title: Hypothalamic Amylin Acts in Concert with Leptin to Regulate Food Intake.
abstract: In this report we evaluated the functions of hypothalamic amylin in vivo and in vitro. Profiling of hypothalamic neurons revealed that islet amyloid polypeptide (Iapp, precursor to amylin) is expressed in neurons in the lateral hypothalamus, arcuate nucleus, medial preoptic area, and elsewhere. Hypothalamic expression of lapp is markedly decreased in ob/ob mice and normalized by exogenous leptin. In slices, amylin and leptin had similar electrophysiologic effects on lateral hypothalamic leptin receptor ObRb-expressing neurons, while the amylin antagonist AC187 inhibited their activity and blunted the effect of leptin. Finally, i.c.v. infusion of AC187 acutely reduced the anorectic effects of leptin. These data show that hypothalamic amylin is transcriptionally regulated by leptin, that it can act directly on ObRb neurons in concert with leptin, and that it regulates feeding. These findings provide a potential mechanism for the increased efficacy of a metreleptin/pramlintide combination therapy for obesity.
authors.affiliation: Laboratory of Molecular Genetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Genetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Kelly
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02138, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Heiman
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.affiliation: Laboratory of Molecular Genetics, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815-6789, USA. Electronic address: friedj@rockefeller.edu.
authors.forename: Jeffrey Michael
authors.initials: JM
authors.lastname: Friedman
mesh_terms: D000818:Animals; D004435:Eating / Q000187:drug effects; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D020738:Leptin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism
chemical_list: D004745:Enkephalins; D058228:Islet Amyloid Polypeptide; D020738:Leptin; D010446:Peptide Fragments; D011498:Protein Precursors; D012333:RNA, Messenger; D054411:Receptors, Leptin; C087166:AC 187; C033660:preproenkephalin