Role of Hypothalamic Reactive Astrocytes in Diet-Induced Obesity

Abstract

Hypothalamus is a brain region that controls food intake and energy expenditure while sensing signals that convey information about energy status. Within the hypothalamus, molecularly and functionally distinct neurons work in concert under physiological conditions. However, under pathological conditions such as in diet-induced obesity (DIO) model, these neurons show dysfunctional firing patterns and distorted regulation by neurotransmitters and neurohormones. Concurrently, resident glial cells including astrocytes dramatically transform into reactive states. In particular, it has been reported that reactive astrogliosis is observed in the hypothalamus, along with various neuroinflammatory signals. However, how the reactive astrocytes control and modulate DIO by influencing neighboring neurons is not well understood. Recently, new lines of evidence have emerged indicating that these reactive astrocytes directly contribute to the pathology of obesity by synthesizing and tonically releasing the major inhibitory transmitter GABA. The released GABA strongly inhibits the neighboring neurons that control energy expenditure. These surprising findings shed light on the interplay between reactive astrocytes and neighboring neurons in the hypothalamus. This review summarizes recent discoveries related to the functions of hypothalamic reactive astrocytes in obesity and raises new potential therapeutic targets against obesity.

Unaltered Tonic Inhibition in the Arcuate Nucleus of Diet-induced Obese Mice

“…1C ). As reported previously [ 12 - 15 ], the intensity of GFAP was significantly increased in HFD mice ( Fig. 1D ).…”

“…Astrocytes in the ARC participate in brain energy metabolism by controlling glycogen storage, sensing glucose, and supplying fuel to neurons under physiological conditions [ 8 - 11 ]. When mice are challenged by chronic high-fat diet (HFD) feeding, reactive astrocytes are observed in the ARC [ 12 - 15 ]. However, the pathophysiological role of reactive astrocytes in maintaining homeostasis in the ARC remains to be elucidated.…”

The role of hypothalamic endoplasmic reticulum stress in schizophrenia and antipsychotic-induced weight gain: A narrative review

“…Pharmacological deletion of astrocytes and microglia or reducing their capability for activating inflammation in the hypothalamus reduces food intake and weight gain and enhances leptin signaling in HFD-fed rodents (Valdearcos et al, 2019;Varela et al, 2021). Reactive astrocytes and microglia activate inflammatory signals such as inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ)/nuclear factor κB (NF-κB) signaling and produce inflammatory cytokines during HFD feeding (Valdearcos et al, 2019;Sa et al, 2022). Moreover, hypothalamic astrocytes reduce ghrelininduced food intake by affecting AgRP neurons (Yang L. et al, 2015).…”

Special Issues on Neurobiology: From Gene, Network to Behavior

“…The recent advent of organoid biology started with a shift from 3-D culture, allowing us to better understand brain development and function, together with providing novel models of human brain diseases, high-throughput screening of drug discovery platforms, and supply of surrogate sources of transplantation, as briefly discussed in this review article. Sa et al (2022) discussed a new research avenue for non-neuronal glial cells, particularly astrocytes in the hypothalamus. The hypothalamus is responsible for coordinating many physiological processes and behaviors, together with neuroendocrine functions, by linking the nervous and endocrine systems via the pituitary gland.…”

“… Sa et al (2022) discussed a new research avenue for non-neuronal glial cells, particularly astrocytes in the hypothalamus. The hypothalamus is responsible for coordinating many physiological processes and behaviors, together with neuroendocrine functions, by linking the nervous and endocrine systems via the pituitary gland.…”