Improved satiety effect of leptin fusion proteins with prolonged plasma half‐life in mice

Abstract

Leptin, a 16 kDa hormone derived from adipocytes, plays a key role in energy balance regulation. Its clinical application in disorders associated with low plasma leptin levels, like genetically caused leptin deficiency, has been proposed. Due to its low hydrodynamic volume leptin is rapidly eliminated by renal clearance. Thus, daily injections would be needed to perpetuate a constant effect, which is not acceptable as therapy.To improve leptin therapy, we have engineered leptin with an enlarged hydrodynamic volume using PASylation technology, which involves fusion with a disordered poly‐amino acid sequence comprising 200, 400 or 600 Pro, Ala and Ser residues (PAS). The expanded hydrodynamic volume reduces renal clearance in a length‐dependent manner. The affinity of the fusion proteins to the leptin receptor was almost fully retained as demonstrated by surface plasmon resonance analysis.Cell culture assays revealed that PAS‐variants were nearly as potent in activating receptor signaling as native leptin. In C57BL/6J mice, PAS‐derivates were able to reduce food intake and body weight in a more effective manner than native leptin. The strongest effect was observed for PAS600‐leptin with a 10 % weight loss over 5 days.Thus, PASylation is promising to maintain a lasting therapeutic effect without the need for daily injections.Supported by National Genome Research Network plus to M. Klingenspor (01GS0822)