Elsevier

Molecular Metabolism

Volume 4, Issue 11, November 2015, Pages 867-880
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2015.08.002Get rights and content
Under a Creative Commons license
open access

Highlights

  • Hypothalamic TrkB deletion increases body weight and adiposity.

  • Female Nkx2.1-Ntrk2−/− mice have a more robust metabolic phenotype than males.

  • Hindbrain deletion of TrkB results in a perinatal lethal phenotype.

  • Phox2b-Ntrk2+/− heterozygous mice are hyperphagic despite normal body weight.

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.

Keywords

TrkB
BDNF
Hypothalamus
Hindbrain
Obesity

Abbreviations

HFD
high-fat diet
BDNF
brain-derived neurotrophic factor
TrkB
tropomyosin receptor kinase B
VMH
ventromedial nucleus of the hypothalamus
PVH
paraventricular nucleus of the hypothalamus
NTS
nucleus of the solitary tract
DVC
dorsal vagal complex
eWAT
epididymal white adipose tissue
BAT
brown adipose tissue
GTT
glucose tolerance test
HPA axis
hypothalamic-pituitary-adrenal axis
Cre
Cre recombinase
Nkx2.1
Nk2 homeobox 1 protein
Phox2b
paired-like homeobox 2b protein
Pomc
pro-opiomelanocortin
Npy
neuropeptide Y
Agrp
agouti-related peptide
LepR
leptin receptor
Mc4R
melanocortin 4 receptor
Ucp1
uncoupling protein 1
Cidea
cell death-inducing DFFA-like effector a
Elovl3
elongation of very long fatty acids-like 3
Pgc1α
peroxisome proliferator-activated receptor gamma coactivator 1 alpha
Pparγ
peroxisome proliferator-activated receptor gamma
Prdm16
PR domain containing 16

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