Rapid and Lasting Effects of Activating BDNF-Expressing PVH Neurons on Energy Balance

Abstract

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 (PVH BDNF ) neurons, we injected Cre-dependent adeno-associated virus (AAV) expressing the excitatory DREADD hM3Dq bilaterally into the PVH of Bdnf 2A-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 PVH BDNF neurons promotes negative energy balance and weight loss. However, the rapid decrease in RER after activation of PVH BDNF 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 PVH BDNF 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.

Function of brain-derived neurotrophic factor in the hypothalamus: Implications for depression pathology

“…As expected, viral overexpression of BDNF in the PVH decreases body weight in male rats ( Erdos et al, 2015 ). Activation of BDNF-expressing neurons of the PVH using a chemogenetic approach leads to suppressed food intake in male and female mice in both a fed and fasted state ( Wu and Xu, 2022 ). The same manipulation also raises respiratory exchange ratio (RER), and oxygen consumption in both sexes ( Wu and Xu, 2022 ).…”

“…On the other hand, viral overexpression of BDNF in the PVH in male rats increases locomotor activity ( Erdos et al, 2015 ). Chemogenetic activation of BDNF-expressing neurons in the PVH also leads to increased locomotion in both male and female mice ( Wu and Xu, 2022 ). Altogether, these data show BDNF signaling in the hypothalamus plays a critical sex- and stress-dependent role in the coordination of satiety and body weight maintenance in part by increasing psychomotor activity.…”

“…This effect was rescued by infusion of a TrkB agonist into the lateral hypothalamus ( You et al, 2020 ). Stimulation of PVH BDNF neurons leads to increased core body temperature and brown adipose tissue thermogenesis ( Wu and Xu, 2022 ). Neurons responsible for warm sensing in the MPOA express BDNF and pituitary adenylate cyclase-activating polypeptide (PACAP) and translating ribosome affinity-purification from each population demonstrates that these peptides are co-expressed in a subset of MPOA neurons ( Tan et al, 2016 ).…”

Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling

“…Deleting Bdnf from the PVH results in obesity due to increased food intake, reduced energy expenditure, and reduced locomotion (An et al ., 2015). While PVH neuronal activity is reduced during feeding (Xu et al , 2019), activation of PVH BDNF neurons results in weight loss (Wu & Xu, 2022). We recently found that RAI1 promotes Bdnf expression in the hypothalamus throughout life (Javed et al , 2021).…”

A Subcortical Feeding Circuit Linking Interoception to Jaw movement

“…l, Quantification of food intake of GtACR (n=6) and control mice (n=6). m, Comparison of the latency to approach the chow pellet in open and closed inhibition for GtACR mice 72…”