Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studies

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2008
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Abstract
Body weight is regulated by complex neurohormonal interactions between endocrine signals of long-term adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety (e.g., amylin, a hindbrain signal). We report that concurrent peripheral administration of amylin and leptin elicits synergistic, fat-specific weight loss in leptin-resistant, diet-induced obese rats. Weight loss synergy was specific to amylin treatment, compared with other anorexigenic peptides, and dissociable from amylin9s effect on food intake. The addition of leptin after amylin pretreatment elicited further weight loss, compared with either monotherapy condition. In a 24-week randomized, double-blind, clinical proof-of-concept study in overweight/obese subjects, coadministration of recombinant human leptin and the amylin analog pramlintide elicited 12.7% mean weight loss, significantly more than was observed with either treatment alone (P < 0.01). In obese rats, amylin pretreatment partially restored hypothalamic leptin signaling (pSTAT3 immunoreactivity) within the ventromedial, but not the arcuate nucleus and up-regulated basal and leptin-stimulated signaling in the hindbrain area postrema. These findings provide both nonclinical and clinical evidence that amylin agonism restored leptin responsiveness in diet-induced obesity, suggesting that integrated neurohormonal approaches to obesity pharmacotherapy may facilitate greater weight loss by harnessing naturally occurring synergies.
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baron2008proceedingsleptin Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Jonathan D. Roth,Barbara L. Roland,Rebecca L. Cole,James Trevaskis,Christian Weyer,Joy E. Koda,Christen M. Anderson,David G. Parkes,Alain D. Baron;Jonathan D. Roth;Barbara L. Roland;Rebecca L. Cole;James Trevaskis;Christian Weyer;Joy E. Koda;Christen M. Anderson;David G. Parkes;Alain D. Baron;
Journal proceedings of the national academy of sciences
Year 2008
DOI
10.1073/pnas.0706473105
URL
https://sciprofiles.com/publication/view/4bc016d9fa7c9f7c6a5d63b4c8778d6c
Keywords
adiposity synergy leptin resistance pramlintide metreleptin

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