Continuous Intravenous Infusion of Ghrelin Does Not Stimulate Feeding in Tumor-Bearing Rats

Abstract

The development of anorexia continues to be a serious treatment issue for cancer patients. Because the orexigenic peptide, ghrelin, is active through systemic routes and activates hypothalamic neuropeptide systems known to be refractory in anorectic tumor-bearing (TB) rats, we investigated whether it would prevent the development of cancer anorexia when infused continuously intravenously. The 24-h food intake was increased in nontumor-bearing (NTB) rats at a dose of 288 ug/day ghrelin. However, no tested dose of ghrelin, up to 576 ug/day, elicited increased feeding in TB rats prior to or subsequent to the development of anorexia. In hypothalamus, ghrelin-infused TB rats exhibited significantly increased concentration of neuropeptide Y (NPY) as compared to saline-infused TB rats. Hypothalamic expression of NPY and agouti-related protein (AgRP) messenger RNA were elevated in ghrelin-infused TB rats as compared to NTB rats, but saline-infused TB rats also exhibited increased expression of AgRP. Proopiomelanocortin message was reduced in ghrelin-infused and saline-infused TB rats as compared to noninfused TB control rats. Although ghrelin infusion did not preserve muscle protein, a significant saving in body fat was observed in TB rats. Thus, the adiposity effects of ghrelin did not require an orexigenic response to the peptide. These results suggest that continuous ghrelin infusion may not be an effective treatment for cancer anorexia.

ACKNOWLEDGMENTS

Supported by VA Merit Review Grant (W. T. Chance), American Institute for Cancer Research Grant 03B056 (W. T. Chance) and NIH DK–53548 (S. Sheriff). Appreciation is expressed to Steve Woods for the HPLC analyses of ghrelin.

Notes

^aFollowing the initial denaturation, 40 cycles of secondary denaturation, annealing, and extension were performed on the samples. At the conclusion of the extension period, one cycle (1 min @ 95°C, 30 s @ 55°C, 30 s @ 95°C) was performed to generate a dissociation curve for each compound. Abbreviations are as follows: RT-PCR, reverse transcription polymerase chain reaction; UCP, uncoupling protein; AgRP, agouti related protein; NPY, neuropeptide Y; Y₁R, Y-1 receptor; POMC, proopiomelanocortin; MC-3R, melanocortin receptor-3; MC-4R, MC-receptor-4; CRF, corticotrophin releasing factor; UCN, urocortin; CRF R-2, CRF receptor-2.

^aAbbreviations are as follows: SEM, standard error of the mean; NTB, nontumor-bearing; TB, tumor-bearing; SAL, saline; GHR, ghrelin.

**P < 0.01 vs

NTB-C; *P < 0.05 vs.

NTB-C; +P < 0.05 vs. TB-C.

^aAbbreviations are as follows: SEM, standard error of the mean; NTB, nontumor-bearing; TB, tumor-bearing; SAL, saline; GHR, ghrelin.

*P <0.05 vs. NTB-C.