Mechanisms of amylin/leptin synergy in rodent models
| Autor: | Victoria F. Turek, David G. Parkes, Barry E. Levin, Calvin Vu, Peter S. Griffin, Ambrose A. Dunn-Meynell, James L. Trevaskis, Boman G. Irani, Jonathan D. Roth, Carrie Wittmer, Guibao Gu |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Leptin
Male STAT3 Transcription Factor endocrine system medicine.medical_specialty Amyloid endocrine system diseases Amylin Adipose tissue Adipokine Endogeny Rodentia macromolecular substances Rats Sprague-Dawley Mice Endocrinology Internal medicine medicine Animals Mice Knockout Leptin receptor Chemistry digestive oral and skin physiology Area postrema Arcuate Nucleus of Hypothalamus Drug Synergism Islet Amyloid Polypeptide Rats Mice Inbred C57BL Area Postrema Hypothalamus Models Animal Female Proto-Oncogene Proteins c-fos hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Endocrinology. 151(1) |
| ISSN: | 1945-7170 |
| Popis: | 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 μg/kg, ip) amplified low-dose leptin-stimulated (15 μg/kg, ip) phosphorylated signal transducer and activator of transcription-3 signaling within the arcuate nucleus (ARC) in lean rats. Amylin (50 μg/kg · d) or leptin (125 μg/kg · 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 · 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. |
| Databáze: | OpenAIRE |
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