Discrete TrkB-expressing neurons of the dorsomedial hypothalamus regulate feeding and thermogenesis

Abstract

Mutations in the TrkB neurotrophin receptor lead to profound obesity in humans, and expression of TrkB in the dorsomedial hypothalamus (DMH) is critical for maintaining energy homeostasis. However, the functional implications of TrkB-fexpressing neurons in the DMH (DMHTrkB) on energy expenditure are unclear. Additionally, the neurocircuitry underlying the effect of DMHTrkBneurons on energy homeostasis has not been explored. In this study, we show that activation of DMHTrkBneurons leads to a robust increase in adaptive thermogenesis and energy expenditure without altering heart rate or blood pressure, while silencing DMHTrkBneurons impairs thermogenesis. Furthermore, we reveal neuroanatomically and functionally distinct populations of DMHTrkBneurons that regulate food intake or thermogenesis. Activation of DMHTrkBneurons projecting to the raphe pallidus (RPa) stimulates thermogenesis and increased energy expenditure, whereas DMHTrkBneurons that send collaterals to the paraventricular hypothalamus (PVH) and preoptic area (POA) inhibit feeding. Together, our findings provide evidence that DMHTrkBneuronal activity plays an important role in regulating energy expenditure and delineate distinct neurocircuits that underly the separate effects of DMHTrkBneuronal activity on food intake and thermogenesis.