Fueling up skeletal muscle to reduce obesity: A TrkB story

Abstract

Targeting TrkB signaling could represent a good therapeutic strategy to prevent obesity. In this issue of Chemistry & Biology, Chan et al. report the efficacy of 7,8-DHT, a TrkB agonist, in preventing obesity in female mice. The underlying molecular mechanisms behind this activity seem to involve increased energy expenditure in skeletal muscle.

Figure 1

Skeletal muscle centric signaling pathways mediating obesity protective effects of TrkB. TrkB agonist, 7,8-DHF, activates AKT and ERK1/2 activation. Activated AKT and ERK1/2 are known to phosphorylate cAMP responsive element binding protein (CREB). Once phosphorylated CREB binds to CRE, transcription of uncoupling protein 1 (UCP1) is induced. Upregulation of mitochondrial UCP1 is associated with thermogenesis and activation of AMPK, an important sensor for maintaining energy homeostasis. Activated AMPK inhibits substrate acetyl coA carboxylase (ACC) by phosphorylation which leads increased lipid oxidation. On the other hand, AKT and AMPK have been implicated in glucose uptake in skeletal muscle. Collectively, activation of signaling network by 7,8-DHF/TrkB markedly increases skeletal muscle centric energy expenditure, which appears to be the molecular mechanisms responsible for reduced obesity.