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

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          Abstract

          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.

          Highlights

          • Diet-induced obesity alters reelin protein levels and expression of ApoER2 and VLDLR.

          • Reelin has direct, but divergent actions on GABAergic inputs onto POMC neurons.

          • Central administration of reelin protein decreases food intake and body weight.

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          Most cited references56

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          A protein related to extracellular matrix proteins deleted in the mouse mutant reeler.

          The autosomal recessive mouse mutation reeler leads to impaired motor coordination, tremors and ataxia. Neurons in affected mice fail to reach their correct locations in the developing brain, disrupting the organization of the cerebellar and cerebral cortices and other laminated regions. Here we use a previously characterized reeler allele (rl(tg)) to close a gene, reelin, deleted in two reeler alleles. Normal but not mutant mice express reelin in embryonic and postnatal neurons during periods of neuronal migration. The encoded protein resembles extracellular matrix proteins involved in cell adhesion. The reeler phenotype thus seems to reflect a failure of early events associated with brain lamination which are normally controlled by reelin.
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            Neurobiology of food intake in health and disease.

            Under normal conditions, food intake and energy expenditure are balanced by a homeostatic system that maintains stability of body fat content over time. However, this homeostatic system can be overridden by the activation of 'emergency response circuits' that mediate feeding responses to emergent or stressful stimuli. Inhibition of these circuits is therefore permissive for normal energy homeostasis to occur, and their chronic activation can cause profound, even life-threatening, changes in body fat mass. This Review highlights how the interplay between homeostatic and emergency feeding circuits influences the biologically defended level of body weight under physiological and pathophysiological conditions.
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              Reelin and brain development.

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                Author and article information

                Contributors
                Journal
                Mol Metab
                Mol Metab
                Molecular Metabolism
                Elsevier
                2212-8778
                08 June 2019
                August 2019
                08 June 2019
                : 26
                : 18-29
                Affiliations
                [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
                [4 ]Department of Physiology, Monash University Biomedicine Discovery Institute, Clayton, Victoria, Australia
                Author notes
                []Corresponding author. Division of Cardiometabolic Health Oregon National Primate Research Center, 505 NW 185th Avenue, Beaverton, OR, 97006, USA. kievitp@ 123456ohsu.edu
                Article
                S2212-8778(19)30147-4
                10.1016/j.molmet.2019.06.001
                6667498
                31230943
                e83af193-84b5-4075-9ef5-7667860161d0
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 13 February 2019
                : 22 May 2019
                : 4 June 2019
                Categories
                Original Article

                reelin,proopiomelanocortin,arcuate nucleus,obesity
                reelin, proopiomelanocortin, arcuate nucleus, obesity

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