Mechanisms of amylin/leptin synergy in rodent models

Endocrinology. 2010 Jan;151(1):143-52. doi: 10.1210/en.2009-0546. Epub 2009 Oct 29.

Abstract

The present studies aimed to identify mechanisms contributing to amylin/leptin synergy in reducing body weight and adiposity. We reasoned that if amylin/leptin harnessed complementary neuronal pathways, then in the leptin-sensitive state, amylin should augment leptin signaling/binding and that in the absence of endogenous amylin, leptin signaling should be diminished. Amylin (50 microg/kg, ip) amplified low-dose leptin-stimulated (15 microg/kg, ip) phosphorylated signal transducer and activator of transcription-3 signaling within the arcuate nucleus (ARC) in lean rats. Amylin (50 microg/kg x d) or leptin (125 microg/kg x d) infusion to lean rats decreased 28-d food intake (14 and 10%, respectively), body weight (amylin by 4.3%, leptin by 4.9%), and epididymal fat (amylin by 19%, leptin by 37%). Amylin/leptin co-infusion additively decreased food intake (by 26%) and reduced body weight (by 15%) and epididymal fat (by 78%; all P < 0.05 vs. all groups) in a greater than mathematically additive manner, consistent with synergy. Amylin increased leptin binding within the ventromedial hypothalamus (VMN) by 35% and dorsomedial hypothalamus by 47% (both P < 0.05 vs. vehicle). Amylin/leptin similarly increased leptin binding in the VMN by 40% and ARC by 70% (P < 0.05 vs. vehicle). In amylin-deficient mice, hypothalamic leptin receptor mRNA expression was reduced by 50%, leptin-stimulated phosphorylated signal transducer and activator of transcription-3 within ARC and VMN was reduced by 40%, and responsiveness to leptin's (1 mg/kg x d for 28 d) weight-reducing effects was attenuated (all P < 0.05 vs. wild-type controls). We suggest that amylin/leptin's marked weight- and fat-reducing effects are due to activation of intrinsic synergistic neuronal signaling pathways and further point to the integrated neurohormonal therapeutic potential of amylin/leptin agonism in obesity.

MeSH terms

  • Amyloid / genetics
  • Amyloid / metabolism
  • Amyloid / pharmacology
  • Amyloid / physiology*
  • Animals
  • Arcuate Nucleus of Hypothalamus / drug effects
  • Arcuate Nucleus of Hypothalamus / metabolism
  • Area Postrema / drug effects
  • Area Postrema / metabolism
  • Drug Synergism*
  • Female
  • Islet Amyloid Polypeptide
  • Leptin / genetics
  • Leptin / metabolism
  • Leptin / pharmacology
  • Leptin / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Rodentia* / genetics
  • Rodentia* / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics

Substances

  • Amyloid
  • Islet Amyloid Polypeptide
  • Leptin
  • Proto-Oncogene Proteins c-fos
  • STAT3 Transcription Factor