Interactions of the growth hormone secretory axis and the central melanocortin system

Ghrelin acts on the growth hormone secretagogue receptor (GHS-R) in the hypothalamus and pituitary to potently stimulate growth hormone (GH) secretion. Ghrelin also stimulates food intake and affects energy balance in part by activating neuropeptide Y (NPY) neurons containing the melanocortin receptor antagonist agouti related peptide (AGRP) in the arcuate nucleus. We therefore sought to further investigate the role of AGRP/melanocortin signaling in mediating the orexigenic effects of ghrelin by studying mice deficient in the melanocortin 3 (MC3R) and 4 (MC4R) receptors. We also sought to determine whether reduced ghrelin levels and/or an altered sensitivity to the GH-stimulating effects of ghrelin accompany the obesity syndromes of MC3R knockout (MC3R KO) and MC4R knockout (MC4R KO) mice. We measured various components of the GH axis in several age groups of male and female MC3R KO, MC4R KO and WT mice. Overall, MC4R KO mice displayed normal to elevated levels of the GH effector protein, insulin-like growth factor-I (IGF-I), in spite of reduced serum GH levels. In addition, pituitary GH content was reduced in some age groups in both MC3R KOs and MC4R KOs however; no clear cut trend was established. The effects of peripheral ghrelin on food intake were reduced in both male and female MC3R KO and MC4R KO mice compared to wild-type controls. In addition, circulating ghrelin levels were reduced in MC4R KO mice, with significance observed in females. Female MC3R KO and MC4R KO mice exhibited a diminished responsiveness to the GH-releasing effects of peripheral ghrelin, and these effects were age-dependent. Our data indicate that 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.