Regulation of food intake by astrocytes in the brainstem dorsal vagal complex

Abstract

Short title: Brainstem astrocytes regulate feeding 12 Keywords: astrocyte, feeding, chemogenetic, nucleus of the solitary tract, metabolism 13 Declaration of conflict of interest: none 14 15Food intake is controlled by the coordinated action of numerous brain regions but a complete 16 understanding remains elusive 1 . Of these brain regions the brainstem dorsal vagal complex (DVC) is 17 the first site for integration of visceral synaptic and hormonal cues that act to inhibit food intake 2 . 18The DVC consists of three nuclei: the nucleus of the solitary tract (NTS), area postrema (AP) and 19 dorsal motor nucleus of the vagus (DMX). Targeted chemogenetic activation of appetite-responsive 20 NTS neuronal populations causes short term decreases in food intake [3][4][5][6][7] . Astrocytes are a class of 21 glial cell which provide metabolic and structural support to neurons and play an active role in 22 modulating neurotransmission. Within the hypothalamic arcuate nucleus (ARC) astrocytes are 23 regulated by both positive and negative energy balance and express receptors for hormones that 24 influence satiety and hunger [8][9][10][11] . Chemogenetic activation of these ARC astrocytes alters food 25 intake [11][12][13] . Since NTS astrocytes respond to vagal stimulation 14 , we hypothesised that they may be 26 involved in mediating satiety. Here we show that NTS astrocytes show plastic alterations in 27 morphology following excess food consumption and that chemogenetic activation of DVC astrocytes 28 causes a decrease in food intake, by recruiting an appetite-inhibiting circuit, without producing 29 aversion. These findings are the first using genetically-targeted manipulation of DVC astrocytes to 30 demonstrate their role in the brain's regulation of food intake. 31In order to examine whether NTS astrocytes respond to changes in energy status we induced short-32 term positive energy balance by allowing mice to exclusively eat a high-fat chow for 12 hours during 33 the dark-phase. This paradigm induced a feeding binge when compared with standard chow-fed 34 mice ( Fig. 1a). High-fat fed mice had a greater number of glial fibrillary acidic protein (GFAP)-35 immunoreactive astrocytes within the NTS when compared with controls, with the changes being 36 most pronounced in the NTS at the level of the AP ( Fig. 1c-e). GFAP-immunoreactive astrocytes in 37 the NTS adjacent to the AP of high-fat fed mice had greater morphological complexity, as assessed 38 by Sholl analysis 15,16 , and a greater number of processes than those of standard chow fed controls 39 ( Fig. 1f,g). These findings suggest that NTS astrocytes show dynamic reactive changes to the acute 40 nutritional excess caused by consumption of a high-fat diet. 41It is established that Gq-coupled designer receptors exclusively activated by designer drugs 42 (DREADDs) can be used to selectively activate astrocytes by driving increases in intracellular Ca 2+ , the 43 main signalling modality of these cells 11,[17][18][19] . We bilaterally injected the DVC of mice with ...

Manipulating mitochondrial dynamics in the NTS prevents diet-induced deficits in brown fat morphology and glucose uptake

“…Astrocytes are important for sensing metabolic changes [38]. In the DVC, they can proliferate and become reactive in response to HFD-feeding and can directly alter feeding behaviour when chemo-genetically activated [39]. In the hypothalamus, short-term HFD-feeding altered astrocyte number, density, and activity [37] and ablation of insulin receptors in astrocytes affected glial morphology and mitochondrial function leading to POMC neuronal activation [40].…”