Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

Abstract

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol x kg(-1) x day(-1) using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia.

Ghrelin treatment protects lactotrophs from apoptosis in the pituitary of diabetic rats

“…In our experimental model, diabetic rats treated with ghrelin did not gain significantly more weight than diabetic rats administered saline. In agreement with our data, although a marked increase in body weight gain is reported in control rats treated with ghrelin (Dembinski et al, 2005;Nakazato et al, 2001;Strassburg et al, 2008), this effect has not always been found in animals suffering from catabolic diseases such as cancer, colitits or diabetes (de Smet et al, 2009;Irako et al, 2006). Thus, the lack of significant weight gain in response to ghrelin could be due to the state of catabolism and extreme weight loss of the diabetic rats.…”

β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals

“…When the action of fasting-induced elevated ghrelin is blocked pharmacologically in mice, rebound overeating is blunted, and when the action of weight loss-associated elevated ghrelin is similarly blocked, as in a rat cancer cachexia model, worsened anorexia and hastened death have been described (12,13). Exogenous infusions of ghrelin or GHSR agonists similarly increase eating and, in addition, lower energy expenditure and upregulate the expression of lipogenic and fat storage-promoting enzymes (5,(14)(15)(16)(17). Ghrelin also shifts food preference toward high-fat diets (HFDs), shifts fuel preference away from metabolic utilization of fat, and engages several food reward behaviors (5,13,18,19).…”

Therapeutic Applications of Ghrelin Agonists in the Treatment of Gastroparesis

“…RM-131 also displayed anti-inflammatory effects and increased survival in models of inflammatory bowel disease. In dogs and rodents, treatment with RM-131 showed transient increased in GH levels that returned to baseline with continued administration [85].…”

“…In pre-clinical studies prior to acquisition of RM-131 by Rhythm Pharmaceuticals, RM-131 has been shown to cause a dose-dependent increase in food intake and weight gain (both fat and lean mass) with greater potency than human ghrelin [85]. In a rat models, RM-131 was successful in reversing postsurgical, opiate-induced gastric ileus while in normal, nonsurgical primates, RM-131 increased the GE rate [86].…”