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

Abstract

ObjectiveBrain-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.MethodsWe 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.ResultsOur 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.ConclusionTaken 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.

Neurotrophic factor control of satiety and body weight

“…As expected, these structures include several hypothalamic nuclei such as ARH, VMH, and PVH 72,85–91 . In addition, some evidence indicates that TrkB neurons in nucleus accumbens and NTS are also involved in regulating energy balance 92,93 .…”

The association between serum brain-derived neurotrophic factor and a cluster of cardiovascular risk factors in adolescents: The CHAMPS-study DK

“…Therefore, serum BDNF level is sensitive to clotting time and storage duration [ 34 , 35 ]. Animal models have shown that high BDNF levels in the hypothalamus seem to have a positive effect on metabolic health, for example on weight control and glucose regulation [ 10 ]. However, in the present study high serum BDNF levels seem to be associated with a higher cardiovascular risk.…”

“…High levels of both BDNF and TrkB have been identified in the hypothalamus, which is a brain region important in appetite- and glucose regulation, weight control, and energy homeostasis [ 7 , 9 ]. A recent study found that the deletion of TrkB (destroying the putative causal chain) in the hypothalamus in mice resulted in increased body weight, adiposity and impaired glucose homeostasis [ 10 ]. It has been hypothesized that BDNF has metabotrophic potential and may have and important role in cardiometabolic homeostasis maintenance [ 11 ]…”

BDNF/TrkB signaling mediates the anorectic action of estradiol in the nucleus tractus solitarius

“…While global knockout of the bdnf gene is lethal [ 13 ], mice heterozygous for BDNF display chronic hyperphagia and age-dependent obesity [ 14 , 15 ], and selective deletion of bdnf in the brain causes a phenotype characterized by hyperphagia and obesity, as well as increased abdominal white adipose tissue, changes that are significantly more pronounced in females [ 16 ]. Similarly, mice with central TrkB gene deletion also have increased body weight, an effect that is significantly more robust in females than in males [ 17 ]. These findings highlight the need for focused examination of the role of BDNF/TrkB receptor signaling in mediating E2's anorectic effects.…”