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.

Protein-tyrosine Phosphatase 1B (PTP1B) Is a Novel Regulator of Central Brain-derived Neurotrophic Factor and Tropomyosin Receptor Kinase B (TrkB) Signaling

“…In fact, sensitivity to hindbrain/nucleus tractus solitarius BDNF may underlie the enhanced thermogenic response to fourth i.c.v. BDNF (31). It remains to be determined whether PTP1B regulates BDNF/ TrkB signaling in the hindbrain.…”

“…Cannulae were attached to the skull with glue adhesive and closed with an obturator. During the same surgery, miniature telemetric transponders (G2 E-mitters, Mini Mitter) were securely anchored to the abdominal muscle wall as described previously (31). Following surgery, mice were given approximately a week to fully recover.…”

“…In addition to its effects on food intake, BDNF administration into the ventromedial nucleus and paraventricular nucleus of the hypothalamus as well as the nucleus tractus solitarius of the hindbrain increases energy expenditure through changes in spontaneous physical activity, resting metabolic rate, core temperature, and thermogenic gene expression (24,26,31). To test the hypothesis that PTP1B-deficient mice may display differential energy expenditure responses to exogenous BDNF, core body temperature and spontaneous physical activity were recorded in Ptpn1 Ϫ/Ϫ and wild-type littermates in response to aCSF or a lower dose of BDNF that did not reduce food intake in either group (data not shown).…”

Leptin Signaling in the Medial Nucleus Tractus Solitarius Reduces Food Seeking and Willingness to Work for Food

“…Bilateral guide cannulae (26-gauge; Plastics One, Roanoke, VA; 1.5 mm spacing between cannulae) were implanted with the tip stereotaxically positioned above the mNTS target injection site using one of two coordinate systems (coordinates varied by surgeon to maximize overall accuracy): (1) midline, 1.0 mm posterior to occipital crest, 6.7 mm ventral from skull surface, injection targeted 2.0 mm below end of guide cannula; or (2) midline, 2.0 mm anterior to occipital crest, 6.8 mm ventral from skull surface using a 15-degree angle (negative slope in anterior to posterior direction), injection targeted 1.5 mm below end of guide cannula. Procedures for unilateral mNTS injections (right side) were based on our previous work (eg, Hayes et al, 2009Hayes et al, , 2011Kanoski et al, 2012a, b;Spaeth et al, 2012) and involve 100 nl infusion (delivery rate of 5 ml/min via Harvard Apparatus PHD 2000 infusion pump; 28 gauge indwelling injector cannulae) followed by a 30-to 40-s diffusion period where the injectors are left in place. Intended anatomic positions of mNTS injection sites were evaluated 1 week post-surgery by measurement of the sympathoadrenal-mediated glycemic response to an injection of 5-thio-D-glucose (24 mg/100 nl unilateral mNTS injection; Ritter et al, 1981).…”

TrkB blockade in the hippocampus after training or retrieval impairs memory: protection from consolidation impairment by histone deacetylase inhibition

“…In the second experiment, rats received a bilateral intrahippocampal 1.0-ll infusion of saline or NaB (100 mM dissolved in saline) and immediately after reactivation they were infused with vehicle (1 % DMSO in saline) or ANA-12 (1.0 lg/ll dissolved in vehicle). The doses of NaB and ANA-12 were chosen on the basis of previous studies (Blank et al 2014;Spaeth et al 2012). Drug solutions were freshly prepared before each experiment.…”