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Roles of Selenoprotein M (SELENOM) in Hypothalamic Leptin Signaling and Calcium Regulation.

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Title:Roles of Selenoprotein M (SELENOM) in Hypothalamic Leptin Signaling and Calcium Regulation.
Authors:Gong, Ting
Contributors:Molecular Biosciences & Bioeng (department)
Keywords:SELENOM
Leptin Signaling
Ca2+ Homeostasis
Endoplasmic Reticulum Stress
Thioredoxin
Date Issued:Aug 2018
Publisher:University of Hawaiʻi at Mānoa
Abstract:Selenium is an essential trace element that is critical for human health. The biological effects of selenium are largely mediated by selenoproteins, a unique class of proteins that contain selenocysteine (Sec) as an integral part of their polypeptide chain. Selenoprotein M (SELENOM) is an ER-resident thiol-disulfide oxidoreductase that is most abundant in the brain. It contains a thioredoxin-like domain (cysteine-X-X-selenocysteine) that catalyzes thiol-disulfide exchange. It has been reported that SELENOM has neuroprotective functions and is implicated in regulation of Ca2+ homeostasis. Our group previously published that Selenom-/- mice display increased weight gain, elevated white adipose tissue deposition, and impaired hypothalamic leptin sensitivity compared to wild-type mice, suggesting a role for SELENOM in energy homeostasis. Therefore, we performed a series of studies using in vivo and in vitro models to investigate the specific influence of SELENOM on hypothalamic leptin signaling, ER stress, and Ca2+ signaling. The evidence gathered in this study revealed that SELENOM promotes hypothalamic leptin signaling, inhibits ER stress, and regulates Ca2+ influx. To further delineate the underlying mechanism, we then assessed the subcellular localization and binding partners of SELENOM. Using co-immunoprecipitation and liquid chromatography–mass spectrometry/mass spectrometry (LC-MS/MS) to screen for SELENOM-binding partners, we discovered and verified two proteins, microtubule associated protein 6 (MAP6) and choline-phosphate cytidylyltransferase 1 alpha (PCYT1A). In addition, we found that SELENOM localizes not only in ER but also in mitochondria-associated ER-membranes (MAMs), suggesting a potential role of SELENOM in regulation of Ca2+ signaling. Finally, we performed microarray analysis using both Selenom-/- hypothalamic tissue and mHypoE-44 cells to identify the genes and signaling pathways most affected by SELENOM. Our results revealed 11 genes that were significantly altered by SELENOM deficiency, including thioredoxin-interacting protein (TXNIP), a negative regulator of the thioredoxin (TXN) system. SELENOM deficiency also significantly reduced TXN activity in both hypothalamic tissue and mHypoE-44 cells. In summary, our studies reveal that SELENOM promotes hypothalamic leptin signaling, potentially due to its functions in ER stress, Ca2+ signaling, and the hypothalamic TXN system. In addition, we further determined that SELENOM localizes in MAMs and interacts with MAP6 and PCYT1A, suggesting an important role in MAMs-modulated Ca2+ homeostasis.
Description:Ph.D. Thesis. University of Hawaiʻi at Mānoa 2018.
URI:http://hdl.handle.net/10125/62564
Rights:All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections: Ph.D. - Molecular Biosciences and Bioengineering


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