Ghrelin Treatment Causes Increased Food Intake and Retention of Lean Body Mass in a Rat Model of Cancer Cachexia

Abstract

Cancer cachexia is a debilitating syndrome of anorexia and loss of lean body mass that accompanies many malignancies. Ghrelin is an orexigenic hormone with a short half-life that has been shown to improve food intake and weight gain in human and animal subjects with cancer cachexia. We used a rat model of cancer cachexia and administered human ghrelin and a synthetic ghrelin analog BIM-28131 via continuous infusion using sc osmotic minipumps. Tumor-implanted rats receiving human ghrelin or BIM-28131 exhibited a significant increase in food consumption and weight gain vs. saline-treated animals. We used dual-energy x-ray absorptiometry scans to show that the increased weight was due to maintenance of lean mass vs. a loss of lean mass in saline-treated animals. Also, BIM-28131 significantly limited the loss of fat mass normally observed in tumor-implanted rats. We further performed real-time PCR analysis of the hypothalami and brainstems and found that ghrelin-treated animals exhibited a significant increase in expression of orexigenic peptides agouti-related peptide and neuropeptide Y in the hypothalamus and a significant decrease in the expression of IL-1 receptor-I transcript in the hypothalamus and brainstem. We conclude that ghrelin and a synthetic ghrelin receptor agonist improve weight gain and lean body mass retention via effects involving orexigenic neuropeptides and antiinflammatory changes.

Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study

“…We found no major differences for these efficacy parameters between ghrelin and placebo in preliminary analyses. Our finding contrasts with the data observed in animal models (Hanada et al, 2003;Wang et al, 2006;DeBoer et al, 2007). Our methodology with treatment of secondary anorexia, nutritionist-monitored lunch meals, full placebo control of all outcomes, and standardised procedures and time schedules makes systemic errors unlikely.…”

“…In cachectic tumour-bearing mice (MCG101), higher ghrelin doses were required to increase food intake and body weight than in control mice . Other interventional CACS studies did not compare ghrelin doses (Hanada et al, 2003;Neary et al, 2004;DeBoer et al, 2007).…”

“…The hepatic GH effector IGF-1 levels are not correspondingly increased in conditions with high endogenous plasma ghrelin levels, such as ghrelin-producing tumours (Corbetta et al, 2003;Tsolakis et al, 2004). Furthermore, the administration of ghrelin does not significantly affect the IGF-1 level in healthy volunteers (Enomoto et al, 2003), patients with cardiovascular (Nagaya et al, 2004) or pulmonary diseases (Nagaya et al, 2005), tumour-bearing animals (DeBoer et al, 2007), or our patients with CACS. In contrast, studies using synthetic oral ghrelin mimetics have shown a significant effect on the IGF-1 level in volunteers and in the frail elderly (Smith, 2005) or patients with cancer cachexia (Garcia et al, 2007).…”

“…Ghrelin, which is predominantly secreted by gastric endocrine cells, stimulates food intake and triggers a positive energy balance through a central mechanism involving hypothalamic neuropeptides. In preclinical cachexia models, ghrelin has had stimulatory effects on appetite and food intake (Hanada et al, 2003;Wang et al, 2006), lean body mass (DeBoer et al, 2007), gastrointestinal motility (Date et al, 2002), energy metabolism, and proinflammatory cytokine expression (Dixit et al, 2004), and it has also alleviated cancer chemotherapy-associated dyspepsia and vomiting (Rudd et al, 2006). These experimentally induced cancer models provide promising but not sufficient evidence for an effect of ghrelin in human cancer, prompting clinical studies in a representative clinical population, including long-term studies in humans.…”

Ghrelin Gene Products in Acute and Chronic Inflammation

“…In addition, in both human patients and experimental animal models, ghrelin administration ameliorates the cachectic state associated with several pathological conditions-such as chronic heart failure , chronic kidney disease (DeBoer et al 2008), cancer (Argilés andStemmler 2013;Neary et al 2004;DeBoer et al 2007), burn injuries (Balasubramaniam et al 2006), and COPD (Nagaya et al 2005)-likely through activity on both the immune system and the skeletal muscle (Reano et al 2014).…”