Role of the central nervous system and adipose tissue BDNF/TrkB axes in metabolic regulation

Abstract

Brain-derived neurotrophic factor (BDNF) and its receptor (tropomyosin-related kinase B: TrkB, also known as Ntrk2) have a key role in central regulation of the energy balance. BDNF and TrkB are also expressed in the peripheral tissues, including adipose tissue, but their peripheral role has been unclear. Here we report on the functional significance of the adipose tissue BDNF/TrkB axis in metabolic homeostasis. To examine the role of the BDNF/TrkB axis in the central nervous system and in adipose tissue, we generated adipocyte-specific or neuron-specific BDNF/TrkB conditional knockout (CKO) mice. Then we compared the feeding behavior and metabolic profile between each type of CKO mouse and their littermates. Bdnf expression was significantly increased in the adipose tissue of mice receiving a high-calorie diet, whereas Ntrk2 expression was decreased. The Bdnf/Ntrk2 expression ratio of adipose tissue was higher in female mice than male mice. Fabp4-Cre mice are widely used to establish adipocyte-specific CKO mice. However, we found that Fabp4-Cre-induced deletion of Bdnf or Ntrk2 led to hyperphagia, obesity, and aggressiveness, presumably due to ectopic Fabp4-Cre mediated gene recombination in the brain. Next, we attempted to more specifically delete Bdnf or Ntrk2 in adipocytes using Adipoq-Cre mice. Expression of Ntrk2, but not Bdnf, in the adipose tissue was reduced by Adipoq-Cre mediated gene recombination, indicating that adipocytes only expressed TrkB. No phenotypic changes were detected when Adipoq-Cre TrkB CKO mice were fed a normal diet, whereas female CKO mice receiving a high-calorie diet showed a decrease in food intake and resistance to obesity. The adipose tissue BDNF/TrkB axis has a substantial influence on the feeding behavior and obesity in female mice. A signaling pathway that inhibits appetite in the brain plays an opposite role in fat tissue, with a particularly strong effect in females. Within the brain, the interaction between brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB) promotes weight loss and reduced eating. Researchers led by Tohru Minamino at Niigata University in Japan have demonstrated that these proteins exhibit a different activity in fat. Whereas mice lacking BDNF or TrkB in the brain were prone to overeating and obesity, these traits were absent when this pathway was disrupted in fat. Intriguingly, female mice lacking TrkB in their fat cells proved less prone to obesity when fed a high-fat diet, while little change was seen in males. This may result from interactions with estrogen signaling, and the researchers see a potential target for treating female obesity.