GFRAL-expressing Neurons Suppress Food Intake via Aversive Pathways
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA672712 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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.
2021-01-01 | GSE160257 | GEO
Project description: Not available
| S-EPMC7923658 | biostudies-literature
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
Project description:Ambiguity regarding the role of glucose-dependent insulinotropic polypeptide (GIP) in obesity arises from conflicting reports asserting that both GIP receptor (GIPR) agonism and antagonism are effective strategies for inhibiting weight gain. To enable identification and manipulation of Gipr-expressing (Gipr) cells we created GIPR-Cre knock-in mice. As GIPR-agonists have recently been reported to suppress food intake we aimed to identify central mediators of this effect. Gipr cells were identified in the arcuate, dorsomedial, and paraventricular nuclei of the hypothalamus, as confirmed by RNAscope in mouse and human. Single cell RNAseq identified clusters of hypothalamic Gipr cells exhibiting transcriptomic signatures for mural, glial and neuronal cells, the latter expressing somatostatin, but little proopiomelanocortin or agouti-related peptide. Activation of Gq-DREADDs in hypothalamic Gipr cells suppressed food intake in vivo, which was not obviously additive with concomitant GLP1R activation. These data identify hypothalamic GIPR as a target for the regulation of energy balance.
2019-07-24 | GSE134726 | GEO
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.
2013-04-09 | GSE45858 | GEO
Project description:DNA methylation is an important regulatory mechanism in the control of neuronal function. Both during development and following exposure to salient stimuli, plasticity in the methylation of cytosine residues leads to a change in neuron excitability that subsequently sculpts animal behavior. However, while the response of DNA methyltransferase enzymes in adult neurons to stimuli such as drugs of abuse have been described, less is known about how these enzymes regulate methylation at specific loci to change an animal’s inclination to ingest natural rewards. Specifically, we do not understand how changes in methylation within important brain areas known to regulate palatable food intake can affect ingestion, and detailed investigation of the neurophysiological and genomic effects of perturbing methyltransferase function has not been pursued. By deleting DNA methyltransferase 1 and 3a in the mouse prefrontal cortex, we observed the requirement for these enzymes in the regulation of nutrient rich food consumption in the absence of any effect on the intake of low fat and low sugar chow. We also determined that the deletion profoundly affected neuron excitability within pyramidal cells resident in superficial layers II/III of the cortex but had little effect in deep layer V neurons. Finally, reduced representation bisulfite sequencing revealed both hypo and hypermethylation in response to methyltransferase deletion, an effect that was observed in binding sites for retinoic acid receptor beta (RARβ) located within regulatory regions of genes known to affect neuronal function. Together, our data suggest that alterations in the actions of RARβ could shift neuronal activity to reduce palatable food intake.
2021-05-24 | GSE175380 | GEO
Project description:Background: Anorexia is a common symptom among cancer patients and contributes to malnutrition and strongly impinges on quality of life. Cancer-induced anorexia is thought to be caused by an inability of food intake-regulating systems in the hypothalamus to respond adequately to negative energy balance during tumour growth. Here, we show that this impaired response of food-intake control is likely to be mediated by altered serotonin signalling and by failure in post-transcriptional neuropeptide Y (NPY) regulation. Methods: Two tumour cachectic mouse models with different food intake behaviours were used: a C26-colon adenocarcinoma model with increased food intake and a Lewis lung carcinoma model with decreased food intake. This contrast in food intake behaviour between tumour-bearing (TB) mice in response to growth of the two different tumours was used to distinguish between processes involved in cachexia and mechanisms that might be important in food intake regulation. The hypothalamus was used for transcriptomics (affymetrix chips). Results: In both models, hypothalamic expression of orexigenic NPY was significantly higher compared with controls, suggesting that this change does not directly reflect food intake status but might be linked to negative energy balance in cachexia. Expression of genes involved in serotonin signalling showed to be different between C26-TB mice and Lewis lung carcinoma-TB mice and was inversely associated with food intake. In vitro, using hypothalamic cell lines, serotonin repressed neuronal hypothalamic NPY secretion while not affecting messenger NPY expression, suggesting that serotonin signalling can interfere with NPY synthesis, transport, or secretion. Conclusions: Altered serotonin signalling is associated with changes in food intake behaviour in cachectic TB mice. Serotonins' inhibitory effect on food intake under cancer cachectic conditions is probably via affecting the NPY system. Therefore, serotonin regulation might be a therapeutic target to prevent the development of cancer-induced eating disorders.
2014-10-31 | GSE57188 | GEO
Project description:Background: Anorexia is a common symptom among cancer patients and contributes to malnutrition and strongly impinges on quality of life. Cancer-induced anorexia is thought to be caused by an inability of food intake-regulating systems in the hypothalamus to respond adequately to negative energy balance during tumour growth. Here, we show that this impaired response of food-intake control is likely to be mediated by altered serotonin signalling and by failure in post-transcriptional neuropeptide Y (NPY) regulation. Methods: Two tumour cachectic mouse models with different food intake behaviours were used: a C26-colon adenocarcinoma model with increased food intake and a Lewis lung carcinoma model with decreased food intake. This contrast in food intake behaviour between tumour-bearing (TB) mice in response to growth of the two different tumours was used to distinguish between processes involved in cachexia and mechanisms that might be important in food intake regulation. The hypothalamus was used for transcriptomics (affymetrix chips). Results: In both models, hypothalamic expression of orexigenic NPY was significantly higher compared with controls, suggesting that this change does not directly reflect food intake status but might be linked to negative energy balance in cachexia. Expression of genes involved in serotonin signalling showed to be different between C26-TB mice and Lewis lung carcinoma-TB mice and was inversely associated with food intake. In vitro, using hypothalamic cell lines, serotonin repressed neuronal hypothalamic NPY secretion while not affecting messenger NPY expression, suggesting that serotonin signalling can interfere with NPY synthesis, transport, or secretion. Conclusions: Altered serotonin signalling is associated with changes in food intake behaviour in cachectic TB mice. Serotonins' inhibitory effect on food intake under cancer cachectic conditions is probably via affecting the NPY system. Therefore, serotonin regulation might be a therapeutic target to prevent the development of cancer-induced eating disorders.
2014-10-31 | GSE57189 | GEO
Project description:Obesity occurs when energy expenditure is outweighed by food intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), regulate feeding amount as well as energy expenditure. Here we report that mice lacking circadian nuclear receptors REV-ERBa and b in the tuberal hypothalamus (HDKO) gain excessive weight on an obesogenic diet due both to decreased energy expenditure and increased food consumption during the light phase. Moreover, rebound food intake after fasting is markedly increased in HDKO mice. Integrative transcriptomic and cistromic analyses revealed that such disruption in feeding behavior is due to perturbed REV-ERB-dependent leptin signaling in the ARC. Indeed, in vivo leptin sensitivity is impaired in HDKO mice on an obesogenic diet in a circadian manner. Thus, REV-ERBs play a crucial role in hypothalamic regulation of food intake and circadian leptin sensitivity in diet-induced obesity.
2020-10-11 | GSE148641 | GEO
Project description:Obesity occurs when energy expenditure is outweighed by food intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), regulate feeding amount as well as energy expenditure. Here we report that mice lacking circadian nuclear receptors REV-ERBa and b in the tuberal hypothalamus (HDKO) gain excessive weight on an obesogenic diet due both to decreased energy expenditure and increased food consumption during the light phase. Moreover, rebound food intake after fasting is markedly increased in HDKO mice. Integrative transcriptomic and cistromic analyses revealed that such disruption in feeding behavior is due to perturbed REV-ERB-dependent leptin signaling in the ARC. Indeed, in vivo leptin sensitivity is impaired in HDKO mice on an obesogenic diet in a circadian manner. Thus, REV-ERBs play a crucial role in hypothalamic regulation of food intake and circadian leptin sensitivity in diet-induced obesity.
2020-10-11 | GSE148599 | GEO