Leptin Agonist and Methods of Use

Temple University
posted on 08/05/2011

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Leptin, a multifunctional hormone, controls various processes in both the central nervous system and in peripheral tissues. Agonists and antagonists of the leptin receptor are being investigated as potential therapeutics for diseases characterized by leptin insufficiency and associated co-morbidities as well as conditions associated with leptin overabundance. Temple scientists developed a family of 12-13 amino acid residue-long glycosylated leptin fragments containing additional non-natural amino acid residues that induce leptin effects in leptin receptor-positive cell lines at picomolar concentrations, and when added intraperitoneally readily cross the blood-brain barrier. These peptides mimic all in vivo functions of leptin, but unlike the native protein and derivatives currently undergoing clinical trials do not invoke resistance from the host. A first generation leptin receptor agonist glycopeptide, similar to leptin, reduces food intake and increases thermogenesis in a sheep model. A second generation leptin receptor agonist glycopeptide added intraperitoneally at 0.1-0.5 mg/kg/day reduces weight, blood glucose levels and fatty liver pathology as well as restores fertility in diet-induced obese mice. The pathology changes are superior to leptin protein treatment. The same glycopeptide at 0.5 mg/kg/day reduces normal weight gain in rats for 21 days without signs of resistance development. The weight control effects in rats persist beyond the treatment period. The peptides also show the positive effects leptin makes on central nervous system functions.

Treatment and prevention of:
• Development of obesity and metabolic diseases, such as lipodystrophy, obesity-related infertility, metabolic syndrome, hypothalamic amenorrhea, diet-induced food craving, weight-loss management and insulin resistance.
• Improving cognitive functions.

• Superior brain penetration vs. leptin
• Superior response (resistance avoidance) vs. leptin

Recombinant human leptin protein is currently subject of many clinical trials with questionable success. The main drawback to current leptin therapies against obesity, lipodystrophy and weight-related infertility is the emerging resistance to leptin treatment in the subjects. Obese mice receiving the Temple peptide E1/Aca for 11 days at a 0.1 – 0.5 mg/kg/day dose lose weight, corresponding to a net 6.5% total body weight loss, unlike similar mice treated with leptin protein. Upon cessation of the weight loss experiment, the clinical signs of high-dose peptide-treated mice, but not those of leptin-treated, return to normal.