Activation of GFRAL+ Neurons Induces Hypothermia and Glucoregulatory Responses Associated with Nausea and Torpor
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1075320 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27937407.fastq.gz | Fastqsanger.gz | |||
| SRR27937408.fastq.gz | Fastqsanger.gz | |||
| SRR27937409.fastq.gz | Fastqsanger.gz | |||
| SRR27937410.fastq.gz | Fastqsanger.gz | |||
| SRR27937411.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Homeotherms maintain a stable internal body temperature despite changing environments. During energy deficiency, some species can cease to defend their body temperature and enter a hypothermic and hypometabolic state known as torpor. Despite recent advances in our understanding of thermoregulation, the precise neurons that coordinate these profound thermoregulatory and metabolic changes remain largely unknown. Here, we demonstrate that estrogen-sensitive neurons in the medial preoptic area (MPA) are key drivers of hypothermia and hypometabolism in mice. We find that selectively activating estrogen-sensitive MPA neurons was sufficient to drive a coordinated depression of metabolic rate and body temperature similar to torpor, as measured by body temperature, physical activity, indirect calorimetry, heart rate, and brain activity. Inducing torpor with a prolonged fast revealed larger and more variable calcium transients from estrogen-sensitive MPA neurons during bouts of hypothermia. Finally, selective ablation of estrogen-sensitive MPA neurons demonstrated that these neurons are required for the full expression of fasting-induced torpor. Together, these findings suggest a role for estrogen-sensitive MPA neurons in directing the thermoregulatory and metabolic responses to energy deficiency.
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Project description:The advent of endothermy more than a hundred million years ago is thought to have been a defining feature of mammalian and avian evolution, achieved through continuous fine-tuned homeostatic regulation of core body temperature and metabolism. However, when challenged by food deprivation or harsh environmental conditions, many mammalian species initiate adaptive energy-conserving survival strategies, including torpor and hibernation, during which their core body temperature decreases far below its homeostatic setpoint. How homeothermic mammals initiate and regulate these extraordinary hypothermic states remains largely unknown. Here, we discover that entry into mouse torpor, a fasting-induced state with greatly decreased metabolic rate and body temperature as low as 20°C, is regulated by a population of neurons in the preoptic area of the hypothalamus. We show that re-stimulation of neurons activated during a previous bout of torpor is sufficient to initiate torpor, even in animals that are not calorically restricted. We localize these torpor-regulating neurons to the anteroventral medial and lateral preoptic area and molecularly identify a population of glutamatergic Adcyap1+ neurons whose activity accurately determines when calorically-restricted animals naturally initiate and exit torpor, and whose inhibition disrupts the natural process of torpor entry, maintenance and arousal. Taken together, we discover a specific hypothalamic neuronal subpopulation in the mouse brain that serves as a core regulator of torpor. This work forms the basis for future explorations of mechanisms and circuitry regulating extreme hypothermic and hypometabolic states, enabling genetic access to monitor, initiate, manipulate and study these ancient adaptations of homeotherm biology.
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Project description:Torpor is an energy-conserving state in which animals dramatically decrease their metabolic rate and body temperature to survive harsh environmental conditions. Here, we report the noninvasive, precise, and safe induction of a torpor-like hypothermic and hypometabolic state in rodents by remote transcranial ultrasound stimulation at the hypothalamus preoptic area (POA). We achieve a long-lasting (> 24 hours) torpor-like state in mice via closed-loop feedback control of ultrasound stimulation with automated detection of body temperature. Ultrasound-induced hypothermia and hypometabolism (UIH) is triggered by activation of POA neurons, involves the dorsomedial hypothalamus as a downstream brain region and subsequent inhibition of thermogenic brown adipose tissue. Single-nucleus RNA-sequencing of POA neurons reveals TRPM2 as an ultrasound-sensitive ion channel, the knockdown of which suppresses UIH. We also demonstrate that UIH is feasible in a non-torpid animal, the rat. Our findings establish UIH as a promising technology for the noninvasive and safe induction of a torpor-like state. To investigate the mechanism of ultrasound-induced neuronal activation, we applied ultrasound stimulation in hypothalamic preoptic area region and performed single-nuclei RNA sequencing in the ultrasound stimulated neurons (US+) and neurons without ultrasound stimulation (US-). In our sn-RNAseq analysis, we examined the association between the expression of neuronal activation markers (or IEGs) and ion channels, as well as neuron types.
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Project description:Hypothermia affects the body in positive and negative consequences. In cardiac, hypothermia depresses myocardial contraction, slows conduction, and decreases metabolic rate. However, little is known about the molecular mechanism. Here we compare the genes expression of human adult ventricular cardiomyocyte cells (AC16) treated with hypothermia, trying to find changes under different temperatures and then elucidate the candidate genes that may play important roles in the response to hypothermia. A total of 2413 differentially expressed genes (DEGs) were identified by microarray hybridization, which provided abundant data for further analysis. Gene Ontology enrichment analysis revealed that genes related to gene transcriptions, protein and lipid metabolic were significantly enriched. KEGG analysis showed that DEGs were significantly enriched in TGF-β pathway and cytokine-cytokine receptor interaction, which may play important roles in response to hypothermia. A set of TFs (CPBP, Churchill, NF-AT1, GKLF, SRY, ZNF333, ING4, myogenin, DRI1 and CRX) was recognized to be the functional layer of key nodes, which mapped the signal of hypothermia to transcriptome. These identified DEGs, pathways and predicted TF could facilitate further investigations of the detailed molecular mechanisms, making it possible to take advantage of the potential applications of hypothermia in broader ranger AC16 cell lines was treated by hypothermia (n=3) and control group (n=3) for 6 hours.
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Project description:Hypothermia affects the body in positive and negative consequences. In cardiac, hypothermia depresses myocardial contraction, slows conduction, and decreases metabolic rate. However, little is known about the molecular mechanism. Here we compare the genes expression of human adult ventricular cardiomyocyte cells (AC16) treated with hypothermia, trying to find changes under different temperatures and then elucidate the candidate genes that may play important roles in the response to hypothermia. A total of 2413 differentially expressed genes (DEGs) were identified by microarray hybridization, which provided abundant data for further analysis. Gene Ontology enrichment analysis revealed that genes related to gene transcriptions, protein and lipid metabolic were significantly enriched. KEGG analysis showed that DEGs were significantly enriched in TGF-β pathway and cytokine-cytokine receptor interaction, which may play important roles in response to hypothermia. A set of TFs (CPBP, Churchill, NF-AT1, GKLF, SRY, ZNF333, ING4, myogenin, DRI1 and CRX) was recognized to be the functional layer of key nodes, which mapped the signal of hypothermia to transcriptome. These identified DEGs, pathways and predicted TF could facilitate further investigations of the detailed molecular mechanisms, making it possible to take advantage of the potential applications of hypothermia in broader ranger
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