Arcuate nucleus glutamatergic neurons modulate energy homeostasis

Summary

Principal Investigator: Anthony N van den Pol
Abstract: DESCRIPTION (provided by applicant): The underlying health problem that this application addresses is the growing epidemic of obesity that now affects 30% of the adult population, and the resultant increase in heart disease, hypertension, diabetes, joint dysfunction, stroke, cancer, and early death that is estimated to cost upwards of 75 billion dollars per year. Many factors contribute to the obesity problem today. The hypothalamic arcuate nucleus in the brain acts like the information hub of energy balance, receiving information both from peripheral organs involved in energy storage or release, and receiving axonal information from other regions of the brain that also play important roles in CNS regulation of energy homeostasis, and sending out efferent information that regulates food intake and utilization. A focus for many years in this field has been the neuropeptides involved in energy regulation, and the hypothalamic neurons that secrete them. Most of the critical peptides involved in the regulation of energy homeostasis have been colocalized with the inhibitory transmitter GABA in the arcuate nucleus. This application focuses on what appears to be a new cellular player in the CNS regulation of energy balance that we have identified, the arcuate glutamatergic neuron, a cell that has the profile of one that reduces food intake. In most other regions of the brain glutamate is recognized as a major neurotransmitter. But in the hypothalamus, relatively little attention has been given to glutamate neurons, despite the fact that in the presence of glutamate receptor antagonists there is virtually no excitatory synaptic activity in the arcuate nucleus, or elsewhere in the hypothalamus. Prior to submitting this application, we have solved a central problem, that of recognizing these glutamate cells that exhibit no morphological difference from other hypothalamic cells, by generating a transgenic mouse that expresses the reporter GFP under the control of the vesicular glutamate transporter 2 (vGluT2) selectively in glutamate neurons. Our experiments utilize a combination of whole cell patch clamp electrophysiology, tract tracing with fluorogold and pseudorabies virus, ultrastructural immunocytochemistry, and altered gene expression in the context of challenges to whole animal energy balance. The first set of experiments address the hypothesis that the glutamate neurons show the same efferent axonal projections as the inhibitory neurons of the arcuate nucleus. This will be tested with fluorogold and recombinant pseudorabies virus microinjections into putative target regions. To test the hypothesis that arcuate glutamate cells regulate the activity of anorexigenic proopiomelanocortin (POMC) neurons, we will record from POMC neurons while stimulating local glutamate cells with the excitatory microdrop method to activate cell bodies but not axons of passage. Parallel experiments address the question of whether glutamate cells innervate each other, thereby increasing the timing and power of their output. Ultrastructural dual label immunocytochemistry will be used to test the hypothesis that local orexigenic neuropeptide Y (NPY) immunoreactive axons make synaptic contact with the glutamate cells, similar to the NPY axons that synapse with the anorexigenic POMC neurons. A second set of experiments, using whole cell patch clamp recording in hypothalamic slices, addresses the question of "What active or passive membrane characteristics make the glutamate neurons unique", compared with the GABAergic neurons of the arcuate nucleus that have received substantial attention. A third set of electrophysiological experiments tests the hypothesis that neuropeptides released from other arcuate nucleus neurons involved in the regulation of energy homeostasis modulate the activity of the arcuate glutamate neurons. In the fourth set of experiments, we ask whether arcuate glutamate neurons respond to long distance cues relating to energy homeostasis, particularly glucose and leptin. Together, these experiments will reveal the organization and cellular actions and responses of a unique and previously uncharacterized excitatory neuron in the arcuate nucleus. Understanding these glutamatergic cells should give us a better appreciation of the cellular mechanisms underlying energy homeostasis and body weight regulation, and should give us new insight into the potential treatment of obesity through those neurons that control food intake and expenditure. Many neurons in the arcuate nucleus have multiple roles;it is possible that the glutamate cell is no exception, and may play a role in other functions that this small but critical part of the brain controls, including regulation of the pituitary and other endocrine organs, reproduction and lactation, growth, metabolism, and response to stress.
Funding Period: 2010-04-10 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. pmc Cannabinoids excite circadian clock neurons
    Claudio Acuna-Goycolea
    Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA
    J Neurosci 30:10061-6. 2010
  2. pmc Kisspeptin directly excites anorexigenic proopiomelanocortin neurons but inhibits orexigenic neuropeptide Y cells by an indirect synaptic mechanism
    Li ying Fu
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
    J Neurosci 30:10205-19. 2010
  3. pmc Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice
    Meng Liu
    Veterans Affairs Boston Healthcare System and Harvard Medical School, West Roxbury, Massachusetts 02132, USA
    J Neurosci 31:6028-40. 2011
  4. pmc Thyrotropin-releasing hormone (TRH) inhibits melanin-concentrating hormone neurons: implications for TRH-mediated anorexic and arousal actions
    Xiaobing Zhang
    Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    J Neurosci 32:3032-43. 2012
  5. pmc Neuropeptide transmission in brain circuits
    Anthony N van den Pol
    Department of Neurosurgery, Yale University, New Haven, CT 06520, USA
    Neuron 76:98-115. 2012
  6. pmc Reversed synaptic effects of hypocretin and NPY mediated by excitatory GABA-dependent synaptic activity in developing MCH neurons
    Ying Li
    Dept of Neurosurgery, Yale Univ School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    J Neurophysiol 109:1571-8. 2013
  7. pmc Direct inhibition of arcuate proopiomelanocortin neurons: a potential mechanism for the orexigenic actions of dynorphin
    Xiaobing Zhang
    Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA
    J Physiol 591:1731-47. 2013

Research Grants

  1. Response properties of hypothalamic MCH neurons
    Anthony N van den Pol; Fiscal Year: 2013
  2. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
  3. ROLE OF FORKHEAD PROTEINS IN INSULIN ACTION
    Domenico Accili; Fiscal Year: 2013

Detail Information

Publications7

  1. pmc Cannabinoids excite circadian clock neurons
    Claudio Acuna-Goycolea
    Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA
    J Neurosci 30:10061-6. 2010
    ..These data raise the possibility that the time dissociation described by cannabinoid users may result in part from altered circadian clock function and/or entrainment to environmental time cues...
  2. pmc Kisspeptin directly excites anorexigenic proopiomelanocortin neurons but inhibits orexigenic neuropeptide Y cells by an indirect synaptic mechanism
    Li ying Fu
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
    J Neurosci 30:10205-19. 2010
    ..POMC cells may hypothetically serve as a conditional relay station downstream of kisspeptin and GnIH to signal the availability of energy resources relevant to reproduction...
  3. pmc Orexin gene transfer into zona incerta neurons suppresses muscle paralysis in narcoleptic mice
    Meng Liu
    Veterans Affairs Boston Healthcare System and Harvard Medical School, West Roxbury, Massachusetts 02132, USA
    J Neurosci 31:6028-40. 2011
    ..In turn, the ZI projects to the locus ceruleus, indicating that the ZI is part of a circuit that stabilizes motor tone. Our results indicate that these neurons might also be recruited to block the muscle paralysis in narcolepsy...
  4. pmc Thyrotropin-releasing hormone (TRH) inhibits melanin-concentrating hormone neurons: implications for TRH-mediated anorexic and arousal actions
    Xiaobing Zhang
    Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    J Neurosci 32:3032-43. 2012
    ..Together, our data suggest that TRH inhibits MCH neurons by increasing synaptic inhibition from local GABA neurons. Inhibition of MCH neurons may contribute to the TRH-mediated reduction in food intake and sleep...
  5. pmc Neuropeptide transmission in brain circuits
    Anthony N van den Pol
    Department of Neurosurgery, Yale University, New Haven, CT 06520, USA
    Neuron 76:98-115. 2012
    ....
  6. pmc Reversed synaptic effects of hypocretin and NPY mediated by excitatory GABA-dependent synaptic activity in developing MCH neurons
    Ying Li
    Dept of Neurosurgery, Yale Univ School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    J Neurophysiol 109:1571-8. 2013
    ....
  7. pmc Direct inhibition of arcuate proopiomelanocortin neurons: a potential mechanism for the orexigenic actions of dynorphin
    Xiaobing Zhang
    Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA
    J Physiol 591:1731-47. 2013
    ..A number of orexigenic hypothalamic neurons release dynorphin along with other neuropeptides. The inhibition of anorexigenic POMC neurons may be one mechanism underlying the orexigenic actions of dynorphin...

Research Grants30

  1. Response properties of hypothalamic MCH neurons
    Anthony N van den Pol; Fiscal Year: 2013
    ..abstract_text> ..
  2. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  3. ROLE OF FORKHEAD PROTEINS IN INSULIN ACTION
    Domenico Accili; Fiscal Year: 2013
    ..Therefore, it is hoped that by parsing its modes of action and interacting partners, new ways to modulate its function can be found. ..