PMID- 26629410 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20151202 LR - 20181113 IS - 2212-8778 (Print) IS - 2212-8778 (Electronic) IS - 2212-8778 (Linking) VI - 4 IP - 11 DP - 2015 Nov TI - Ablation of intact hypothalamic and/or hindbrain TrkB signaling leads to perturbations in energy balance. PG - 867-80 LID - 10.1016/j.molmet.2015.08.002 [doi] AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), play a paramount role in the central regulation of energy balance. Despite the substantial body of genetic evidence implicating BDNF- or TrkB-deficiency in human obesity, the critical brain region(s) contributing to the endogenous role of BDNF/TrkB signaling in metabolic control remain unknown. METHODS: We assessed the importance of intact hypothalamic or hindbrain TrkB signaling in central regulation of energy balance by generating Nkx2.1-Ntrk2-/- and Phox2b-Ntrk2+/- mice, respectively, and comparing metabolic parameters (body weight, adiposity, food intake, energy expenditure and glucose homeostasis) under high-fat diet or chow fed conditions. RESULTS: Our data show that when fed a high-fat diet, male and female Nkx2.1-Ntrk2-/- mice have significantly increased body weight and adiposity that is likely driven by reduced locomotor activity and core body temperature. When maintained on a chow diet, female Nkx2.1-Ntrk2-/- mice exhibit an increased body weight and adiposity phenotype more robust than in males, which is accompanied by hyperphagia that precedes the onset of a body weight difference. In addition, under both diet conditions, Nkx2.1-Ntrk2-/- mice show increased blood glucose, serum insulin and leptin levels. Mice with complete hindbrain TrkB-deficiency (Phox2b-Ntrk2-/-) are perinatal lethal, potentially indicating a vital role for TrkB in visceral motor neurons that control cardiovascular, respiratory, and digestive functions during development. Phox2b-Ntrk2+/- heterozygous mice are similar in body weight, adiposity and glucose homeostasis parameters compared to wild type littermate controls when maintained on a high-fat or chow diet. Interestingly, despite the absence of a body weight difference, Phox2b-Ntrk2+/- heterozygous mice exhibit pronounced hyperphagia. CONCLUSION: Taken together, our findings suggest that the hypothalamus is a key brain region involved in endogenous BDNF/TrkB signaling and central metabolic control and that endogenous hindbrain TrkB likely plays a role in modulating food intake and survival of mice. Our findings also show that female mice lacking TrkB in the hypothalamus have a more robust metabolic phenotype. FAU - Ozek, Ceren AU - Ozek C AD - Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. FAU - Zimmer, Derek J AU - Zimmer DJ AD - Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. FAU - De Jonghe, Bart C AU - De Jonghe BC AD - Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA. FAU - Kalb, Robert G AU - Kalb RG AD - Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. FAU - Bence, Kendra K AU - Bence KK AD - Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. LA - eng GR - P60 DK020593/DK/NIDDK NIH HHS/United States GR - P30 DK020593/DK/NIDDK NIH HHS/United States GR - S10 RR027128/RR/NCRR NIH HHS/United States GR - R01 DK082417/DK/NIDDK NIH HHS/United States GR - P30 DK019525/DK/NIDDK NIH HHS/United States GR - U24 DK059637/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20150818 PL - Germany TA - Mol Metab JT - Molecular metabolism JID - 101605730 PMC - PMC4632115 OTO - NOTNLM OT - Agrp, agouti-related peptide OT - BAT, brown adipose tissue OT - BDNF OT - BDNF, brain-derived neurotrophic factor OT - Cidea, cell death-inducing DFFA-like effector a OT - Cre, Cre recombinase OT - DVC, dorsal vagal complex OT - Elovl3, elongation of very long fatty acids-like 3 OT - GTT, glucose tolerance test OT - HFD, high-fat diet OT - HPA axis, hypothalamic-pituitary-adrenal axis OT - Hindbrain OT - Hypothalamus OT - LepR, leptin receptor OT - Mc4R, melanocortin 4 receptor OT - NTS, nucleus of the solitary tract OT - Nkx2.1, Nk2 homeobox 1 protein OT - Npy, neuropeptide Y OT - Obesity OT - PVH, paraventricular nucleus of the hypothalamus OT - Pgc1alpha, peroxisome proliferator-activated receptor gamma coactivator 1 alpha OT - Phox2b, paired-like homeobox 2b protein OT - Pomc, pro-opiomelanocortin OT - Ppargamma, peroxisome proliferator-activated receptor gamma OT - Prdm16, PR domain containing 16 OT - TrkB OT - TrkB, tropomyosin receptor kinase B OT - Ucp1, uncoupling protein 1 OT - VMH, ventromedial nucleus of the hypothalamus OT - eWAT, epididymal white adipose tissue EDAT- 2015/12/03 06:00 MHDA- 2015/12/03 06:01 PMCR- 2015/08/18 CRDT- 2015/12/03 06:00 PHST- 2015/07/29 00:00 [received] PHST- 2015/08/10 00:00 [revised] PHST- 2015/08/11 00:00 [accepted] PHST- 2015/12/03 06:00 [entrez] PHST- 2015/12/03 06:00 [pubmed] PHST- 2015/12/03 06:01 [medline] PHST- 2015/08/18 00:00 [pmc-release] AID - S2212-8778(15)00156-8 [pii] AID - 10.1016/j.molmet.2015.08.002 [doi] PST - epublish SO - Mol Metab. 2015 Aug 18;4(11):867-80. doi: 10.1016/j.molmet.2015.08.002. eCollection 2015 Nov.