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GFRAL-expressing Neurons Suppress Food Intake via Aversive Pathways

ABSTRACT: The TGFβ cytokine family member, GDF15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brain stem-restricted expression pattern of its receptor, GDNF Family Receptor α–like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake, we generated GfralCre and conditional GfralCreERT mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating GfralCre-expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated, pathophysiologic signals to suppress nutrient uptake and absorption.

ORGANISM(S): Mus musculus

PROVIDER: GSE160257 | GEO | 2021/01/01

REPOSITORIES: GEO

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GFRAL-expressing Neurons Suppress Food Intake via Aversive Pathways

Project description:GFRAL-expressing Neurons Suppress Food Intake via Aversive Pathways

| PRJNA672712 | ENA

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

BI 456906: a dual glucagon-like peptide-1/glucagon agonist promoting bodyweight reduction

Project description:Glucagon and glucagon-like peptide-1 (GLP-1) are hormones involved in energy homeostasis. GLP-1 receptor (GLP-1R) agonism reduces food intake and delays gastric emptying, and glucagon receptor (GCGR) agonism increases energy expenditure by thermogenesis. BI 456906 is a subcutaneous, once-weekly injectable dual GLP-1R/GCGR agonist in development for the treatment of obesity or non-alcoholic steatohepatitis. Here we show that BI 456906 is a potent dual agonist with an extended half-life in human plasma. Key GLP-1R-mediated mechanisms of reduced food intake, delayed gastric emptying and improved glucose tolerance were confirmed in GLP-1R knockout mice. GCGR activity was confirmed by reduced plasma amino acids, increased hepatic expression of nicotinamide N-methyltransferase and increased energy expenditure. BI 456906 produced greater bodyweight reductions than maximally efficacious semaglutide doses and modulated gene expression, including genes involved in amino acid metabolism. BI 456906 is a potent dual agonist that produces bodyweight-lowering effects through both GLP-1R and GCGR agonism.

2022-12-09 | GSE211105 | GEO

Transcriptomic changes in the duodenum mucosa after a high-fat (HF) or low-fat (LF) meal ingestion.

Project description:Fat intake is an important determinant in the development of obesity. The small intestine is the principal site of digestion and absorption of nutrients, and these short-term circulating nutrients and hormones as well as neural signals derived from the peripheral tissues in responses to a meal act at multiple central nervous system sites where food intake is controlled. In order to identify the HF-specific peripheral signals that can be therapeutic targets of obesity, we investigated transcriptomic changes in the duodenum mucosa after a HF or LF meal ingestion.

2017-11-26 | GSE59453 | 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

Activation of GFRAL+ Neurons Induces Hypothermia and Glucoregulatory Responses Associated with Nausea and Torpor

Project description:GFRAL-expressing neurons actuate aversion and nausea, are targets for obesity treatment and may mediate metformin effects by long-term GDF15-GFRAL agonism. If GFRAL+ neurons acutely regulate glucose and energy homeostasis is however underexplored. Here, we report that cell-specific activation of GFRAL+ neurons using a variety of techniques causes a torpor-like state, including hypothermia, the release of stress hormones, a shift from glucose to lipid oxidation, and impaired insulin sensitivity, glucose tolerance and skeletal muscle glucose uptake but augmented glucose uptake in visceral fat. Metabolomic analysis of blood and transcriptomics of muscle and fat indicate alterations in ketogenesis, insulin signaling, adipose tissue differentiation and mitogenesis, or energy fluxes. Our findings reveal that acute GFRAL+ neuron activation induces endocrine and gluco- and thermoregulatory responses associated with nausea and torpor. While chronic activation of GFRAL signaling promotes weight loss in obesity, these results show that acute activation of GFRAL+ neurons causes hypothermia and hyperglycemia.

2024-03-21 | GSE255540 | 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

Modulation of the post meal PBMC transcriptomic response of shift workers after four weeks of a dietary intervention implementing a dedicated overnight fast

Project description:In a cross-over randomised controlled trial,19-night shift workers with abdominal obesity, completed two diet conditions separated by a two week wash out period; a) the control period = four weeks of habitual eating overnight and b) the intervention period = four weeks of avoiding food intake between 1 AM – 6 AM. At the end of each intervention period participants were given a high fat/high carbohydrate challenge meal in the morning and peripheral blood mononuclear cells were isolated from whole bood sampled at fasting, 2 and 4 hours after eating the meal.

2024-02-16 | GSE225493 | GEO

FoxO1 target Gpr17 activates AgRP neurons to regulate food intake.

2013-04-09 | GSE45858 | GEO

Molecular profiling of dorsal raphe nucleus Vgat and VGLUT3-expressing neurons

Project description:Hunger, driven by negative energy balance, elicits the search for and consumption of food. In mammals, this is orchestrated principally through the activity of neurons in the hypothalamus, direct manipulation of which can potently drive food intake. However, the neural circuits outside of the hypothalamus that control feeding are poorly understood. Here, we identify two functionally opponent cell types within the dorsal raphe nucleus (DRN), marked by the vesicular transporters for GABA (Vgat) or glutamate (VGLUT3), that project to many known feeding centers and rapidly control feeding. We find that DRNVgat neurons drive, while DRNVGLUT3 neurons suppress, food intake. Furthermore, through the development and application of cell type-specific molecular profiling technologies, we identify many differentially expressed transmembrane receptors, which may represent unique druggable targets. Local application of agonists for these receptors potently modulates feeding, recapitulating the effects of cell-specific manipulations. Together, these data establish a key role for the DRN in controlling food intake and add an important anatomic site that controls energy balance.

2017-06-09 | GSE87890 | GEO

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