Key result
Hypothalamic TrkB deficiency increases body weight, adiposity, and hyperphagia in mice, particularly in females.
Why the study?
Does ablation of hypothalamic or hindbrain TrkB signaling alter energy balance and metabolic parameters in mice?
Does ablation of hypothalamic or hindbrain TrkB signaling alter energy balance and metabolic parameters in mice?
Hypothalamic TrkB signaling is critical for central metabolic control, with its ablation leading to increased body weight, adiposity, and altered glucose homeostasis, particularly in females.
Supports hypothalamic TrkB in energy homeostasis; hypothesis-generating for human obesity therapies.
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.
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Ozek et al. (2015) studied Energy balance and obesity. Ablation of hypothalamic and/or hindbrain TrkB signaling vs. Wild type littermate controls was evaluated on Metabolic parameters including body weight, adiposity, food intake, energy expenditure and glucose homeostasis. Hypothalamic TrkB deficiency in mice led to significantly increased body weight, adiposity, and hyperphagia, with female mice exhibiting a more robust metabolic phenotype.
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