TrkB Agonist Antibody Dose-Dependently Raises Blood Pressure in Mice With Diet-Induced Obesity

BACKGROUND Brain-derived neurotrophic factor (BDNF) regulates food intake and body weight, but is not useful as a therapeutic because of its short half-life. Chronic activation of its receptor, tyrosine kinase receptor B (TrkB), represents an alternative strategy for lowering body weight. However, because BDNF can raise blood pressure (BP) acutely, it is possible that chronicTrkB activation will produce adverse cardiovascular effects. METHODS We used radiotelemetry to test whether treatment with aTrkB agonist antibody (Ab) causes adverse cardiovascular effects in mice with diet-induced obesity. RESULTS High-dose (1 mg/kg)TrkB Ab reduced body weight and significantly increased BP, whereas low-dose (0.3 mg/kg) treatment lowered body weight without adverse cardiovascular effects. Rimonabant, through a different mechanism of action, lowered body weight in this model more than TrkB activation, but showed no adverse effects on heart rate (HR) or BP These data suggest that elevated BP was a direct effect of high-doseTrkB Ab treatment rather than secondary to substantial weight loss. CONCLUSIONS Overall, high-doseTrkB Ab lowered body weight and increased BP, whereas low-doseTrkB Ab treatment caused therapeutic weight loss without adverse cardiovascular effects. We conclude thatTrkB activation dose-dependently lowers body weight and transiently raises BP in mice with diet-induced obesity.