Analysis of Medicine:The role of specific neural circuits in the regulation of food intake by external stimuli

Image by AI

Tanycytes are specialized cells located in the wall of the third ventricle that form a cellular interface between the brain parenchyma and the ventricular system. Benevento et al. investigates the role of tanycytes in the regulation of food intake and energy balance in response to temperature changes. The research demonstrates that tanycytes are activated by acute thermal challenge and are necessary to reduce food intake afterwards. This activation is mediated by thermosensing glutamatergic neurons of the parabrachial nucleus, which directly innervate tanycytes. The study further reveals that tanycytes produce vascular endothelial growth factor A (VEGFA) in response to heat and chemical genetic activation of glutamatergic parabrachial neurons. VEGFA is released along the basal processes of tanycytes and acts on adjacent orexigenic neurons in the arcuate nucleus to reduce their excitability and food intake.

These findings provide new insights into the neural mechanisms underlying the integration of sensory information into metabolic responses. By linking temperature sensing in the parabrachial nucleus to the regulation of appetite in the hypothalamus, this study identifies tanycytes as a critical node in a multimodal neurocircuit that integrates sensory information into metabolic changes. This circuit enables the body to respond to brief thermal challenges by prioritizing metabolic needs.

Further research is needed to fully understand the molecular mechanisms underlying the activation of tanycytes and the release of VEGFA. However, these findings have potential implications for the treatment of obesity and metabolic disorders, as well as for understanding and managing thermal stress-related conditions. By manipulating the tanycyte-parabrachial circuit, it may be possible to develop new strategies for promoting healthy eating habits and metabolic balance.

In addition to heat stress, a previous study conducted by Osterhout et al. also found that inflammation can lead to reduced appetite. This study presents a comprehensive investigation into the neural circuitry involved in generating fever and coordinating sickness behaviors in mammals during infection. The authors identified a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) that are activated in response to inflammation, specifically after administration of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly(I:C)) mimicking infection. These VMPO neurons (VMPO^LPS) are distinct from previously identified warm-sensitive neurons in the anteroventral periventricular nucleus (AVPe) and median preoptic nucleus (MnPO), and their activation was found to be essential for generating fever and coordinating sickness symptoms.

The activation of VMPO^LPS neurons is triggered by immune signals released by non-neuronal cells near the blood-brain barrier, such as endothelial cells, astrocytes, and microglia. These cells secrete interleukin-1β (IL-1β), prostaglandin E2 (PGE2), and chemokine ligand 2 (CCL2) in response to infection, which directly increase the excitability of VMPO^LPS neurons and enhance excitatory synaptic inputs to them.

Upon activation, VMPO^LPS neurons generate fever by inhibiting warm-sensitive neurons in the AVPe/MnPO area through direct inhibitory synaptic connections. This inhibition leads to reduced behavioral and autonomic thermoregulation, thereby increasing body temperature. Additionally, VMPO^LPS neurons exert an indirect influence on body temperature by exciting neurons in the dorsal medial hypothalamus (DMH) that are involved in thermoregulation and metabolism.

Furthermore, VMPO^LPS neurons suppress appetite by inhibiting hunger neurons (Arcuate AgRP neurons) and indirectly exciting appetite-suppressing neurons (Arcuate CART neurons) through synaptic connections. This dual mechanism contributes to the reduced food intake observed during inflammation.

Osterhout et al. propose that VMPO^LPS neurons serve as a control hub that integrates immune signals to orchestrate multiple sickness symptoms in response to infection. Their activation leads to changes in brain activity that elicit fever, warmth seeking, and appetite suppression. The study's findings provide valuable insights into the neural circuitry underlying the response to infection and inflammation in mammals, shedding light on the complex interplay between the immune system, nervous system and metabolic responses.

References:

1. Benevento M, Alpár A, Gundacker A, Afjehi L, Balueva K, Hevesi Z, Hanics J, Rehman S, Pollak DD, Lubec G, Wulff P, Prevot V, Horvath TL, Harkany T. A brainstem-hypothalamus neuronal circuit reduces feeding upon heat exposure. Nature. 2024 Mar 27.

2. Osterhout JA, Kapoor V, Eichhorn SW, Vaughn E, Moore JD, Liu D, Lee D, DeNardo LA, Luo L, Zhuang X, Dulac C. A preoptic neuronal population controls fever and appetite during sickness. Nature. 2022 Jun;606(7916):937-944.