Ghrelin stimulates food intake in part by activating hypothalamic neuropeptide Y (NPY) neurons/agouti related peptide (AGRP) neurons. We investigated the role of AGRP/melanocortin signaling in ghrelin-induced food intake by studying melanocortin 3 and 4 receptor knockout (MC3R KO and MC4R KO) mice. We also determined whether reduced ghrelin levels and/or an altered sensitivity to the GH-stimulating effects of ghrelin accompany the obesity syndromes of MC3R KO and MC4R KO mice. Compared to wild-type (WT) mice, the effects of ghrelin on food intake were reduced in MC3R KO and MC4R KO mice and circulating ghrelin levels were reduced in female MC4R KO mice. Female MC3R KO and MC4R KO mice exhibited a diminished responsiveness to the GH-releasing effects of ghrelin. Thus, deletion of the MC3R or MC4R results in a decreased sensitivity to ghrelin and verifies the involvement in the melanocortin system in ghrelin-induced food intake.
Bibliographical noteFunding Information:
The MC4R KO mice were originally provided by Dr. Dennis Huszar (Millennium Pharmaceuticals) and the MC3R KO mice were originally provided by Dr. Lex Van der Ploeg (Merck Research Laboratories). This work was supported by NIH Grants AG-10485 (WJM), DK-57080 (CH-L) and an American Heart Association predoctoral fellowship (BGI).
- Agouti related protein
- Growth hormone