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

Xu, Lingfei and Zhang, Yunyu and Cohen, Steven and Dipetrillo, Keith (2010) TrkB Agonist Antibody Dose-Dependently Raises Blood Pressure in Mice with Diet-Induced Obesity. American Journal of Hypertension.

Abstract

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, TrkB, represents an alternative strategy for lowering body weight. However, because BDNF can raise blood pressure acutely, it is possible that chronic TrkB activation will produce adverse cardiovascular effects. METHODS: We used radiotelemetry to test whether treatment with a TrkB agonist antibody causes adverse cardiovascular effects in mice with diet-induced obesity. RESULTS: High-dose (1 mg/kg) TrkB antibody reduced body weight and significantly increased blood pressure, 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 or blood pressure. These data suggest that elevated blood pressure was a direct effect of high-dose TrkB antibody treatment rather than secondary to substantial weight loss. CONCLUSIONS: Overall, high-dose TrkB antibody lowered body weight and increased blood pressure, whereas low-dose TrkB antibody treatment caused therapeutic weight loss without adverse cardiovascular effects. We conclude that TrkB activation dose-dependently lowers body weight and raises blood pressure in mice with diet-induced obesity.

Item Type: Article
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Keywords: BDNF; blood pressure; diet-induced obesity; hypertension; LDN743; TrkB
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/1977

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