title: Amylin and GLP-1 target different populations of area postrema neurons that are both modulated by nutrient stimuli.
abstract: The area postrema mediates the hypophagic effect of the pancreatic hormone amylin and is also sensitive to glucagon-like peptide 1 (GLP-1). Protein seems to modulate amylin responsiveness because amylin seems to produce a stronger hypophagic effect and a stronger c-Fos expression when protein is absent from the diet. Accordingly, amylin induces a stronger c-Fos expression in the AP when injected in fasted compared to ad libitum fed rats. Here we tested the hypothesis that diet-derived protein attenuates the amylin dependent suppression of feeding and AP activation using isocaloric diets that differed in their protein content. Moreover, we investigated whether peripheral amino acid injection attenuates amylin-induced c-Fos expression in fasted rats. Since recent evidence suggests that GLP-1 may also reduce eating via the AP we tested whether 24 h fasting also increases neuronal AP responsiveness to GLP-1 similar to the fasting-induced increase in amylin responsiveness. Finally, we used the calcitonin receptor (CTR) as an immunohistochemical marker for amylin-receptive AP neurons to investigate whether amylin's target neurons differ from GLP-1 responsive AP neurons. We also dissociated amylin responsive cells from neurons implicated in other AP-mediated functions such as aversion or blood pressure regulation. For this purpose, we conducted c-Fos/CTR double staining after LiCl or angiotensin II treatment, respectively. Amylin (5 μg/kg s.c.) was more effective to reduce the intake of a 1% vs. an 8% or 18% protein diet and to induce c-Fos expression in the AP in rats receiving 1% vs. 18% protein diet. Increased protein intake was associated with increased blood amino acid levels. Peripheral injection of amino acids (1 g/kg i.p.) attenuated the amylin-induced AP activation in 24 h fasted rats. Similar to amylin, GLP-1 (100 μg/kg i.p.) elicited a significant c-Fos response only in fasted but not in ad libitum fed rats. However, in contrast to a high co-localization of amylin-induced c-Fos and CTR (68%), no c-Fos/CTR co-localization occurred after treatment with GLP-1 or the GLP-1R agonist exendin 4 (2 μg/kg ip). Similarly, LiCl (76 mg/kg ip) or AngII (50 μg/kg sc) led to c-Fos expression only in CTR negative AP neurons. In conclusion, our findings support a protein-dependent modulation of behavioral and neuronal amylin responsiveness under equicaloric feeding conditions. Amino acids might contribute to the inhibitory effect of diet-derived protein to reduce amylin-induced neuronal AP activation. Neuronal AP responsiveness to GLP-1 is also increased in the fasted state suggesting that diet-derived nutrients may also interfere with AP-mediated GLP-1 effects. Nevertheless, the primary target neurons for amylin appear to be distinct from cells targeted by GLP-1 and by stimuli producing aversion (LiCl) or contributing to blood pressure regulation (AngII) via the AP. Since amylin and GLP-1 analogs are targets for the treatment of obesity, the nutrient-dependent modulation of AP responsiveness might entail implications for such therapeutic approaches.
authors: Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland.
authors: Daniela
authors: D
authors: Züger
authors: Karoline
authors: K
authors: Forster
authors: Thomas A
authors: TA
authors: Lutz
authors: Thomas
authors: T
authors: Riediger
mesh_terms: D000596:Amino Acids / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D000704:Analysis of Variance; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D031608:Area Postrema / Q000166:cytology* / Q000187:drug effects*; D001786:Blood Glucose / Q000187:drug effects; D002452:Cell Count; D018592:Cross-Over Studies; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D005215:Fasting / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects; D005502:Food; D005786:Gene Expression Regulation / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000097:blood / Q000494:pharmacology*; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018003:Receptors, Calcitonin / Q000378:metabolism; D013997:Time Factors; D014688:Venoms / Q000378:metabolism
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D016760:Proto-Oncogene Proteins c-fos; D018003:Receptors, Calcitonin; D014688:Venoms; D000804:Angiotensin II; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D018021:Lithium Chloride; D006152:Cyclic GMP