Philipp Lachenmann: DELPHI Rationale


Schoeller Junkmann Preis 2001

Dr. Matthias Tschoep

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, USA

Ghrelin induces adiposity in rodents

Recent discovery of the peptide hormone ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), reported by Kojima and coworkers yielded the surprising discovery that the principal site of ghrelin synthesis is the stomach and not the hypothalamus. Although an obvious role for ghrelin is in the regulation of pituitary growth hormone secretion along with growth hormone-releasing hormone and somatostatin, GHS-Rs have also been identified on hypothalamic neurons and in the brainstem. Apart from potential paracrine effects, ghrelin may thus offer an endocrine link between stomach, hypothalamus and pituitary, suggesting an involvement in regulation of energy balance.

We show that peripheral daily administration of ghrelin induced weight gain by reducing fat utilization in mice and rats. Intracerebroventricular administration of ghrelin generated a dose-dependent increase in food intake and body weight, indicating a primarily central mechanism. Administration of growth hormone releasing hormone-2 (GHRP-2), a synthetic exogenous ligand of the GHS-R induced gain of fat mass comparable to ghrelin in mice. These effects are independent from ghrelin's ability to increase growth hormone secretion at the pituitary as shown in GH-deficient dwarf rats.

Furthermore ghrelin induced adiposity could still be generated in neuropeptide Y (NPY)-deficient mice, suggesting at least one more hypotalamic pathway in addition to NPY. Endogenous rat serum ghrelin concentrations were increased by fasting and were reduced by refeeding or oral glucose administration, but not by water ingestion. We propose that ghrelin, in addition to its role in regulating GH-secretion, signals the hypothalamus when an increase in metabolic efficiency is necessary. The novel hormone ghrelin might act to povide the calories that growth hormone requires for growth and repair.



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