Regulation of orexin expression and changes in feeding behavior by the serotonin 5 HT₁ᴀ receptor
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2020-08
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Universidad de Valparaíso
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Programa de Doctorado de Ciencias Mención Neurociencia
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Food intake is regulated by the serotonergic (5-HTergic) as well as by the Orexinergic (Orxergic) systems. Orexin-A and Orexin-B are hypothalamic neuropeptides synthesized by a common polypeptide precursor called prepro-Orx those that increase food intake. Serotonin (5-HT) can regulate the activity of Orexinergic neurons through the 5-HT1A receptor expressed in the lateral hypothalamus (LH). 5-HT1A is a Gi/o protein coupled receptor, which canonically inhibits adenylate cyclase (AC) decreasing cyclic adenosine monophosphate (cAMP) levels, however it can activate several intracellular proteins including Akt. A relevant substrate of Akt is the transcription factor Forkhead Box A2 (Foxa2), which can control the Orx gene. In this work, we hypothesized that the 5-HT system, through 5-HT1A-Akt-Foxa2 pathway, can modulate the Orx expression at transcriptional level in Orx-ergic neurons of the LH, causing a decrease in food intake in mice.
Using primary cell culture of hypothalamic neurons, we found that the application of the selective 5-HT1A agonist (R)-8-hydroxy-2(di-n-propylamino)tetralin (DPAT) caused a significant decrease in the expression of prepro-Orx and the protein levels of Orx-A . We also found that the application of DPAT reduces the phosphorylation of Akt at Ser473, along with a reduced translocation to the Foxa2 into the nucleus in vitro; all these effects were effectively blocked by the co application of the selective 5-HT1A antagonist WAY100635. Next, we evaluated the in vivo effects of local activation of 5-HT1A intra-LH on food intake; administration of DPAT significantly decreased food intake. In addition, we found that intra-LH administration of DPAT significantly reduced Akt phosphorylation, Foxa2 nuclear translocation and Orx-A levels in the LH. To assess the direct role of Akt phosphorylation in feeding behavior, we infused an Akt antagonist into the LH of mice and found a significant decrease in food intake.
Finally, we measured the mRNA levels of prepro-Orx and 5-HT1A in the serotonin transporter knockout (SERT KO) mouse, a model that has reportedly about four times higher extracellular 5- HT in the brain. We found a ~ six-fold decrease in prepro-Orx levels and a ~ four-fold decrease in
5-HT1A in SERT-KO compared to control littermates.
Among the several pathways, we show that the Akt-Foxa2 pathway downstream lo 5- HT,AR activation in LH is involved in the regulation of Orx production and controls feeding behavior.
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SEROTONINA, CONSUMO DE ALIMENTOS