leptin and exendin-(9-39)

Leptin and glucagon-like peptide-1 (GLP-1) were proved to act in concert to control the activity of feeding centres. Since leptin receptor was identified in the gut endocrine L cells and neurons producing GLP-1, we have checked whether GLP-1 mediates the effects of leptin on feeding and drinking behaviour. To this aim, an intraperitoneal or intracerebroventricular injection of exendin (9 - 39), a GLP-1 antagonist, (50 or 10 microg per rat, respectively) followed by leptin (100 or 5 microg per rat, respectively) was made and 24-hour food intake and body weight changes were measured. Previous injection of exendin (9-39) completely abolished the supressory effect of peripheral leptin on food intake and body weight gain. Moreover, exendin (9-39) significantly attenuated the effect of intracerebroventricular leptin on food but not water consumption. It is concluded that intact GLP-1 signalling is necessary to mediate the effect of leptin on food intake in the rat. Conversely, leptin seems to affect the thirst center function independently of GLP-1. Also, these findings produce further evidence for close interactions between long- and short-term factors regulating the activity of feeding centres.

Topics: Analysis of Variance; Animals; Appetite Depressants; Body Weight; Central Nervous System; Drinking; Eating; Glucagon-Like Peptide-1 Receptor; Injections, Intraventricular; Leptin; Male; Peptide Fragments; Peripheral Nervous System; Rats; Rats, Wistar; Receptors, Glucagon

The effects of the glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 (EX4) and antagonist EX4(9-39) EX4-A on entero-insular axis have been investigated in normoglycemic and streptozotocin (STZ)-induced diabetic rats. Rats were administered daily subcutaneous injections of 1 nmol/kg EX4 and/or EX4-A for 7 days, and were decapitated 3 h after the last injection. In STZ-untreated rats, EX4 reduced body-weight (BW) gain and raised glycemia, and the effects were prevented by EX4-A; conversely, EX4 did not alter plasma concentrations of insulin, glucagon and leptin. STZ-treated rats displayed body and hematochemical alterations typical of experimental diabetes: decrease in BW and insulin blood level, coupled with normal glucagon plasma concentration and marked hyperglycemia. In diabetic rats, both EX4 and EX4-A decreased BW gain, thereby suggesting a mechanism at least in part independent of GLP-1 receptors. EX4 did not alter glucagon blood level, but decreased glycemia and raised insulin and leptin plasma levels. These effects were annulled by EX4-A, which indicates that they occur through the activation of GLP-1 receptors. Collectively, our findings add support to the view that EX4 can be considered an important therapeutical tool to improve glucose metabolism in diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Exenatide; Female; Glucagon; Glucagon-Like Peptide-1 Receptor; Insulin; Insulin Secretion; Islets of Langerhans; Leptin; Liver Glycogen; Peptide Fragments; Peptides; Rats; Rats, Wistar; Receptors, Glucagon; Venoms

The adipose tissue hormone, leptin, and the neuropeptide glucagon-like peptide-1 (7-36) amide (GLP-1) both reduce food intake and body weight in rodents. Using dual in situ hybridization, long isoform leptin receptor (OB-Rb) was localized to GLP-1 neurons originating in the nucleus of the solitary tract. ICV injection of the specific GLP-1 receptor antagonist, exendin(9-39), at the onset of dark phase, did not affect feeding in saline pre-treated controls, but blocked the reduction in food intake and body weight of leptin pre-treated rats. These findings suggest that GLP-1 neurons are a potential target for leptin in its control of feeding.

Topics: Animals; Body Weight; Carrier Proteins; DNA Probes; Eating; Gene Expression; Glucagon; Glucagon-Like Peptide 1; In Situ Hybridization; Leptin; Light; Male; Mice; Mice, Inbred Strains; Neurons; Peptide Fragments; Proglucagon; Protein Precursors; Proteins; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Leptin; RNA, Messenger; Solitary Nucleus