Leptin administered in physiologic or pharmacologic doses does not regulate circulating angiogenesis factors in humans

Abstract

Introduction Leptin has been shown to regulate angiogenesis in animal and in vitro studies by upregulating the expression of several pro-angiogenic factors, but its role in regulating angiogenesis has never been studied in humans. Methods We conducted 2 studies. First, a short-term, interventional study of 15 healthy, normoleptinemic men and women, to whom metreleptin was administered in escalating doses (physiologic, 0.1 mg/kg, and pharmacologic, 0.3 mg/kg) on two admissions separated by 1–12 weeks. Serum was collected at 0, 6, 12, and 24 hrs post-metreleptin to evaluate its acute effects on angiogenesis. Second, a prospective, double-blinded RCT of 20 women with hypothalamic amenorrhea and hypoleptinemia (leptin levels < 5ng/ml) that were randomized in a 1:1 fashion to receive either metreleptin (0.08–0.12 mg/kg qd) or placebo for 32 weeks. Serum was collected at 0, 8, 20, and 32 wks after randomization to evaluate the long-term effects of metreleptin in replacement doses in hypoleptinemic amenorrheic subjects. Main outcome measures included circulating levels of angiogenin, angiopoietin-1, PDGF-AA, MMP-8 and 9, EGF, and VEGF. Results Circulating concentrations of angiogenesis markers did not change significantly after acute or chronic administration of metreleptin. Conclusions Metreleptin administration does not regulate circulating angiogenesis factors in humans.