases body weight without influencing food intake

Hideo Makimura12, Tooru M Mizuno12, Jason W Mastaitis12, Reuven Agami3 and Charles V Mobbs12*

Author Affiliations

1 Fishberg Center for Neurobiology, Neurobiology of Aging Laboratories, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1639, New York, New York, 10029, USA

2 Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York, 10029, USA

3 Division of Tumor Biology, The Netherlands Cancer Institute, 121 Plesmanlaan 1066 CX, Amsterdam, The Netherlands

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BMC Neuroscience 2002, 3:18  doi:10.1186/1471-2202-3-18

Published: 7 November 2002



Several lines of evidence strongly suggest that agouti-related peptide (AGRP) plays a key role in the regulation of metabolic function but ablation of the AGRP gene has no apparent effect on metabolic function. Since specific pharmacological antagonists of AGRP do not presently exist, we assessed if reduction of hypothalamic AGRP mRNA by RNA interference (RNAI) would influence metabolic function, an outcome suggesting that pharmacological antagonists might constitute useful reagents to treat obesity.


The RNAI protocol specifically reduced hypothalamic expression of AGRP mRNA by 50% and resulted in reduction of AGRP peptide immunoreactivity. Physiologically, the reduction in AGRP levels was associated with increased metabolic rate and reduced body weight without changes in food intake.


AGRP can function to increase body weight and reduce metabolic rate without influencing food intake. The present study demonstrates that RNAI protocols can be used to assess physiological function of neuronal genes in vivo.