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Molecular and Cellular Biology, July 2002, p. 5027-5035, Vol. 22, No. 14
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.14.5027-5035.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Neither Agouti-Related Protein nor Neuropeptide Y Is Critically Required for the Regulation of Energy Homeostasis in Mice

Su Qian,1* Howard Chen,1 Drew Weingarth,1 Myrna E. Trumbauer,1 Dawn E. Novi,1 Xiaoming Guan,1 Hong Yu,1 Zhu Shen,1 Yue Feng,1 Easter Frazier,1 Airu Chen,1 Ramon E. Camacho,2 Lauren P. Shearman,2 Shobhna Gopal-Truter,3 Douglas J. MacNeil,1 Lex H. T. Van der Ploeg,1 and Donald J. Marsh1

Departments of Obesity Research,1 Animal Pharmacology,2 Comparative Medicine, Merck Research Laboratories, Rahway, New Jersey 070653

Received 28 November 2001/ Returned for modification 1 March 2002/ Accepted 17 April 2002

Agouti-related protein (AgRP), a neuropeptide abundantly expressed in the arcuate nucleus of the hypothalamus, potently stimulates feeding and body weight gain in rodents. AgRP is believed to exert its effects through the blockade of signaling by {alpha}-melanocyte-stimulating hormone at central nervous system (CNS) melanocortin-3 receptor (Mc3r) and Mc4r. We generated AgRP-deficient (Agrp-/-) mice to examine the physiological role of AgRP. Agrp-/- mice are viable and exhibit normal locomotor activity, growth rates, body composition, and food intake. Additionally, Agrp-/- mice display normal responses to starvation, diet-induced obesity, and the administration of exogenous leptin or neuropeptide Y (NPY). In situ hybridization failed to detect altered CNS expression levels for proopiomelanocortin, Mc3r, Mc4r, or NPY mRNAs in Agrp-/- mice. As AgRP and the orexigenic peptide NPY are coexpressed in neurons of the arcuate nucleus, we generated AgRP and NPY double-knockout (Agrp-/-;Npy-/-) mice to determine whether NPY or AgRP plays a compensatory role in Agrp-/- or NPY-deficient (Npy-/-) mice, respectively. Similarly to mice deficient in either AgRP or NPY, Agrp-/-;Npy-/- mice suffer no obvious feeding or body weight deficits and maintain a normal response to starvation. Our results demonstrate that neither AgRP nor NPY is a critically required orexigenic factor, suggesting that other pathways capable of regulating energy homeostasis can compensate for the loss of both AgRP and NPY.

* Corresponding author. Mailing address: Dept. of Obesity and Metabolic Research, Merck Research Laboratories, RY80T-100, Rahway, NJ 07065. Phone: (732) 594-3382. Fax: (732) 594-6740. E-mail: su_qian{at}merck.com.

Molecular and Cellular Biology, July 2002, p. 5027-5035, Vol. 22, No. 14
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.14.5027-5035.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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