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

Brandon L. Roberts, Baylin J. Bennett, Camdin M. Bennett, Julie M. Carroll, Louise S. Dalbøge, Colin Hall, Wafa Hassouneh, Kristy M. Heppner, Melissa A. Kirigiti, Sarah R. Lindsley, Katherine G. Tennant, Cadence A. True, Andrew Whittle, Anitra C. Wolf, Charles T. Roberts, Mads Tang-Christensen, Mark W. Sleeman, Michael A. Cowley, Kevin L. Grove, Paul Kievit

Reelin is a large extracellular glycoprotein that is implicated in synaptic formation, remodeling, neuronal migration, and development. There are two known receptors for Reelin, the very low-density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor 2 (ApoER2). Roberts et al. determined the impact of diet-induced obesity on Reelin, ApoER2, and VLDLR expression in the hypothalamus. They demonstrate a possible mechanism by which Reelin could influence energy homeostasis. In addition, consumption of a high fat diet blunts VLDLR and ApoER2 expression in the hypothalamus and disrupts at least one mechanism by which Reelin acts on arcuate proopiomelanocortin neurons.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.