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Long-acting PASylated leptin ameliorates obesity by promoting satiety and preventing hypometabolism in leptin-deficient Lep(ob/ob) mice.

08:00 EDT 22nd October 2015 | BioPortfolio

Summary of "Long-acting PASylated leptin ameliorates obesity by promoting satiety and preventing hypometabolism in leptin-deficient Lep(ob/ob) mice."

Body weight loss of Lep(ob/ob) mice in response to leptin is larger than expected from the reduction in energy intake alone, suggesting a thermogenic action of unknown magnitude. We exploited the superior pharmacological properties of a novel long-acting leptin prepared via PASylation to study the contribution of its anorexigenic and thermogenic effects. PASylation, the genetic fusion of leptin with a conformationally disordered polypeptide comprising 600 Pro/Ala/Ser (PAS) residues, provides a superior way to increase the hydrodynamic volume of the fusion protein, thus retarding kidney filtration and extending plasma half-life. Here, a single PAS(600)-Leptin injection (300 pmol·g(-1)) resulted in a maximal weight reduction of 21% six days after application. The negative energy balance of 300 kJ·(4 days)(-1) was driven by a decrease in energy intake whereas energy expenditure maintained stable. Mice that were food-restricted to the same extent only showed an energy deficit of 220 kJ·(4 days)(-1) owing to recurring torpor bouts. Therefore, the anorexigenic effect of PAS(600)-Leptin contributes 75% to weight loss while the thermogenic action accounts for 25% by preventing hypometabolism. In a second experiment, just four injections of PAS(600)-Leptin (100 pmol·g(-1)) administered in 5-6 days intervals rectified the Lep(ob/ob) phenotype. In total 16 nmol of PAS(600)-Leptin per mouse triggered a weight loss of 43% within 20 days and normalized hypothermia, glucose homeostasis as well as hepatic steatosis. The beneficial properties of PAS(600)-Leptin are substantiated by a comparison with previous studies in which around 400 nmol (∾25fold) unmodified leptin were mandatory to achieve similar improvements.

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This article was published in the following journal.

Name: Endocrinology
ISSN: 1945-7170
Pages: en20151519

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