Hypothalamic Amylin Acts in Concert with Leptin to Regulate Food Intake

Cell Metab. 2015 Dec 1;22(6):1059-67. doi: 10.1016/j.cmet.2015.10.012. Epub 2015 Nov 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Eating / drug effects
  • Enkephalins / genetics
  • Enkephalins / metabolism
  • Female
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism*
  • Islet Amyloid Polypeptide / antagonists & inhibitors
  • Islet Amyloid Polypeptide / metabolism*
  • Islet Amyloid Polypeptide / pharmacology
  • Leptin / blood
  • Leptin / metabolism*
  • Leptin / pharmacology
  • Male
  • Membrane Potentials / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Microscopy, Confocal
  • Neurons / metabolism
  • Patch-Clamp Techniques
  • Peptide Fragments / pharmacology
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Leptin / genetics
  • Receptors, Leptin / metabolism

Substances

  • Enkephalins
  • Islet Amyloid Polypeptide
  • Leptin
  • Peptide Fragments
  • Protein Precursors
  • RNA, Messenger
  • Receptors, Leptin
  • AC 187
  • preproenkephalin