• Neuronal cells expressing pro-opiomelanocortin (POMC), neuropeptide-Y/agouti-related protein (NPY/AgRP) were generated from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) obtained from patients with monogenic forms of obesity. (columbia.edu)
  • Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. (nih.gov)
  • 4 In the ARC, there are two distinct neuronal populations: one group of neurons produces the orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related peptide (AgRP), whereas the other subset of neurons expresses the anorexigenic neuropeptides proopiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript. (nature.com)
  • activation of the so-called POMC neurons decreases food intake, while the stimulation of AGRP neurons increases food intake. (lindau-nobel.org)
  • And this circuit even works the other way around: researchers found that by directly infusing nutrients into the stomach of mice, they were able to inhibit AGRP neurons and their promotion of food intake. (lindau-nobel.org)
  • Neurons in the hypothalamus are known for the molecular messengers, or peptides they produce, like AgRP or POMC, which are thought to encourage or discourage feeding, respectively . (labroots.com)
  • We have observed that suppression of ROS levels diminish pro-opiomelanocortin (POMC) cell activation and promote the activity of neuropeptide Y- (NPY)/ agouti related peptide- (AgRP) neurons and feeding, whereas ROS activates POMC neurons and reduces feeding. (grantome.com)
  • 2014) and preliminary data generated during this funding period showed that mitochondrial size in AgRP and POMC neurons changes according to the metabolic state of the organism: while during negative energy balance, characterized by increased AgRP and decreased POMC neuronal activities, mitochondrial size decreases (fission), during positive energy balance (fed state) mitochondrial size increases in AgRP and POMC (fusion). (grantome.com)
  • Thus, we hypothesize that the activity levels of POMC and NPY/AgRP neurons require UCP2-mediated mitochondrial dynamics. (grantome.com)
  • UCP2-induced mitochondrial fission, by decreasing ROS production, inhibits POMC neurons while activates NPY/AgRP neurons. (grantome.com)
  • Aim 2 will test the hypothesis that UCP2-mediated mitochondrial fission activates NPY/AgRP neurons. (grantome.com)
  • Aim 3 will test the hypothesis that fuel availability drives mitochondrial dynamics in AgRP and POMC neurons. (grantome.com)
  • After screening several morphogens and other molecules affecting neuronal differentiation, we developed a protocol that combined early activation of sonic hedgehog signaling followed by timed NOTCH inhibition resulting in the generation of hypothalamic arcuate nucleus (ARC)-like neurons. (columbia.edu)
  • Here, we show by congenital and adult-onset Rpgrip1l deletion in Pomc-expressing neurons that the hyperphagia and obesity are likely due to neurodevelopmental effects that are characterized by a reduction in the Pomc/Neuropeptide Y (Npy) neuronal number ratio and marked increases in arcuate hypothalamic-paraventricular hypothalamic (ARH-PVH) axonal projections. (jci.org)
  • The robust native fluorescence of these reporters enables direct visualization of fine dendritic structures and axonal projections of the labeled neurons, which is useful in mapping neuronal circuitry, imaging and tracking specific cell populations in vivo. (bioseek.eu)
  • 5 The anorexigenic effect of monoamine serotonin is also mediated by the 5HT-2C receptor in POMC neurons. (nature.com)
  • The anorexigenic neuropeptide α-melanocyte-stimulating hormone (α-MSH) is produced by posttranscriptional processing of POMC and is released from the presynaptic terminals of POMC neurons. (nature.com)
  • These populations include the orexigenic neuropeptide Y (NPY) and anorexigenic proopiomelanocortin (POMC) neurons that have projections to key neurons in other hypothalamic nuclei and higher brain centers in order to orchestrate the feeding responses. (researchgate.net)
  • The consequences of inactivating mutations of PCSK1 include obesity, possibly due to impaired function of anorexigenic POMC arcuate neurons. (columbia.edu)
  • Activation of this receptor has previously been shown to decrease hunger and increase satiety, [ 89 ] the mechanism of which has been proposed to be by increasing pro-opiomelanocortin (POMC) expression with subsequent increased release of α-melanocyte stimulating hormone, which stimulates the anorexigenic melanocortin 4 receptor. (medscape.com)
  • The underlying neurocircuitry responsible for this is poorly understood, in part because of incomplete knowledge regarding first-order, leptin-responsive neurons. (nih.gov)
  • To address this, we and others have been removing leptin receptors from candidate first-order neurons. (nih.gov)
  • As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons probably mediates, at least in part, leptin's antiobesity effects. (nih.gov)
  • These neurons are the first-order neurons on which peripheral metabolic hormones, including leptin, insulin, ghrelin and nutrients, primarily act. (nature.com)
  • Under normal conditions, leptin binds the leptin receptor on proopiomelanocortin (POMC) neurons, and POMC is then cleaved by the protein encoded by PCSK1 . (biomedcentral.com)
  • Neuropeptide Y/agouti-related protein- and proopiomelanocortin-producing neurons in the hypothalamic arcuate nucleus primarily sense the body energy state. (nature.com)
  • My thesis research focused on establishing an in vitro model for understanding the molecular neurophysiology of obesity using, as 'proof-of-principle', neurons derived from human pluripotent stem cells (hPSCs) derived from individuals with monogenic forms of obesity. (columbia.edu)
  • Using stem cell-derived hypothalamic neurons to investigate the neurophysiology of obesity caused by prohormone convertase 1/3 deficiency (Chapter 3). (columbia.edu)
  • To understand the molecular neurophysiology of the obesity in PC1/3-deficient subjects, we generated PCSK1 deficient hESC lines with CRISPR or by knocking down PCSK1 with shRNA, and assessed the POMC processing in the hypothalamic ARC-like neurons made from these lines. (columbia.edu)
  • CRISPR/SaCas9 mutagenesis of stromal interaction molecule 1 in proopiomelanocortin neurons increases glutamatergic excitability and protects against diet-induced obesity. (harvard.edu)
  • Previous studies have shown that congenital Rpgrip1l hypomorphism in murine proopiomelanocortin (Pomc) neurons causes obesity by increasing food intake. (jci.org)
  • Isogenic human ARH-like embryonic stem cell-derived (ESc-derived) neurons homozygous for the obesity-risk alleles at rs8050136 or rs1421085 have decreased RPGRIP1L expression and have lower numbers of POMC neurons. (jci.org)
  • The mice with mild mitochondrial stress in POMC neurons may have avoided obesity due to the fat tissues within their bodies changing. (neurosciencenews.com)
  • Minireview: Regulation of Prohormone Convertases in Hypothalamic Neurons: Implications for ProThyrotropin-Releasing Hormone and Proopiomelanocortin Eduardo A. Nillni Division of Endocrinology, Department of Medicine, Brown Medical School/Rhode Island Hospital, and Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02903 Recent evidence demonstrated that posttranslational processing of neuropeptides is critical in the pathogenesis of obesity. (moam.info)
  • We found that mice lacking Efnb1 in POMC-expressing progenitors display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. (nih.gov)
  • However, despite reduced excitatory inputs, mice lacking Efnb2 in POMC-expressing progenitors showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. (nih.gov)
  • These results are consistent with the elevated plasma POMC and ACTH intermediates levels of in humans segregating for hypomorphic mutations of PCSK1, and the impaired pituitary POMC processing in the PC1/3 mutant mice. (columbia.edu)
  • Combining rabies-virus tracing, optical clearing (CLARITY), and whole-brain light-sheet imaging, we mapped the monosynaptic inputs to midbrain dopamine neurons projecting to different targets (different parts of the striatum, cortex, amygdala, etc) in mice. (elifesciences.org)
  • was decreased within POMC neurons of HFD mice. (bioinf.org)
  • To examine the effects of mitochondrial stress on metabolism, Lee and colleagues examined mice that were bred to be either partially or completely deficient in a single gene within a specific type of brain cell, hypothalamic proopiomelanocortin (POMC) neurons. (neurosciencenews.com)
  • Further study of the mice revealed that their affected neurons expressed both more MOTS-c as well as more beta-endorphin (β-END), a pain-suppressing molecule typically released during exercise. (neurosciencenews.com)
  • This project was designed to establish an in vitro model for studying hypothalamic cell-molecular physiology in neurons derived from hPSCs. (columbia.edu)
  • The ratios of adrenocorticotropic hormone (ACTH)/POMC, αMSH/POMC and β endorphin (BEP)/POMC proteins were significantly decreased, while total quantities of POMC peptides were greatly increased in PCSK1-deficient hESC-derived neurons, indicating impaired POMC processing caused by reduced PC1/3 protein. (columbia.edu)
  • melanocyte-stimulating hormone (MSH) , also called intermedin or melanotropin , any of several peptides derived from a protein known as proopiomelanocortin (POMC) and secreted primarily by the pituitary gland . (britannica.com)
  • Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC-expressing progenitors and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding. (nih.gov)
  • These neurons project to other hypothalamic nuclei and to the nucleus of the solitary tract in the brain stem to control multiple aspects of the homeostatic regulation of energy balance. (nature.com)
  • In vivo loss of Efnb1 in POMC-expressing progenitors decreases the amount of glutamatergic inputs, associated with a reduced number of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits and excitability of these cells. (nih.gov)
  • glutamatergic neurons play only a minor role. (nih.gov)
  • In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. (nih.gov)
  • Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. (nih.gov)
  • Interestingly, in day 28 PC1/3-deficient neurons, in addition to upregulation of POMC gene expression and protein, we found increases in some of the 'downstream' proteolytic enzymes for POMC processing and the 'upstream' transcription factor that regulates PCSK1 expression. (columbia.edu)
  • RPGRIP1L overexpression increases POMC cell number. (jci.org)
  • While functionally relevant neurons have been identified, the observed effects have been small, suggesting that most first-order neurons remain unidentified. (nih.gov)
  • 2002). Accordingly, overexpression of PLIC-1 in neurons promotes the surface expression of GABAARs ( Bedford et al. (vegfr-3inhibitor.com)
  • Aim 1 will test the hypothesis that UCP2-mediated mitochondrial fission inactivates POMC neurons. (grantome.com)
  • Mitohormesis in Hypothalamic POMC Neurons Mediates Regular Exercise-Induced High-Turnover Metabolism. (harvard.edu)
  • The α-MSH peptide , for example, is derived from the middle region of POMC, whereas β-MSH is derived from the C-terminus (the end containing a carboxyl group) and γ-MSH from the N-terminus (the end containing an amine group). (britannica.com)
  • N-terminal peptide of POMC or NPP). (harvard.edu)
  • We generate unique mouse models, using Cre-loxP/Flp-frt strategy, with genes of interest manipulated in specific populations of neurons at the time of choice. (bcm.edu)
  • We found that most populations of dopamine neurons receive a similar set of inputs rather than forming strong reciprocal connections with their target areas. (elifesciences.org)
  • A common feature among most populations of dopamine neurons was the existence of dense 'clusters' of inputs within the ventral striatum. (elifesciences.org)
  • Some small populations of neurons modulate the activity of hundreds or thousands of these synapses all across the brain by releasing 'neuromodulators' that affect how they work. (elifesciences.org)
  • Some stressors involve an immediate threat to physiological homeostasis and require the rapid relay of peripheral signals to PVN neurons via direct serotonergic or catecholaminergic projections from brainstem nuclei [ 9 , 11 ]. (nature.com)
  • These hypothalamic-like neurons accounted for over 90% of differentiated cells and exhibited transcriptional profiles characteristic of specific hypothalamic neurons (and explicitly lacking pituitary markers). (columbia.edu)
  • However, we found that dopamine neurons projecting to the posterior striatum were outliers, receiving relatively few inputs from the ventral striatum and instead receiving more inputs from the globus pallidus, subthalamic nucleus, and zona incerta. (elifesciences.org)
  • These results lay a foundation for understanding the input/output structure of the midbrain dopamine circuit and demonstrate that dopamine neurons projecting to the posterior striatum constitute a unique class of dopamine neurons regulated by different inputs. (elifesciences.org)
  • Most neurons send their messages to recipient neurons by releasing a substance called a 'neurotransmitter' that binds to receptors on the target cell. (elifesciences.org)
  • Congenital hypomorphism for this gene causes a rare autosomal disorder that impairs the processing of specific proproteins to their more bioactive derivatives, affecting, for example, the processing of POMC, proinsulin and proglucagon. (columbia.edu)
  • These findings suggest that apparently functional intronic polymorphisms affect hypothalamic RPGRIP1L expression and impact development of POMC neurons and their derivatives, leading to hyperphagia and increased adiposity. (jci.org)
  • Biallelic RPGRIP1L mutations result in fewer cilia-positive human induced pluripotent stem cell-derived (iPSC-derived) neurons and blunted responses to Sonic Hedgehog (SHH). (jci.org)
  • Specifically, in the absence of Tbx3, the neurons responsible for producing a feeling of satiety are no longer able to synthesize the expected molecular messengers. (labroots.com)
  • In the hippocampal dentate gyrus of the brain, SRC-2 (green) is abundantly expressed, co-localizing with several POMC-lineage neurons (red). (bcm.edu)
  • Dopamine neurons that target part of the brain called the posterior striatum receive relatively little input from the ventral striatum. (elifesciences.org)
  • The "munchies," or that uncontrollable urge to eat after using marijuana, appear to be driven by neurons in the brain that are normally involved in suppressing appetite, according to a new study by Yale School of Medicine researchers in the February 18 issue of the journal Nature. (scitechdaily.com)
  • Thanks to a 2015 study , we now know that THC can 'trick' the brain into making it think the body needs food by activating pro-opiomelanocortin (POMC) neurons, which signal fullness. (analyticalcannabis.com)
  • A diet full of carbs encourages weight gain and simultaneously knocks out the neurons responsible for hunger suppression, making it harder to lose weight once a person's realized it's time to shed the extra poundage. (marksdailyapple.com)
  • Our efforts in these years to avoid excessive carbs can encourage the longevity of these neurons and our hunger-regulating cellular balance. (marksdailyapple.com)
  • We were surprised to find that the neurons we thought were responsible for shutting down eating, were suddenly being activated and promoting hunger, even when you are full. (scitechdaily.com)
  • POMC neurons fail to turn off this hunger signal while under the influence of THC. (analyticalcannabis.com)
  • Astrocytes detect the signal and react within one hour, causing POMC neurons to activate and promote the feeling of satiety. (neurosciencenews.com)
  • Diet-induced hypothalamic inflammation is an important mechanism leading to dysfunction of neurons involved in controlling body mass. (positivehealth.com)
  • 2008). Based on its expression in dI1 commissural neurons and in the floorplate (Figures 1A and 1B), GPC1 was a good candidate as a regulator of Shh activity. (vegfr-3inhibitor.com)
  • Single cell transcriptome analysis of day 27 hESC-derived hypothalamic neurons enabled us to identify specific hypothalamic cell types (e.g. (columbia.edu)