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. 2016 Dec 19;292(5):1925–1933. doi: 10.1074/jbc.M116.748103

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FIGURE 3. — Apelin-36-[L28C(30kDa-PEG)] is >10,000-fold less potent than apelin-36 at activating APJ and does not lower blood pressure, but powerfully lowers blood glucose and improves glucose tolerance in DIO mice. A and B, apelin-36 and [40kDa-PEG]-apelin-36 potently activate APJ, but apelin-36-[L28C(30kDa-PEG)] is >10,000-fold less potent. A U2OS cell line stably expressing human APJ was incubated with apelin peptides at the indicated concentrations. (n = 4 replicates/concentration, error bars indicate standard deviation; data are from one experiment that is representative of three independent experiments). C, 16-week-old C57BL/6 DIO mice (12 weeks on high-fat diet) were administered a single subcutaneous dose of apelin-36-[L28C(30kDa-PEG)] or [40kDa-PEG]-apelin-36 at the indicated dosage level, and fed blood glucose levels were measured before dosing (0 h), and 16, 40, and 64 h after dosing (n = 6 mice/group; data are from one experiment that is representative of three independent experiments). The 3 and 10 mg/kg doses of apelin-36-[L28C(30kDa-PEG)] significantly lowered blood glucose levels 16 h after dosing: glucose levels returned to baseline by 40 h after dose. D, C57BL/6 DIO mice were administered a single subcutaneous dose of apelin-36-[L28C(30kDa-PEG)] or [40kDa-PEG]-apelin-36 at the indicated dosage level, and 16 h after dosing, the mice were fasted for 4 h. Following the fast (20 h after injection), an oral glucose tolerance test (1 g/kg) was performed. Apelin-36-[L28C(30kDa-PEG)] treatment caused a dose-dependent reduction in fasting blood glucose levels (see the 0-min time point) and improvement in glucose tolerance. Inset, glucose area under the curve shown in column graph. E, C57BL/6 DIO mice were administered a single subcutaneous dose of apelin-36-[L28C(30kDa-PEG)] or [40kDa-PEG]-apelin-36 at the indicated dosage level, and overnight food intake was measured (0–16 h after dosing). Apelin-36-[L28C(30kDa-PEG)] treatment caused a dose-dependent reduction in food intake. F, C57BL/6 DIO mice were administered a single subcutaneous dose of apelin-36-[L28C(30kDa-PEG)] or [40kDa-PEG]-apelin-36 at the indicated dosage level, and body weight was measured before dosing (0 h), and 16, 40, and 64 h after dosing. Neither of the peptides impacted body weight during the course of the study. **, p < 0.01 apelin-36-[L28C(30kDa-PEG)] 1 mg/kg versus vehicle. #, p < 0.05; ##, p < 0.01; ###, p < 0.001 apelin-36-[L28C(30kDa-PEG)] 3 mg/kg versus vehicle. ∧∧, p < 0.01; ∧∧∧, p < 0.001 apelin-36-[L28C(30kDa-PEG)] 10 mg/kg versus vehicle. G, apelin-36 lowers mean blood pressure (MBP) in SHR, whereas apelin-36-[L28C(30kDa-PEG)] does not. Blood pressure was measured using a non-invasive tail cuff blood pressure monitor. *, p < 0.05; **, p < 0.01 apelin-36 versus apelin-36-[L28C(30kDa-PEG)]. Statistics were analyzed using Student's t test with two-tailed distribution.