Mechanisms of amylin/leptin synergy in rodent models.
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.
Turek
Victoria F
VF
Amylin Pharmaceuticals, Inc., 9360 Towne Centre Drive, San Diego, California 92121, USA.
Trevaskis
James L
JL
Levin
Barry E
BE
Dunn-Meynell
Ambrose A
AA
Irani
Boman
B
Gu
Guibao
G
Wittmer
Carrie
C
Griffin
Peter S
PS
Vu
Calvin
C
Parkes
David G
DG
Roth
Jonathan D
JD
D000682:Amyloid / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D031608:Area Postrema / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D058228:Islet Amyloid Polypeptide; D020738:Leptin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012377:Rodentia / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D020738:Leptin; D016760:Proto-Oncogene Proteins c-fos; D050796:STAT3 Transcription Factor