CRFR1 in AgRP Neurons Modulates Sympathetic Nervous System Activity to Adapt to Cold Stress and Fasting

Summary Signaling by the corticotropin-releasing factor receptor type 1 (CRFR1) plays an important role in mediating the autonomic response to stressful challenges. Multiple hypothalamic nuclei regulate sympathetic outflow. Although CRFR1 is highly expressed in the arcuate nucleus (Arc) of the hypothalamus, the identity of these neurons and the role of CRFR1 here are presently unknown. Our studies show that nearly half of Arc-CRFR1 neurons coexpress agouti-related peptide (AgRP), half of which originate from POMC precursors. Arc-CRFR1 neurons are innervated by CRF neurons in the hypothalamic paraventricular nucleus, and CRF application decreases AgRP+CRFR1+ neurons’ excitability. Despite similar anatomy in both sexes, only female mice selectively lacking CRFR1 in AgRP neurons showed a maladaptive thermogenic response to cold and reduced hepatic glucose production during fasting. Thus, CRFR1, in a subset of AgRP neurons, plays a regulatory role that enables appropriate sympathetic nervous system activation and consequently protects the organism from hypothermia and hypoglycemia.

• Publication year

  2016

• Venue

  Cell Metabolism

• Publication date

  2016-06-14

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.cmet.2016.04.017PMID 27211900PMCID 4911344
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss

  2015cited by this paper
• Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons

  2015influential reference
• Rapid categorization of natural face images in the infant right hemisphere

  2015cited by this paper
• O-GlcNAc transferase enables AgRP neurons to suppress browning of white fat.

  2014influential reference
• Faculty Opinions recommendation of An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger.

  2014influential reference
• A mesoscale connectome of the mouse brain

  2014cited by this paper
• FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss.

  2014cited by this paper
• A Novel Excitatory Paraventricular Nucleus to AgRP Neuron Circuit that Drives Hunger

  2014cited by this paper
• Arcuate NPY controls sympathetic output and BAT function via a relay of tyrosine hydroxylase neurons in the PVN.

  2013cited by this paper
• Optogenetic strategies to investigate neural circuitry engaged by stress.

  2013cited by this paper
• Parallel, redundant circuit organization for homeostatic control of feeding behavior.

  2013cited by this paper
• Hypothalamic survival circuits: blueprints for purposive behaviors.

  2013cited by this paper
• Brown and beige fat: development, function and therapeutic potential

  2013influential reference
• Neuroanatomy of the kisspeptin signaling system in mammals: comparative and developmental aspects.

  2013cited by this paper
• The Inhibitory Circuit Architecture of the Lateral Hypothalamus Orchestrates Feeding

  2013cited by this paper
• GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure.

  2012cited by this paper
• FoxO1 target Gpr17 activates AgRP neurons to regulate food intake.

  2012cited by this paper
• Defining POMC neurons using transgenic reagents: impact of transient Pomc expression in diverse immature neuronal populations.

  2012cited by this paper
• FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis.

  2012influential reference
• Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone.

  2012cited by this paper
• AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors

  2012cited by this paper
• Visualizing corticotropin‐releasing hormone receptor type 1 expression and neuronal connectivities in the mouse using a novel multifunctional allele

  2012cited by this paper
• Deconstruction of a neural circuit for hunger

  2012cited by this paper
• Glutamatergic and Dopaminergic Neurons Mediate Anxiogenic and Anxiolytic Effects of CRHR1

  2011cited by this paper
• A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex.

  2011cited by this paper
• Perifornical Urocortin-3 mediates the link between stress-induced anxiety and energy homeostasis

  2010cited by this paper
• Pomc-expressing progenitors give rise to antagonistic populations in hypothalamic feeding circuits

  2010cited by this paper
• AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training

  2010cited by this paper
• Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake

  2009cited by this paper
• Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver

  2009cited by this paper
• Neural regulation of endocrine and autonomic stress responses

  2009cited by this paper
• A robust and high-throughput Cre reporting and characterization system for the whole mouse brain

  2009influential reference
• Neurons in the paraventricular nucleus of the hypothalamus inhibit sympathetic outflow to brown adipose tissue.

  2009cited by this paper
• Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation.

  2009cited by this paper
• Activation of Stat3 signaling in AgRP neurons promotes locomotor activity.

  2008cited by this paper
• Collective and individual functions of leptin receptor modulated neurons controlling metabolism and ingestion.

  2008cited by this paper
• Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance

  2008cited by this paper
• Type 1 corticotropin‐releasing factor receptor expression reported in BAC transgenic mice: Implications for reconciling ligand‐receptor mismatch in the central corticotropin‐releasing factor system

  2008cited by this paper
• Sexually different actions of leptin in proopiomelanocortin neurons to regulate glucose homeostasis.

  2008cited by this paper
• Corticotropin‐releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C‐dependent enhancement of Ih

  2008influential reference
• Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding.

  2007cited by this paper
• Differential activation of the sympathetic innervation of adipose tissues by melanocortin receptor stimulation.

  2007cited by this paper
• Type 1 corticotropin-releasing factor receptors in the ventromedial hypothalamus promote hypoglycemia-induced hormonal counterregulation.

  2007cited by this paper
• Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production.

  2007influential reference
• Urocortin 2 modulates glucose utilization and insulin sensitivity in skeletal muscle

  2006cited by this paper
• Corticotropin releasing factor increases in brown adipose tissue thermogenesis and heart rate through dorsomedial hypothalamus and medullary raphe pallidus.

  2006cited by this paper
• NPY/AgRP Neurons Are Essential for Feeding in Adult Mice but Can Be Ablated in Neonates

  2005cited by this paper
• Anatomy and regulation of the central melanocortin system

  2005influential reference
• Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis.

  2005cited by this paper
• Interaction between the Corticotropin-Releasing Factor System and Hypocretins (Orexins): A Novel Circuit Mediating Stress Response

  2004influential reference
• Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus

  2004cited by this paper
• Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis.

  2004cited by this paper
• Suprachiasmatic GABAergic Inputs to the Paraventricular Nucleus Control Plasma Glucose Concentrations in the Rat via Sympathetic Innervation of the Liver

  2004cited by this paper
• The mouse brain in stereotaxic coordinates

  2003cited by this paper
• Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress

  2003cited by this paper
• Differential sensitivity to central leptin and insulin in male and female rats.

  2003influential reference
• Peripheral ghrelin selectively increases Fos expression in neuropeptide Y - synthesizing neurons in mouse hypothalamic arcuate nucleus.

  2002cited by this paper
• Neurotransmitter Regulation of Cellular Activation and Neuropeptide Gene Expression in the Paraventricular Nucleus of the Hypothalamus

  2002cited by this paper
• 4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related

  2002cited by this paper
• The Mouse Brain in Stereotaxic Coordinates

  2001cited by this paper
• New perspectives into the molecular pathogenesis and treatment of type 2 diabetes.

  2001cited by this paper
• Urocortin II: A member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors

  2001cited by this paper
• Identification of NPY‐induced c‐Fos expression in hypothalamic neurones projecting to the dorsal vagal complex and the lower thoracic spinal cord

  2001cited by this paper
• Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor

  2001cited by this paper
• Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse

  2000cited by this paper
• Polysynaptic neural pathways between the hypothalamus, including the suprachiasmatic nucleus, and the liver.

  2000cited by this paper
• Corticotropin-Releasing Factor Increases In VitroFiring Rates of Serotonergic Neurons in the Rat Dorsal Raphe Nucleus: Evidence for Activation of a Topographically Organized Mesolimbocortical Serotonergic System

  2000influential reference
• Dual Roles for Glucokinase in Glucose Homeostasis as Determined by Liver and Pancreatic β Cell-specific Gene Knock-outs Using Cre Recombinase*

  1999cited by this paper
• CNS origins of the sympathetic nervous system outflow to brown adipose tissue.

  1999influential reference
• Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development.

  1998cited by this paper
• Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1

  1998cited by this paper
• The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice.

  1998cited by this paper
• Hypothalamic and Hypophyseal Regulation of Growth Hormone Secretion

  1998cited by this paper
• Targeted disruption of the melanocortin-4 receptor results in obesity in mice.

  1997cited by this paper
• Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor

  1995cited by this paper
• Neuropeptide Y in hypothalamic paraventricular nucleus: a center coordinating energy metabolism.

  1994cited by this paper
• Hormonal regulation of human corticotropin-releasing hormone gene expression: implications for the stress response and immune/inflammatory reaction.

  1994cited by this paper
• Differential expression of corticotropin-releasing hormone in developing mouse embryos and adult brain.

  1994influential reference
• Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.

  1993cited by this paper
• Local origins of some GABAergic projections to the paraventricular and supraoptic nuclei of the hypothalamus in the rat

  1993cited by this paper
• Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity.

  1993cited by this paper
• Differential actions of corticotropin releasing factor on basolateral and central amygdaloid neurones, in vitro.

  1992cited by this paper
• Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism.

  1991cited by this paper
• Increase in sympathetic outflow by paraventricular nucleus stimulation in awake rats.

  1989cited by this paper
• The ontogeny of brain receptors for corticotropin-releasing factor and the development of their functional association with adenylate cyclase

  1988influential reference
• Immunohistochemical identification of corticotropin releasing factor-containing neurons projecting to the stalk-median eminence of the rat

  1988cited by this paper
• Effects of corticotropin-releasing factor on food intake and brown adipose tissue thermogenesis in rats.

  1988cited by this paper
• Activation of brown fat thermogenesis in response to central injection of corticotropin releasing hormone in the rat.

  1987cited by this paper
• Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study.

  1983cited by this paper
• Corticotropin releasing factor decreases postburst hyperpolarizations and excites hippocampal neurons.

  1983cited by this paper
• Corticotropin-releasing factor activates noradrenergic neurons of the locus coeruleus.

  1983influential reference
• Corticotropin releasing factor produces behavioural activation in rats

  1982cited by this paper
• Corticotropin-releasing factor (CRF): central effects on mean arterial pressure and heart rate in rats.

  1982cited by this paper
• Corticotropin-releasing factor: actions on the sympathetic nervous system and metabolism.

  1982influential reference
• Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin.

  1982cited by this paper
• Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin

  1981cited by this paper
• Paraventricular nucleus: a site for the integration of neuroendocrine and autonomic mechanisms.

  1980cited by this paper
• Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits

  year unknowninfluential reference

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• Corticotropin‐releasing hormone receptor 1 mediates the enhanced locomotor activity and metabolic demands to an acute thermal stress in adult zebrafish

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• Sex-Specific changes in stress circuitry of the nucleus tractus solitarius following food deprivation in two rat strains.

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• Molecular and functional mapping of the neuroendocrine hypothalamus: a new era begins

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• Growth hormone receptor (GHR) in AgRP neurons regulates thermogenesis in a sex-specific manner

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• Mechanistic insight into the role of metformin in Alzheimer's disease.

  2022cites this paper
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• The role of central corticotrophin‐releasing factor receptor signalling in plasma glucose maintenance through ghrelin secretion in calorie‐restricted mice

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  2020cites this paper
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  2020cites this paper
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  2020cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2016cites this paper
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  2016cites this paper