title: Ablation of intact hypothalamic and/or hindbrain TrkB signaling leads to perturbations in energy balance.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Ceren
authors.initials: C
authors.lastname: Ozek
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Zimmer
authors.affiliation: Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Bart C
authors.initials: BC
authors.lastname: De Jonghe
authors.affiliation: Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kalb
authors.affiliation: Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Kendra K
authors.initials: KK
authors.lastname: Bence
keywords: Agrp, agouti-related peptide; BAT, brown adipose tissue; BDNF; BDNF, brain-derived neurotrophic factor; Cidea, cell death-inducing DFFA-like effector a; Cre, Cre recombinase; DVC, dorsal vagal complex; Elovl3, elongation of very long fatty acids-like 3; GTT, glucose tolerance test; HFD, high-fat diet; HPA axis, hypothalamic-pituitary-adrenal axis; Hindbrain; Hypothalamus; LepR, leptin receptor; Mc4R, melanocortin 4 receptor; NTS, nucleus of the solitary tract; Nkx2.1, Nk2 homeobox 1 protein; Npy, neuropeptide Y; Obesity; PVH, paraventricular nucleus of the hypothalamus; Pgc1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; Phox2b, paired-like homeobox 2b protein; Pomc, pro-opiomelanocortin; Pparγ, peroxisome proliferator-activated receptor gamma; Prdm16, PR domain containing 16; TrkB; TrkB, tropomyosin receptor kinase B; Ucp1, uncoupling protein 1; VMH, ventromedial nucleus of the hypothalamus; eWAT, epididymal white adipose tissue