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.