Long-Acting PASylated Leptin Ameliorates Obesity by Promoting Satiety and Preventing Hypometabolism in Leptin-Deficient Lep(ob/ob) Mice

Endocrinology. 2016 Jan;157(1):233-44. doi: 10.1210/en.2015-1519. Epub 2015 Oct 22.


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) resulted in a maximal weight reduction of 21% 6 days after application. The negative energy balance of 300 kJ/(4 d) was driven by a decrease in energy intake, whereas energy expenditure remained stable. Mice that were food restricted to the same extent showed an energy deficit of only 220 kJ/(4 d) owing to recurring torpor bouts. Therefore, the anorexigenic effect of PAS(600)-leptin contributes 75% to weight loss, whereas the thermogenic action accounts for 25% by preventing hypometabolism. In a second experiment, just four injections of PAS(600)-leptin (100 pmol/g) administered in 5- to 6-day 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 and glucose homeostasis as well as hepatic steatosis. The beneficial properties of PAS(600)-leptin are substantiated by a comparison with previous studies in which approximately 400 nmol (∼25-fold) unmodified leptin was mandatory to achieve similar improvements.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Appetite Depressants / administration & dosage
  • Appetite Depressants / adverse effects
  • Appetite Depressants / chemistry
  • Appetite Depressants / therapeutic use*
  • Dose-Response Relationship, Drug
  • Energy Intake / drug effects
  • Energy Metabolism / drug effects*
  • Female
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism
  • Hypothalamus / pathology
  • Injections, Subcutaneous
  • Leptin / administration & dosage
  • Leptin / analogs & derivatives*
  • Leptin / genetics
  • Leptin / therapeutic use
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice, Mutant Strains
  • Molecular Weight
  • Motor Activity / drug effects
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Obesity / pathology
  • Peptides / metabolism
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / adverse effects
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / therapeutic use*
  • Satiety Response / drug effects*
  • Specific Pathogen-Free Organisms
  • Thermogenesis / drug effects
  • Weight Loss / drug effects


  • Appetite Depressants
  • Leptin
  • Peptides
  • Recombinant Fusion Proteins