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Reelin is modulated by diet-induced obesity and has direct actions on arcuate proopiomelanocortin neurons.

  • Roberts, Brandon L1
  • Bennett, Baylin J1
  • Bennett, Camdin M1
  • Carroll, Julie M1
  • Dalbøge, Louise S2
  • Hall, Colin2
  • Hassouneh, Wafa2
  • Heppner, Kristy M2
  • Kirigiti, Melissa A1
  • Lindsley, Sarah R1
  • Tennant, Katherine G1
  • True, Cadence A1
  • Whittle, Andrew2
  • Wolf, Anitra C2
  • Roberts, Charles T Jr1
  • Tang-Christensen, Mads3
  • Sleeman, Mark W4
  • Cowley, Michael A4
  • Grove, Kevin L2
  • Kievit, Paul5
  • 1 Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR, 97006, USA.
  • 2 Obesity Research Center, Novo Nordisk, Seattle, WA, 98109, USA.
  • 3 Diabetes Research, Novo Nordisk, Måløv, Denmark. , (Denmark)
  • 4 Department of Physiology, Monash University Biomedicine Discovery Institute, Clayton, Victoria, Australia. , (Australia)
  • 5 Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR, 97006, USA. Electronic address: [email protected]
Published Article
Molecular Metabolism
Elsevier BV
Publication Date
Aug 01, 2019
DOI: 10.1016/j.molmet.2019.06.001
PMID: 31230943


Reelin (RELN) is a large glycoprotein involved in synapse maturation and neuronal organization throughout development. Deficits in RELN signaling contribute to multiple psychological disorders, such as autism spectrum disorder, schizophrenia, and bipolar disorder. Nutritional stress alters RELN expression in brain regions associated with these disorders; however, the involvement of RELN in the neural circuits involved in energy metabolism is unknown. The RELN receptors apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR) are involved in lipid metabolism and expressed in the hypothalamus. Here we explored the involvement of RELN in hypothalamic signaling and the impact of diet-induced obesity (DIO) on this system. Adult male mice were fed a chow diet or maintained on a high-fat diet (HFD) for 12-16 weeks. HFD-fed DIO mice exhibited decreased ApoER2 and VLDLR expression and increased RELN protein in the hypothalamus. Electrophysiology was used to determine the mechanism by which the central fragment of RELN (CF-RELN) acts on arcuate nucleus (ARH) satiety-promoting proopiomelanocortin (POMC) neurons and the impact of DIO on this circuitry. CF-RELN exhibited heterogeneous presynaptic actions on inhibitory inputs onto ARH-POMC-EGFP neurons and consistent postsynaptic actions. Additionally, central administration of CF-RELN caused a significant increase in ARH c-Fos expression and an acute decrease in food intake and body weight. We conclude that RELN signaling is modulated by diet, that RELN is involved in synaptic signaling onto ARH-POMC neurons, and that altering central CF-RELN levels can impact food intake and body weight. Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.

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