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A C-Terminal Fragment of Agouti-Related Protein Increases Feeding and Antagonizes the Effect of Alpha-Melanocyte Stimulating Hormone in Vivo

Endocrine Unit, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom; and Hoffman-La Roche (K.Y.), Nutley, New Jersey

Address all correspondence and requests for reprints to: Stephen R. Bloom, M.D., Hammersmith Hospital, Division of Endocrinology and Metabolism, Royal Postgraduate Medical School, Du Cane Road, London, W12 0NN, United Kingdom.

Agouti-related protein (Agrp) is present in rat and human hypothalamus and is structurally related to agouti protein. Over-expression of either of these proteins results in obesity. However the effect of exogenous Agrp and its in vivo interaction with alpha-melanocyte stimulating hormone (MSH), the likely endogenous melanocortin 3 and 4 receptor (MC3-R and MC4-R) agonist, have not been demonstrated. We report that 1 nmol of Agrp(83-132), a C-terminal fragment of Agrp, when administered intracerebroventricularly (ICV) into rats, increased food intake over a 24-h period (23.0±1.4 g saline vs 32.9±2.3 g Agrp, p<0.05). The hyperphagia was similar to that seen when 1 nmol of the synthetic MC3-R and MC4-R antagonist SHU9119 was given ICV (19.6±1.8 g saline vs 32.5±1.7 g SHU9119, p<0.001). Both Agrp(83-132) and SHU9119 blocked the reduction in 1-h food intake of ICV MSH at the beginning of the dark phase. This effect occurred independently of whether the antagonists were administered simultaneously, or nine hours prior, to the MSH. We have also shown Agrp(83-132) is an antagonist at the MC3-R and MC4-R, with similar inhibition of cAMP activation to that previously reported for the full length peptide. In conclusion, Agrp(83-132) administered ICV increases feeding with long lasting effects and is able to inhibit the action of MSH. This interaction may be mediated by the MC3-R and/or MC4-R.

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				G. Légrádi and R. M. Lechan Agouti-Related Protein Containing Nerve Terminals Innervate Thyrotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus Endocrinology, August 1, 1999; 140(8): 3643 - 3652. [Abstract] [Full Text]

				R. J. Miltenberger, R. L. Mynatt, B. D. Bruce, W. O. Wilkison, R. P. Woychik, and E. J. Michaud An agouti mutation lacking the basic domain induces yellow pigmentation but not obesity in transgenic mice PNAS, July 20, 1999; 96(15): 8579 - 8584. [Abstract] [Full Text] [PDF]

				P. Chen, C. Li, C. Haskell-Luevano, R. D. Cone, and M. S. Smith Altered Expression of Agouti-Related Protein and Its Colocalization with Neuropeptide Y in the Arcuate Nucleus of the Hypothalamus during Lactation Endocrinology, June 1, 1999; 140(6): 2645 - 2650. [Abstract] [Full Text]

				B. D. Wilson, D. Bagnol, C. B. Kaelin, M. M. Ollmann, I. Gantz, S. J. Watson, and G. S. Barsh Physiological and Anatomical Circuitry between Agouti-Related Protein and Leptin Signaling Endocrinology, May 1, 1999; 140(5): 2387 - 2397. [Abstract] [Full Text]

				N. Vrang, P. J. Larsen, J. T. Clausen, and P. Kristensen Neurochemical Characterization of Hypothalamic Cocaine -- Amphetamine-Regulated Transcript Neurons J. Neurosci., May 15, 1999; 19(10): RC5 - RC5. [Abstract] [Full Text] [PDF]

				D. Bagnol, X.-Y. Lu, C. B. Kaelin, H. E. W. Day, M. Ollmann, I. Gantz, H. Akil, G. S. Barsh, and S. J. Watson Anatomy of an Endogenous Antagonist: Relationship between Agouti-Related Protein and Proopiomelanocortin in Brain J. Neurosci., September 15, 1999; 19(18): RC26 - RC26. [Abstract] [Full Text] [PDF]