PT  - JOURNAL ARTICLE
AU  - Kenneth A. Longo
AU  - Elizabeth K. Govek
AU  - Anna Nolan
AU  - Thomas McDonagh
AU  - Soratree Charoenthongtrakul
AU  - Derek J. Giuliana
AU  - Kristen Morgan
AU  - Jeffrey Hixon
AU  - Chaoseng Zhou
AU  - Bruce Kelder
AU  - John J. Kopchick
AU  - Jeffrey O. Saunders
AU  - Manuel A. Navia
AU  - Rory Curtis
AU  - Peter S. DiStefano
AU  - Brad J. Geddes
TI  - Pharmacologic Inhibition of Ghrelin Receptor Signaling Is Insulin Sparing and Promotes Insulin Sensitivity
AID  - 10.1124/jpet.111.183764
DP  - 2011 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 115--124
VI  - 339
IP  - 1
4099  - http://jpet.aspetjournals.org/content/339/1/115.short
4100  - http://jpet.aspetjournals.org/content/339/1/115.full
SO  - J Pharmacol Exp Ther2011 Oct 01; 339
AB  - Ghrelin influences a variety of metabolic functions through a direct action at its receptor, the GhrR (GhrR-1a). Ghrelin knockout (KO) and GhrR KO mice are resistant to the negative effects of high-fat diet (HFD) feeding. We have generated several classes of small-molecule GhrR antagonists and evaluated whether pharmacologic blockade of ghrelin signaling can recapitulate the phenotype of ghrelin/GhrR KO mice. Antagonist treatment blocked ghrelin-induced and spontaneous food intake; however, the effects on spontaneous feeding were absent in GhrR KO mice, suggesting target-specific effects of the antagonists. Oral administration of antagonists to HFD-fed mice improved insulin sensitivity in both glucose tolerance and glycemic clamp tests. The insulin sensitivity observed was characterized by improved glucose disposal with dramatically decreased insulin secretion. It is noteworthy that these results mimic those obtained in similar tests of HFD-fed GhrR KO mice. HFD-fed mice treated for 56 days with antagonist experienced a transient decrease in food intake but a sustained body weight decrease resulting from decreased white adipose, but not lean tissue. They also had improved glucose disposal and a striking reduction in the amount of insulin needed to achieve this. These mice had reduced hepatic steatosis, improved liver function, and no evidence of systemic toxicity relative to controls. Furthermore, GhrR KO mice placed on low- or high-fat diets had lifespans similar to the wild type, emphasizing the long-term safety of ghrelin receptor blockade. We have therefore demonstrated that chronic pharmacologic blockade of the GhrR is an effective and safe strategy for treating metabolic syndrome.