TrkB receptor signaling in the nucleus tractus solitarius mediates the food intake-suppressive effects of hindbrain BDNF and leptin

Abstract

Brain-derived neurotrophic factor (BDNF) and TrkB receptor signaling contribute to the central nervous system (CNS) control of energy balance. The role of hindbrain BDNF/TrkB receptor signaling in energy balance regulation is examined here. Hindbrain ventricular BDNF suppressed body weight through reductions in overall food intake and meal size and by increasing core temperature. To localize the neurons mediating the energy balance effects of hindbrain ventricle-delivered BDNF, ventricle subthreshold doses were delivered directly to medial nucleus tractus solitarius (mNTS). mNTS BDNF administration reduced food intake significantly, and this effect was blocked by preadministration of a highly selective TrkB receptor antagonist {[N2-2-2-Oxoazepan-3-yl amino]carbonyl phenyl benzo (b)thiophene-2-carboxamide (ANA-12)}, suggesting that TrkB receptor activation mediates hindbrain BDNF's effect on food intake. Because both BDNF and leptin interact with melanocortin signaling to reduce food intake, we also examined whether the intake inhibitory effects of hindbrain leptin involve hindbrain-specific BDNF/TrkB activation. BDNF protein content within the dorsal vagal complex of the hindbrain was increased significantly by hindbrain leptin delivery. To assess if BDNF/TrkB receptor signaling acts downstream of leptin signaling in the control of energy balance, leptin and ANA-12 were coadministered into the mNTS. Administration of the TrkB receptor antagonist attenuated the intake-suppressive effects of leptin, suggesting that mNTS TrkB receptor activation contributes to the mediation of the anorexigenic effects of hindbrain leptin. Collectively, these results indicate that TrkB-mediated signaling in the mNTS negatively regulates food intake and, in part, the intake inhibitory effects of leptin administered into the NTS.

Fig. 1.

Effects of acute 4th intrecerebroventricular (icv) brain-derived neurotrophic factor (BDNF) on food intake and body weight (BW). Fourth ventricular delivery of BDNF (4th ventricle) suppressed cumulative food intake (A) and body weight (B) in a dose-dependent manner. Meal pattern analysis revealed that the suppression of cumulative intake at 6 and 24 h by the 1.0- and the 2.0-μg doses is explained by an effect on meal size (C) and not by meal number (D). *P < 0.05; †P = 0.08. aCSF, artificial cerebrospinal fluid.

Fig. 2.

Effects of 4th icv BDNF on correlates of energy expenditure. A: 4th ventricular BDNF increased core temperature significantly when examined in the home cage during the light phase and in the absence of food. B: energy expenditure was quantified as the average core temperature and activity beginning 1.5 h after the injection (when activity levels stabilized following handling) until the end of the 6.5-h recording period. *P < 0.05.

Fig. 3.

Effects of medial nucleus tractus solitarius (mNTS) BDNF on food intake and body weight. Direct mNTS parenchymal delivery of 2 BDNF doses that were shown to be ineffective when delivered to the 4th ventricle suppressed food intake 6 and 24 h after drug administration (A) and body weight change 24 h after drug administration (B). *P < 0.05; †P = 0.08.

Fig. 4.

BDNF/TrkB receptor signaling within the mNTS. The NTS TrkB receptor mediation of the food intake inhibitory effect of mNTS parenchymal BDNF delivery was evaluated using a recently described TrkB antagonist, ANA-12. mNTS BDNF significantly reduced food intake measured 24 h after drug delivery, and preadministration of both doses of ANA-12 significantly attenuated this effect. mNTS BDNF also significantly reduced body weight measured 24 h after drug delivery, and this effect was attenuated by preadministration of the higher dose (3 μg) of ANA-12. *P < 0.05.

Fig. 5.

Effect of hindbrain leptin administration on dorsal vagal complex (DVC) BDNF levels. Fourth ventricular leptin delivery (4 μg) 120 min prior to euthanization increased BDNF protein content significantly within DVC tissue, as measured by ELISA. *P < 0.05.

Fig. 6.

Hindbrain TrkB receptor signaling and leptin. NTS TrkB receptor mediation of the food intake inhibitory effect of mNTS parenchymal leptin delivery was evaluated using the TrkB-specific antagonist ANA-12. Leptin reduced 6-h food intake significantly when administered alone to the mNTS (P < 0.05), but pre-mNTS administration of ANA-12 blocked these intake-suppressive effects. Leptin also decreased intake at 24 h, but there was no significant attenuation of this effect by ANA-12. *P < 0.05; †P = 0.08.