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Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism

ABSTRACT: Agouti-related peptide (AgRP)- and proopiomelanocortin (POMC)-expressing neurons reciprocally regulate food intake. Here, we combined non-interacting recombinases to simultaneously express functionally opposing chemogenetic receptors in AgRP and POMC neurons allowing to compare metabolic responses in mice with simultaneous activation of AgRP and inhibition of POMC neurons with isolated activation of AgRP neurons or isolated inhibition of POMC neurons. These experiments revealed that food intake is regulated by the additive effect of AgRP-neuron activation and POMC-neuron inhibition, while systemic insulin sensitivity and gluconeogenesis are differentially modulated by isolated versus simultaneous regulation of AgRP and POMC neurons. We identified a neurocircuit engaging Npy1R-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH), where activated AgRP- and inhibited POMC neurons synergize to promote food consumption and activate neurons in the nucleus tractus solitarii (NTS). We then performed single-nuclei RNA sequencing to define the molecular nature of Fos+ cells in the posterior NTS/AP area that respond to simultaneous chemogenetic intervention over AgRP and POMC neurons and identified TH+ neurons as candidates for receiving neuronal inputs initiated by the simultaneous and coordinated interplay between AgRP and POMC neurocircuits and relayed to the NTS area by the silenced glutamatergic Npy1R neurons.

ORGANISM(S): Mus musculus

PROVIDER: GSE248391 | GEO | 2024/02/12

REPOSITORIES: GEO

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Dopamine-inhibited POMCDrd2+ neurons in the ARC acutely regulate feeding and body temperature

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2022-11-08 | GSE210311 | GEO

Identification of AgRP cells in the murine hindbrain that drive feeding [scRNA-seq]

Project description:Objective: The central melanocortin system is essential for the regulation of food intake and body weight. Agouti-related protein (AgRP) is the sole orexigenic component of the central melanocortin system and is conserved across mammalian species. AgRP is currently known to be expressed exclusively in the mediobasal hypothalamus, and hypothalamic AgRP-expressing neurons are essential for feeding. Here we characterized a previously unknown population of AgRP cells in the mouse hindbrain. Methods: Expression of AgRP in the hindbrain was investigated using gene expression analysis, single-cell RNA sequencing, immunofluorescent analysis and multiple transgenic mice with reporter expressions. Activation of AgRP neurons was achieved by Designer Receptors Exclusively Activated by Designer Drugs (DREADD) and by transcranial focal photo-stimulation using a step-function opsin with ultra-high light sensitivity (SOUL). Results: AgRP expressing cells were present in the area postrema (AP) and the adjacent subpostrema area (SubP) and commissural nucleus of the solitary tract (cNTS) of the mouse hindbrain (termed AgRPHind herein). AgRPHind cells consisted of locally projecting neurons as well as tanycyte-like cells. Food deprivation stimulated hindbrain Agrp expression as well as neuronal activity of subsets of AgRPHind cells. In adult mice that lacked hypothalamic AgRP neurons, chemogenetic activation of AgRP neurons resulted in hyperphagia and weight gain. In addition, transcranial focal photo-stimulation of hindbrain AgRP cells increased food intake in adult mice with or without hypothalamic AgRP neurons. Conclusions: Our study indicates that the central melanocortin system in the hindbrain possesses an orexigenic component, and that AgRPHind neurons stimulate feeding independently of hypothalamic AgRP neurons.

2024-01-23 | GSE204865 | GEO

FoxO1 target Gpr17 activates AgRP neurons to regulate food intake.

Project description:Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity. We used microarrays to detail the change of gene expression in AgRP neurons after knocking out FoxO1. AgRP neurons from control and KO mice were collected by FACS. Gene expression was analyzed by microarray.

2013-04-09 | E-GEOD-45858 | biostudies-arrayexpress

Antagonistic modulation of NPY/AgRP and POMC neurons in the arcuate nucleus by noradrenaline

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2017-10-26 | GSE106188 | GEO

Comparative transcriptomic analyses of developing melanocortin neurons reveal new regulators for the anorexigenic neuron identity

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2020-03-12 | GSE146816 | GEO

FoxO1 target Gpr17 activates AgRP neurons to regulate food intake.

2013-04-09 | GSE45858 | GEO

Glycogen Metabolism Drives Sensory Activation of Pomc Neurons

Project description:In this study, we aimed at uncovering the molecular mechanisms underlying POMC neuron sensory activation and the mediated behavioral and metabolic processes. Unexpectedly, we found that glycogen metabolism is rapidly engaged in POMC neurons upon sensory food perception. Genetic deletion of glycogen synthase, the sole enzyme able to make glycogen in vivo, in POMC neurons impedes food-related sensory activation while causing impairments in food awareness, short-term food intake and insulin release. These perturbations associate with whole-body metabolic defects, including overweight and insulin resistance, that are exacerbated by high-dense diets or ageing. Collectively, our study identifies glycogen metabolism as an unanticipated mechanistic driver of POMC neuron sensory activation and provides paradigm-shift evidences of the importance of neuronal glycogen for physiology.

2024-01-31 | GSE224274 | GEO

Hypothalamic and dorsal vagal glucose-dependent insulinotropic polypeptide receptor (GIPR) neurons employ distinct mechanisms to affect feeding

Project description:Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signalling is critical for GIP-based therapeutics to lower body weight, but pathways leveraged by GIPR agonism pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC)—brain regions critical to the control of energy balance. Hypothalamic expression of Gipr expression was not necessary for the synergistic effect of GIPR/ agonism combined with GLP-1R co-agonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (SAGIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to the parabrachial nucleus and paraventricular hypothalamic nucleusdistal brain regions. ScRNAseq and FISH analysis showed that Gipr neurons in the NTS and AP Gipr neurons were transcriptomically distinct. Peripherally-dosed fluorescent GIPR agonists (GIPRAs) revealed that GIPRA access was restricted to circumventricular organs in the CNS. Together tThese data demonstrate that while the hypothalamus, AP and NTS are key sites for Gipr expression, these subpopulations of Gipr neurons in the hypothalamus, AP and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility to peripherally administered GIPRAs, and the appetite controlling pathways they employ. These results highlight the heterogeneity of the central GIPR signalling axis, and suggest that studies aimed at understandinginto the effects of GIP pharmacology on feeding behaviour should consider the interplay of multiple regulatory pathways.

2023-04-07 | GSE228192 | GEO

Liver phosphoproteomics in response to AgRP activated neurons in the presence/absence of NPY

Project description:Autophagy represents a key regulator of aging and metabolism upon cell autonomous sensing of energy deprivation. We find that fasting in mice activates autophagy in liver paralleled by activation of hypothalamic AgRP neurons. Optogenetic and chemogenetic activation of AgRP neurons induces autophagy, alters phosphorylation of autophagy regulators and promotes ß-oxidation in the liver. AgRP neuron dependent induction of liver autophagy relies on NPY expression in these neurons. AgRP neuron projections in the paraventricular nucleus of the hypothalamus (PVH) and the lateral hypothalamus (LHA) mediate AgRP neuron-dependent control of liver autophagy. Conversely, inhibiting AgRP neurons during energy deprivation abrogates induction of hepatic autophagy and re-wiring of metabolism. Finally, AgRP neuron activation increases circulating corticosterone concentrations, and reduction of hepatic glucocorticoid receptor expression attenuates AgRP neuron-dependent activation of hepatic autophagy. Collectively, our study reveals a fundamental regulatory principle of non-cell autonomous control of liver autophagy in control of metabolic adaptation during nutrient deprivation.

2023-04-18 | PXD029247 | Pride

Sensory Food Perception Rapidly Primes Postprandial ER-Homeostasis through Melanorcortin-Dependent Control of Liver mTOR Activation

Project description:Adaptation of liver to the postprandial state requires coordinate regulation of protein synthesis and folding aligned with changes in lipid metabolism. Here we demonstrate that sensory food perception is sufficient to elicit early activation of hepatic mTOR-signaling, Xbp1-splicing, increased expression of ER-stress genes and phosphatidylcholine synthesis, which translate into a rapid morphological ER-remodeling. These responses overlap with those activated during refeeding, where they are maintained and constantly increase upon nutrient supply. Sensory food perception activates POMC-neurons in the hypothalamus, optogenetic activation of POMC-neurons activates hepatic mTOR-signaling and Xbp1-splicing and lack of MC4R-expression attenuates these responses to sensory food perception. Chemogenetic POMC-neuron activation promotes sympathetic nerve activity (SNA) subserving the liver, and norepinephrine evokes the same responses in hepatocytes in vitro and liver in vivo as observed upon sensory food perception. Collectively, our experiments unravel that sensory food perception coordinatly primes postprandrial liver ER adaption through a melanocortin-SNA-mTOR-Xbp1s-axis

2018-10-31 | GSE118973 | GEO

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