Ablation of intact hypothalamic and/or hindbrain TrkB signaling leads to perturbations in energy balance

• Published in: Molecular metabolism (Germany) Vol. 4; no. 11; pp. 867 - 880
• Main Authors: Ozek, Ceren, Zimmer, Derek J, De Jonghe, Bart C, Kalb, Robert G, Bence, Kendra K
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.11.2015; Elsevier
• Subjects: BDNF; Endocrinology & Metabolism; Hindbrain; Hypothalamus; Obesity; Original; TrkB; melanocortin 4 receptor; tropomyosin receptor kinase B; PVH; cell death-inducing DFFA-like effector a; GTT; HFD; neuropeptide Y; dorsal vagal complex; HPA axis; Pparγ; brain-derived neurotrophic factor; Agrp; LepR; Obesity; hypothalamic-pituitary-adrenal axis; pro-opiomelanocortin; nucleus of the solitary tract; Nk2 homeobox 1 protein; ventromedial nucleus of the hypothalamus; paraventricular nucleus of the hypothalamus; Cre recombinase; peroxisome proliferator-activated receptor gamma coactivator 1 alpha; uncoupling protein 1; high-fat diet; Cre; peroxisome proliferator-activated receptor gamma; Phox2b; PR domain containing 16; epididymal white adipose tissue; glucose tolerance test; Ucp1; Hypothalamus; paired-like homeobox 2b protein; NTS; Elovl3; Pomc; Npy; elongation of very long fatty acids-like 3; Cidea; Pgc1α; BDNF; leptin receptor; Prdm16; eWAT; Nkx2.1; VMH; DVC; Mc4R; TrkB; brown adipose tissue; BAT; agouti-related peptide; Hindbrain; DVC, dorsal vagal complex; Mc4R, melanocortin 4 receptor; Pomc, pro-opiomelanocortin; HPA axis, hypothalamic-pituitary-adrenal axis; Cre, Cre recombinase; Npy, neuropeptide Y; PVH, paraventricular nucleus of the hypothalamus; HFD, high-fat diet; Phox2b, paired-like homeobox 2b protein; Prdm16, PR domain containing 16; TrkB, tropomyosin receptor kinase B; VMH, ventromedial nucleus of the hypothalamus; GTT, glucose tolerance test; eWAT, epididymal white adipose tissue; BAT, brown adipose tissue; Agrp, agouti-related peptide; Pgc1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; BDNF, brain-derived neurotrophic factor; Pparγ, peroxisome proliferator-activated receptor gamma; NTS, nucleus of the solitary tract; Ucp1, uncoupling protein 1; Elovl3, elongation of very long fatty acids-like 3; Nkx2.1, Nk2 homeobox 1 protein; LepR, leptin receptor; Cidea, cell death-inducing DFFA-like effector a
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2015.08.002

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. 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.