Elevation of ghrelin by B-adrenergic activation is independent of glucose variations and feeding regimen in the rat.

Abstract

Ghrelin is a signal involved in the initiation of meals in rodents and humans. Circulating ghrelin levels are elevated before mealwes and reduced after food intake. Several factors have been identified as effective modulators of ghrelin levels. Vagal activation reduced ghrelin in rats, as well as oral carbohydrate and lipid administration in rats and humans. Some hormones, such as incretins, also reduce ghrelin: GLP-1 reduced ghrelin in humans, and Ex4, a GLP-1 receptor agonist, potently inhibited ghrelin in rodents. On the other hand, fasting promotes increases in ghrelin that anticipate the start of meals. We report that beta-adrenergic activation with isoproterenol promotes large acute elevations of circulating ghrelin levels, both in anesthetized and conscious freely-moving rats, either on "ad libitum" feeding or on a fasting regimen.These effects are dose-dependent, caused by intravenous, intraperitoneal, and oral administration, and independent of variations in glucose levels. Pharmacological modulation of β1 and β2 adrenergic receptors with specific agonists and antagonists showed that ghrelin increases are stimulated by β1-adrenergic activation, but also partially by β2-adrenergic activation, suggesting that activation of both is necessary to elicit complete ghrelin elevations. Meanwhile, glucose increases dependent on adrenergic activation appear to be mediated only by β2-adrenergic receptors. In addition, the effects of isoproterenol on increasing ghrelin levels are potent enough to overcome the marked inhibition exerted by exendin-4 that we have previously demonstrated. We also found that administration of isoproterenol in drinking water increases basal ghrelin levels and simultaneous food intake in animals eating ad libitum. Beta-adrenergic activation promotes increases in ghrelin levels in vivo prior to food intake, both in rats eating ad libitum and in fasting rats that already have elevated ghrelin levels, in a time- and dose-dependent manner. In addition, the effects of isoproterenol on increasing ghrelin levels are potent enough to overcome the marked inhibition exerted by exendin-4 that we have previously demonstrated. We also found that administration of isoproterenol in drinking water increases basal ghrelin levels and simultaneous food intake in animals eating ad libitum. Beta-adrenergic activation promotes increases in ghrelin levels in vivo prior to food intake, both in eating ad libitum and in fasting rats that already have elevated ghrelin levels, in a time- and dose-dependent manner.