Brain-derived neurotrophic factor (
BDNF) and its receptor,
tropomyosin receptor
kinase B (TrkB), are implicit in causing
obesity. Mutations that reduce
BDNF and TrkB expression are associated with
obesity in humans and mice. Recently, it was reported that
Bdnf gene deletion in the neurons of the paraventricular hypothalamus (PVH) caused positive energy balance and
severe obesity in the form of
hyperphagia, impaired adaptive thermogenesis, and decreased energy expenditure. Thus, we hypothesize that activation of these neurons will have the opposite effect and provide an opportunity for long-lasting
obesity treatment. To specifically activate
BDNF-expressing PVH (PVHBDNF) neurons, we injected Cre-dependent adeno-associated virus (AAV) expressing the excitatory DREADD hM3Dq bilaterally into the PVH of Bdnf2A-Cre/+ knock-in mice and then administered
clozapine-N-oxide (CNO). Using this technique, we demonstrated that acute activation of these neurons rapidly decreased normal nocturnal feeding and fasting-induced feeding in male and female mice. At thermoneutral temperatures, acute activation also rapidly increased adaptive thermogenesis, increased core body temperature, increased locomotion, increased energy expenditure, and decreased respiratory exchange ratio (RER) in male and female mice. These observations indicate that acute stimulation of PVHBDNF neurons promotes negative energy balance and
weight loss. However, the rapid decrease in RER after activation of PVHBDNF neurons was followed by a delayed and prolonged increase in RER that remained elevated for 3 d in female mice. Thus, although acute activation of PVHBDNF neurons promotes negative energy balance in the short term, long-term effects of activation include sexually dimorphic overcompensatory mechanisms that may promote positive energy balance in female mice.