Weekly Subcutaneous Pegylated Recombinant Native Human Leptin (PEG-OB) Administration in Obese Men

Abstract

To assess the biological activity and tolerability of pegylated recombinant native human leptin (PEG-OB), 30 obese men (mean body mass index, 33.9 kg/m2) were randomized to a double-blind treatment with weekly sc injections of 20 mg PEG-OB or placebo for 12 weeks, in addition to a hypocaloric diet (deficit, 2 MJ/day). Body composition, energy expenditure, and metabolic parameters were measured before and after treatment. PEG-OB was generally well tolerated based on adverse event reports, lab values, and vital signs. Weekly sc PEG-OB led to sustained serum concentrations of PEG-OB and leptin throughout treatment. No significant differences in the delta or percent weight loss, percent body fat, sleeping metabolic rate, or respiratory quotient were observed between the PEG-OB and placebo groups. Percent change in serum triglycerides from baseline was significantly correlated with body weight loss in the PEG-OB group, but not in the placebo group. Although larger reductions in serum triglycerides were observed in the PEG-OB group compared with the placebo group, these differences were not statistically significant. We concluded that weekly injection of PEG-OB leads to sustained serum concentration of PEG-OB and leptin throughout the 12-week treatment period and is generally well tolerated. The trends observed in serum triglycerides suggest that a weekly 20-mg sc treatment with PEG-OB may have biological effects in obese men.

Adipokines in health and disease

“…Given its appetite-reducing function in normal or low circulating leptin states, recombinant leptin has been developed as a weight loss pharmacotherapy for obesity [10,11,29]. Against expectations, leptin treatment of obese patients had only a little effect on weight loss; both high leptin doses or treatment with pegylated leptin once weekly did not cause significant weight loss, but did increase the risk for adverse effects of recombinant leptin therapy [33,34]. The most likely reason for the lack of leptin effects on body weight reduction is the development of central leptin resistance or tolerance in obese patients with already very high circulating leptin levels [10,11].…”

From leptin to other adipokines in health and disease: Facts and expectations at the beginning of the 21st century

“…Leptin in low leptin states plays an important role in satiety, appetite [99,100], food intake, reproductive function and puberty [101][102][103][104][105][106] activity and energy expenditure regulation [107]. Originally, leptin was viewed as a potential anti-obesity therapeutic agent and was originally developed mainly with the aim to reduce body fat mass in obesity [18,[108][109][110][111]. In mice [108] and humans [109] with genetically inherited leptin deficiency, leptin has been proven as an effective weight loss drug.…”

“…In mice [108] and humans [109] with genetically inherited leptin deficiency, leptin has been proven as an effective weight loss drug. In contrast to leptin substitution treatment, in human obese patients [110,111] with obesity as well as in high caloric diet induced obesity in mice [112], leptin had only little effects on weight loss [113,114]. Even high doses of leptin and once weekly treatment with pegylated leptin did not A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 15 improve weight loss effects, but increased the risk for side effects of recombinant leptin therapy of obesity [111].…”

Medical Therapy for Obesity—Current Status and Future Hopes

“…The discovery of leptin generated hope that leptin would be an effective treatment for many overweight patients. Leptin at subcutaneous doses of 0.0 mg/kg, 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, and 0.3 mg/kg daily was tested in lean [75] and obese [76] human beings of both sexes. Lean subjects were treated for 4 weeks and lost À0.4 kg to À1.9 kg.…”