A role for agouti-related protein in appetite regulation in a species with continuous nutrient delivery

Knowledge of specific neurotransmitters as well as the pathways and mechanisms regulating appetite in ruminants that continually graze, such as sheep, is incomplete. Although fundamentally agouti-related protein (AGRP) has a similar function across species to increase food intake, the regulation of...

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Bibliographic Details
Published in:	Neuroendocrinology Vol. 80; no. 4; p. 210
Main Authors:	Wagner, Christine G, McMahon, Chris D, Marks, Daniel L, Daniel, Joseph A, Steele, Barbara, Sartin, James L
Format:	Journal Article
Language:	English
Published:	Switzerland 01-01-2004
Subjects:	Agouti Signaling Protein Agouti-Related Protein Analysis of Variance Animals Appetite Regulation - drug effects Appetite Regulation - physiology Castration - methods Cell Count - methods Cloning, Molecular - methods Dose-Response Relationship, Drug Drug Combinations Eating - drug effects Eating - physiology Food Deprivation Gene Expression Regulation - physiology Humans Hypothalamus - cytology Hypothalamus - drug effects Hypothalamus - metabolism Immunohistochemistry - methods Injections, Intraventricular - methods Intercellular Signaling Peptides and Proteins - pharmacology Intercellular Signaling Peptides and Proteins - physiology Male Mice Neurons - drug effects Neurons - metabolism Neuropeptide Y - pharmacology Proto-Oncogene Proteins c-fos - metabolism Rats Reverse Transcriptase Polymerase Chain Reaction - methods RNA, Messenger - metabolism Sequence Alignment - methods Sheep Species Specificity Time Factors
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Summary:	Knowledge of specific neurotransmitters as well as the pathways and mechanisms regulating appetite in ruminants that continually graze, such as sheep, is incomplete. Although fundamentally agouti-related protein (AGRP) has a similar function across species to increase food intake, the regulation of AGRP may vary across grazing and intermittent feeders. To investigate the role of orexigenic peptides in the regulation of feed intake, we first extracted messenger RNA from sheep that were fasted for 3 days, which was then used for PCR followed by cloning and sequencing to demonstrate the presence of hypothalamic AGRP expression. Ovine AGRP was closely related to the bovine, but contained sequence differences with human and mouse AGRP. Analysis of genomic DNA also revealed a similar gene structure to other published species. Secondly, using dual-labeled immunohistochemistry, we determined that there was both increased AGRP immunoreactivity and increased abundance of c-Fos immunoreactivity in AGRP neurons in the arcuate nucleus of fasted sheep. Because AGRP neurons are activated by fasting, we hypothesized that AGRP would stimulate feeding in this ruminant species. Sheep fed ad libitum were injected intracerebroventricularly with concentrations of AGRP at 0.2 and 2.0 nmol/kg. AGRP at 2.0 nmol/kg significantly increased food intake at 4, 6 and 12 h (p < 0.05). A 4th study was done to investigate the interactions of AGRP and neuropeptide Y (NPY) on food intake over a 24-hour period. Intracerebroventricular injections of either AGRP or NPY significantly increased cumulative food intake over saline controls. When AGRP and NPY were injected in combination, food intake was increased over saline controls; however, AGRP did not potentiate the effects of NPY. These results demonstrate that AGRP stimulates food intake in sheep and highlights the important differences between this species and rodent models.
ISSN:	0028-3835
DOI:	10.1159/000082735