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Articles in PresS, published online ahead of print May 6, 2002
Am J Physiol Regu Physiol, 10.1152/ajpregu.00019.2002
Submitted on January 14, 2002
Accepted on February 6, 2002
1 Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
* To whom correspondence should be addressed. E-mail: berthohr{at}pbrc.edu.
Agouti-related protein (AgRP) is co-expressed with NPY in a population of neurons in the arcuate nucleus of the hypothalamus, and stimulates food intake for up to seven days if injected intracerebroventricularly. The prolonged stimulation of food intake does not seem to depend on continued competition at the Mc4r melanocortin receptor as the relatively specific Mc4r agonist MTII regains its ability to suppress food intake 24h after AgRP injection. Since parallel to food intake, ICV AgRP also stimulates c-Fos expression 24h after injection in several brain areas, the neurons exhibiting delayed Fos expression might be particularly important in feeding behavior. Thus, we aimed at identifying the neurochemical phenotype of some of these neurons in select hypothalamic areas, using double-label immunohistochemistry. AgRP-injected rats ingested significantly more chow (10.2 ± 0.6g) than saline controls (3.4 ± 0.7) during the first 9 hours (light phase) after injection. 23h after AgRP-injection, in the lateral hypothalamus, particularly the perifornical area, AgRP induced significantly more Fos as compared to saline in orexin-A neurons (25.6 ± 4.9 % vs. 4.8 ± 3.1 %), but not in MCH or CART neurons. In the arcuate nucleus, AgRP induced significantly more Fos in CART neurons (40.6 ± 5.9 % vs. 13.4 ± 1.8 %), but not in NPY neurons. In the PVN there was no significant difference in Fos expression induced by AgRP as compared to saline in oxytocin and CART neurons. We conclude that the long-lasting hyperphagia induced by AgRP is correlated with and possibly partially mediated by hyperactive orexin-neurons in the LH and CART-neurons in the ARC, but not by NPY- and MCH-neurons. The substantial increase of light phase food intake by AgRP supports a role of orexin's arousing effects. Activation of CART-neurons in the arcuate nucleus (that likely co-express POMC) could indicate attempts to activate counterregulatory decreases of food intake.
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