Hunger-promoting AgRP neurons trigger an astrocyte-mediated feed-forward autoactivation loop in mice
Luis Varela, … , Xiao-Bing Gao, Tamas L. Horvath
Luis Varela, … , Xiao-Bing Gao, Tamas L. Horvath
Published April 13, 2021
Citation Information: J Clin Invest. 2021;131(10):e144239. https://doi.org/10.1172/JCI144239.
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Research Article Neuroscience

Hunger-promoting AgRP neurons trigger an astrocyte-mediated feed-forward autoactivation loop in mice

Abstract

Hypothalamic feeding circuits have been identified as having innate synaptic plasticity, mediating adaption to the changing metabolic milieu by controlling responses to feeding and obesity. However, less is known about the regulatory principles underlying the dynamic changes in agouti-related protein (AgRP) perikarya, a region crucial for gating of neural excitation and, hence, feeding. Here we show that AgRP neurons activated by food deprivation, ghrelin administration, or chemogenetics decreased their own inhibitory tone while triggering mitochondrial adaptations in neighboring astrocytes. We found that it was the inhibitory neurotransmitter GABA released by AgRP neurons that evoked this astrocytic response; this in turn resulted in increased glial ensheetment of AgRP perikarya by glial processes and increased excitability of AgRP neurons. We also identified astrocyte-derived prostaglandin E2, which directly activated — via EP2 receptors — AgRP neurons. Taken together, these observations unmasked a feed-forward, self-exciting loop in AgRP neuronal control mediated by astrocytes, a mechanism directly relevant for hunger, feeding, and overfeeding.

Authors

Luis Varela, Bernardo Stutz, Jae Eun Song, Jae Geun Kim, Zhong-Wu Liu, Xiao-Bing Gao, Tamas L. Horvath

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Figure 2

Ghrelin promotes changes in astrocytes and glial coverage on AgRP neurons.

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Ghrelin promotes changes in astrocytes and glial coverage on AgRP neuron...
(A) GFAP levels (representative Western blot images and quantification) from MBH of saline- and ghrelin-treated mice (n = 5/5). (B) Representative electron micrographs of mitochondria profiles in Arc astrocytes from saline- and ghrelin-treated mice (scale bars: 500 nm). (C) Mitochondrial density in Arc astrocytes of saline- and ghrelin-treated mice (n = 18/20 cells from 4 mice per group). (D) Cumulative distribution and mean of mitochondrial area in Arc astrocytes of saline- and ghrelin-treated mice (n = 164/199 mitochondria). (E) Glial coverage on AgRP cells of saline- and ghrelin-treated mice (n = 8/15). (F) Inhibitory synapses onto AgRP neurons of saline- and ghrelin-treated mice (n = 15/15). (G) Representative electron micrographs showing glial coverage on AgRP neurons from saline- and ghrelin-treated mice. Red traces indicate presence of glial coverage on cell perikarya (scale bars: 2 μm). (H) Mitochondrial density in NPY cells of saline- and ghrelin-treated mice (n = 16/17 cells). (I) Cumulative distribution and mean of mitochondrial area in NPY neurons of saline- and ghrelin-treated mice (n = 463/370 mitochondria). (J) Representative electron micrographs of mitochondria profiles in NPY neurons from saline- and ghrelin-treated mice (scale bars: 500 nm). Data are presented as mean ± SEM. *P ≤ 0.05 and ***P ≤ 0.001 as determined by 2-tailed t test or Kolmogorov-Smirnov test for analyses of cumulative distribution.