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A critical period for the trophic actions of leptin on AgRP neurons in the arcuate nucleus of the hypothalamus.
Kamitakahara A, Bouyer K, Wang CH, Simerly R
(2018) J Comp Neurol 526: 133-145
MeSH Terms: Age Factors, Agouti-Related Protein, Analysis of Variance, Animals, Animals, Newborn, Arcuate Nucleus of Hypothalamus, Axons, ELAV-Like Protein 3, Estrogen Receptor alpha, Female, Green Fluorescent Proteins, Integrases, Leptin, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Neuropeptide Y, Receptors, Leptin, STAT3 Transcription Factor
Show Abstract · Added April 11, 2019
In the developing hypothalamus, the fat-derived hormone leptin stimulates the growth of axons from the arcuate nucleus of the hypothalamus (ARH) to other regions that control energy balance. These projections are significantly reduced in leptin deficient (Lep ) mice and this phenotype is largely rescued by neonatal leptin treatments. However, treatment of mature Lep mice is ineffective, suggesting that the trophic action of leptin is limited to a developmental critical period. To temporally delineate closure of this critical period for leptin-stimulated growth, we treated Lep mice with exogenous leptin during a variety of discrete time periods, and measured the density of Agouti-Related Peptide (AgRP) containing projections from the ARH to the ventral part of the dorsomedial nucleus of the hypothalamus (DMHv), and to the medial parvocellular part of the paraventricular nucleus (PVHmp). The results indicate that leptin loses its neurotrophic potential at or near postnatal day 28. The duration of leptin exposure appears to be important, with 9- or 11-day treatments found to be more effective than shorter (5-day) treatments. Furthermore, leptin treatment for 9 days or more was sufficient to restore AgRP innervation to both the PVHmp and DMHv in Lep females, but only to the DMHv in Lep males. Together, these findings reveal that the trophic actions of leptin are contingent upon timing and duration of leptin exposure, display both target and sex specificity, and that modulation of leptin-dependent circuit formation by each of these factors may carry enduring consequences for feeding behavior, metabolism, and obesity risk.
© 2017 Wiley Periodicals, Inc.
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MeSH Terms
A framework on surface-based connectivity quantification for the human brain.
Huang H, Prince JL, Mishra V, Carass A, Landman B, Park DC, Tamminga C, King R, Miller MI, van Zijl PC, Mori S
(2011) J Neurosci Methods 197: 324-32
MeSH Terms: Adult, Arcuate Nucleus of Hypothalamus, Brain Mapping, Cerebral Cortex, Diffusion Tensor Imaging, Female, Humans, Male, Models, Neurological, Nerve Net, Schizophrenia, Surface Properties
Show Abstract · Added March 26, 2014
Quantifying the connectivity between arbitrary surface patches in the human brain cortex can be used in studies on brain function and to characterize clinical diseases involving abnormal connectivity. Cortical regions of human brain in their natural forms can be represented in surface formats. In this paper, we present a framework to quantify connectivity using cortical surface segmentation and labeling from structural magnetic resonance images, tractography from diffusion tensor images, and nonlinear inter-subject registration. For a single subject, the connectivity intensity of any point on the cortical surface is set to unity if the point is connected and zero if it is not connected. The connectivity proportion is defined as the ratio of the total connected surface area to the total area of the surface patch. By nonlinearly registering the connectivity data of a group of normal controls into a template space, a population connectivity metric can be defined as either the average connectivity intensity of a cortical point or the average connectivity proportion of a cortical region. In the template space, a connectivity profile and a connectivity histogram of an arbitrary cortical region of interest can then be derived from these connectivity quantification values. Results from the application of these quantification metrics to a population of schizophrenia patients and normal controls are presented, revealing connectivity signatures of specified cortical regions and detecting connectivity abnormalities.
Copyright © 2011 Elsevier B.V. All rights reserved.
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12 MeSH Terms
Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin.
Ghamari-Langroudi M, Srisai D, Cone RD
(2011) Proc Natl Acad Sci U S A 108: 355-60
MeSH Terms: Animals, Arcuate Nucleus of Hypothalamus, Electrophysiology, Energy Metabolism, Green Fluorescent Proteins, Homeostasis, Immunohistochemistry, Leptin, Melanocortins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Neurological, Neurons, Neuropeptide Y, Paraventricular Hypothalamic Nucleus, Polymerase Chain Reaction, Receptor, Melanocortin, Type 4, Signal Transduction, alpha-MSH
Show Abstract · Added December 10, 2013
Melanocortin-4 receptor (MC4R) is critical for energy homeostasis, and the paraventricular nucleus of the hypothalamus (PVN) is a key site of MC4R action. Most studies suggest that leptin regulates PVN neurons indirectly, by binding to receptors in the arcuate nucleus or ventromedial hypothalamus and regulating release of products like α-melanocyte-stimulating hormone (α-MSH), neuropeptide Y (NPY), glutamate, and GABA from first-order neurons onto the MC4R PVN cells. Here, we investigate mechanisms underlying regulation of activity of these neurons under various metabolic states by using hypothalamic slices from a transgenic MC4R-GFP mouse to record directly from MC4R neurons. First, we show that in vivo leptin levels regulate the tonic firing rate of second-order MC4R PVN neurons, with fasting increasing firing frequency in a leptin-dependent manner. We also show that, although leptin inhibits these neurons directly at the postsynaptic membrane, α-MSH and NPY potently stimulate and inhibit the cells, respectively. Thus, in contrast with the conventional model of leptin action, the primary control of MC4R PVN neurons is unlikely to be mediated by leptin action on arcuate NPY/agouti-related protein and proopiomelanocortin neurons. We also show that the activity of MC4R PVN neurons is controlled by the constitutive activity of the MC4R and that expression of the receptor mRNA and α-MSH sensitivity are both stimulated by leptin. Thus, leptin acts multinodally on arcuate nucleus/PVN circuits to regulate energy homeostasis, with prominent mechanisms involving direct control of both membrane conductances and gene expression in the MC4R PVN neuron.
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20 MeSH Terms
Regulation of thyrotropin-releasing hormone-expressing neurons in paraventricular nucleus of the hypothalamus by signals of adiposity.
Ghamari-Langroudi M, Vella KR, Srisai D, Sugrue ML, Hollenberg AN, Cone RD
(2010) Mol Endocrinol 24: 2366-81
MeSH Terms: Adiposity, Animals, Arcuate Nucleus of Hypothalamus, Fasting, Humans, Hypothalamo-Hypophyseal System, Leptin, Melanocortins, Mice, Mice, Transgenic, Neurons, Neuropeptide Y, Paraventricular Hypothalamic Nucleus, Pituitary Gland, Rats, Thyroid Gland, Thyroid Hormones, Thyrotropin-Releasing Hormone, alpha-MSH
Show Abstract · Added December 10, 2013
Fasting-induced suppression of thyroid hormone levels is an adaptive response to reduce energy expenditure in both humans and mice. This suppression is mediated by the hypothalamic-pituitary-thyroid axis through a reduction in TRH levels expressed in neurons of the paraventricular nucleus of the hypothalamus (PVN). TRH gene expression is positively regulated by leptin. Whereas decreased leptin levels during fasting lead to a reduction in TRH gene expression, the mechanisms underlying this process are still unclear. Indeed, evidence exists that TRH neurons in the PVN are targeted by leptin indirectly via the arcuate nucleus, whereas correlative evidence for a direct action exists as well. Here we provide both in vivo and in vitro evidence that the activity of hypothalamic-pituitary-thyroid axis is regulated by both direct and indirect leptin regulation. We show that both leptin and α-MSH induce significant neuronal activity mediated through a postsynaptic mechanism in TRH-expressing neurons of PVN. Furthermore, we provide in vivo evidence indicating the contribution of each pathway in maintaining serum levels of thyroid hormone.
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19 MeSH Terms
Characterization of leptin-responsive neurons in the caudal brainstem.
Ellacott KL, Halatchev IG, Cone RD
(2006) Endocrinology 147: 3190-5
MeSH Terms: Animals, Arcuate Nucleus of Hypothalamus, Brain, Brain Stem, Cholecystokinin, Gene Expression Regulation, Leptin, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Pro-Opiomelanocortin
Show Abstract · Added December 10, 2013
The central melanocortin system plays a key role in the regulation of energy homeostasis. Neurons containing the peptide precursor proopiomelanocortin (POMC) are found at two sites in the brain, the arcuate nucleus of the hypothalamus (ARC) and the caudal region of the nucleus of the solitary tract (NTS). ARC POMC neurons, which also express cocaine- and amphetamine-regulated transcript (CART), are known to mediate part of the response to factors regulating energy homeostasis, such as leptin and ghrelin. In contrast, the physiological role(s) of the POMC neurons in the caudal brainstem are not well characterized. However, development of a transgenic mouse expressing green fluorescent protein under the control of the POMC promoter [POMC-enhanced green fluorescent protein (EGFP) mouse] has aided the study of these neurons. Indeed, recent studies have shown significant activation of NTS POMC-EGFP cells by the gut released satiety factor cholecystokinin (CCK). Here we show that peripheral leptin administration induces the expression of phospho-signal transducer and activator of transcription 3 immunoreactivity (pSTAT3-IR), a marker of leptin receptor signaling, in more than 50% of NTS POMC-EGFP neurons. Furthermore, these POMC-EGFP neurons comprise 30% of all pSTAT3-IR cells in the NTS. Additionally, we also show that in contrast to the ARC population, NTS POMC-EGFP neurons do not coexpress CART immunoreactivity. These data suggest that NTS POMC neurons may participate with ARC POMC cells in mediating some of the effects of leptin and thus comprise a novel cell group regulated by both long-term adipostatic signals and satiety factors such as CCK.
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13 MeSH Terms
The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R).
Marks DL, Hruby V, Brookhart G, Cone RD
(2006) Peptides 27: 259-64
MeSH Terms: Animals, Appetite Regulation, Arcuate Nucleus of Hypothalamus, Circadian Rhythm, Dose-Response Relationship, Drug, Drug Administration Schedule, Eating, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor, Melanocortin, Type 3, gamma-MSH
Show Abstract · Added December 10, 2013
High levels of binding sites for melanocortin peptides exist within the arcuate nucleus, and a functional response to melanocortin peptides has been demonstrated in arcuate POMC neurons. Because the MC3R is thought to function as an inhibitory autoreceptor on POMC neurons, we reasoned that peripheral injections of MC3R-specific agonists would act within the arcuate nucleus to inhibit POMC neurons and thereby stimulate feeding. We demonstrate that the peptidergic MC3R agonist, d-Trp(8)-gamma-MSH, stimulates feeding via the MC3R when injected peripherally. These data provide the first evidence that feeding can be stimulated by peripheral injection of MC3R-specific agonists.
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12 MeSH Terms
PYY3-36 inhibits the action potential firing activity of POMC neurons of arcuate nucleus through postsynaptic Y2 receptors.
Ghamari-Langroudi M, Colmers WF, Cone RD
(2005) Cell Metab 2: 191-9
MeSH Terms: Action Potentials, Animals, Arcuate Nucleus of Hypothalamus, Dose-Response Relationship, Drug, Green Fluorescent Proteins, Mice, Mice, Transgenic, Neurons, Patch-Clamp Techniques, Peptide YY, Pro-Opiomelanocortin, Receptors, Neuropeptide Y, Time Factors
Show Abstract · Added December 10, 2013
Intracerebroventricular administration of gut peptide PYY3-36 stimulates food intake. In contrast, peripheral administration inhibits food intake, suggesting that the peptide has the opposite effect by virtue of accessing a unique subset of brain sites. A previous study suggested that peripheral PYY3-36 activates anorexigenic POMC neurons in the arcuate nucleus, and this was proposed to be the mechanism underlying the peptide's anorexigenic activity. Here, we demonstrate in an electrophysiological slice preparation that, in contrast to the original model, PYY3-36 potently and reversibly inhibits POMC neurons via postsynaptic Y2 receptors. These data show a complex role for Y2 receptors in regulation of the NPY/POMC circuitry, as they are present as inhibitory receptors on both the orexigenic NPY neurons as well as the anorexigenic POMC neurons. Secondly, these data argue against a direct role of POMC neurons in mediating the anorexigenic response to administration of peripheral PYY3-36.
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13 MeSH Terms
Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling.
Morrison CD, Morton GJ, Niswender KD, Gelling RW, Schwartz MW
(2005) Am J Physiol Endocrinol Metab 289: E1051-7
MeSH Terms: Agouti-Related Protein, Animals, Arcuate Nucleus of Hypothalamus, Chromones, Enzyme Inhibitors, Fasting, Gene Expression Regulation, Hypothalamus, Injections, Intraventricular, Intercellular Signaling Peptides and Proteins, Leptin, Male, Morpholines, Neurons, Neuropeptide Y, Paraventricular Hypothalamic Nucleus, Phosphatidylinositol 3-Kinases, Proteins, Proto-Oncogene Proteins c-fos, RNA, Messenger, Rats, Rats, Sprague-Dawley, STAT3 Transcription Factor, Signal Transduction, Suppressor of Cytokine Signaling 3 Protein, Suppressor of Cytokine Signaling Proteins
Show Abstract · Added February 15, 2016
Phosphatidylinositol 3-OH-kinase (PI3K) and STAT3 are signal transduction molecules activated by leptin in brain areas controlling food intake. To investigate their role in leptin-mediated inhibition of hypothalamic neuropeptide Y (Npy) and agouti-related peptide (Agrp) gene expression, male Sprague-Dawley rats (n = 5/group) were either fed ad libitum or subjected to a 52-h fast. At 12-h intervals, the PI3K inhibitor LY-294002 (LY, 1 nmol) or vehicle was injected intracerebroventricularly (ICV) as a pretreatment, followed 1 h later by leptin (3 microg icv) or vehicle. Fasting increased hypothalamic Npy and Agrp mRNA levels (P < 0.05), and ICV leptin administration prevented this increase. As predicted, LY pretreatment blocked this inhibitory effect of leptin, such that Npy and Agrp levels in LY-leptin-treated animals were similar to fasted controls. By comparison, leptin-mediated activation of hypothalamic STAT3 signaling, as measured by induction of both phospho-STAT3 immunohistochemistry and suppressor of cytokine signaling-3 (Socs3) mRNA, was not significantly attenuated by ICV LY pretreatment. Because NPY/AgRP neurons project to the hypothalamic paraventricular nucleus (PVN), we next investigated whether leptin activation of PVN neurons is similarly PI3K dependent. Compared with vehicle, leptin increased the number of c-Fos positive cells within the parvocellular PVN (P = 0.001), and LY pretreatment attenuated this effect by 35% (P = 0.043). We conclude that leptin requires intact PI3K signaling both to inhibit hypothalamic Npy and Agrp gene expression and activate neurons within the PVN. In addition, these data suggest that leptin activation of STAT3 is insufficient to inhibit expression of Npy or Agrp in the absence of PI3K signaling.
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26 MeSH Terms
Anatomy and regulation of the central melanocortin system.
Cone RD
(2005) Nat Neurosci 8: 571-8
MeSH Terms: Adipose Tissue, Animals, Appetite Regulation, Arcuate Nucleus of Hypothalamus, Brain Stem, Energy Metabolism, Humans, Neural Pathways, Neuropeptides, Receptors, Melanocortin, Signal Transduction, alpha-MSH
Show Abstract · Added December 10, 2013
The central melanocortin system is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis. This collection of circuits is unique in having the capability of sensing signals from a staggering array of hormones, nutrients and afferent neural inputs. It is likely to be involved in integrating long-term adipostatic signals from leptin and insulin, primarily received by the hypothalamus, with acute signals regulating hunger and satiety, primarily received by the brainstem. The system is also unique from a regulatory point of view in that it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.
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12 MeSH Terms
Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system.
Fan W, Ellacott KL, Halatchev IG, Takahashi K, Yu P, Cone RD
(2004) Nat Neurosci 7: 335-6
MeSH Terms: Animals, Arcuate Nucleus of Hypothalamus, Down-Regulation, Eating, Energy Metabolism, Feeding Behavior, Female, Hypothalamus, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Neural Pathways, Neurons, Pro-Opiomelanocortin, Proto-Oncogene Proteins c-fos, Rats, Rats, Sprague-Dawley, Receptor, Melanocortin, Type 4, Satiety Response, Sincalide, Solitary Nucleus
Show Abstract · Added December 10, 2013
Hypothalamic pro-opiomelanocortin (POMC) neurons help regulate long-term energy stores. POMC neurons are also found in the nucleus tractus solitarius (NTS), a region regulating satiety. We show here that mouse brainstem NTS POMC neurons are activated by cholecystokinin (CCK) and feeding-induced satiety and that activation of the neuronal melanocortin-4 receptor (MC4-R) is required for CCK-induced suppression of feeding; the melanocortin system thus provides a potential substrate for integration of long-term adipostatic and short-term satiety signals.
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23 MeSH Terms