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Cheng, Chloe Barrow, Joeva Schimenti, John Sethupathy, Praveen Lujan, Marla 2025-06-30T22:02:40Z 2025-06-30T22:02:40Z 2024-12 ProQuest Submission ID: 14725 ProQuest Publication ID: 31639364 https://hdl.handle.net/1813/117122 http://doi.org/10.7298/6jhn-cx64 16921927 116 pages The activation of non-shivering thermogenesis (NST) in brown adipose tissue (BAT) by environmental cold challenge yields strong metabolic benefit in the face of diet-induced obesity (DIO). Yet, a critical barrier to leveraging brown fat NST for therapeutic use against metabolic disease is that BAT is silenced and inactive at physiological ambient temperature conditions in humans and the mechanisms that govern this silencing process remain poorly understood. Here, I present a putative BAT-silencing factor, aquaporin-1 (AQP1), as a novel therapeutic target to protect subjects against DIO and metabolic dysfunction. Interrogation of in vivo metabolic parameters revealed BAT-specific AQP1 knockout mice (AQP1-KO) on high fat diet (HFD) experienced reduced diet-induced weight gain and fat mass, improved glucose tolerance, and increased whole body energy expenditure compared to control mice. Mechanistically, AQP1 ablation in mice on HFD had upregulated gene expression related to the electron transport chain (ETC) and mitochondrial translation. Thus, I demonstrate that ablation of AQP1 in BAT protects mice against DIO by increasing whole body energy expenditure through upregulation of the core ETC and mitochondrial translation gene program. My findings identify AQP1 as a novel regulatory factor that plays a potent role in modulating BAT metabolism and curbing the growing obesity epidemic in the United States. en Attribution-NonCommercial-NoDerivatives 4.0 International https://creativecommons.org/licenses/by-nc-nd/4.0/ Aquaporin Brown Adipose Tissue Metabolic Dysfunction Negative Regulators Obesity Thermogenic Silencing AQP1—A REGULATORY FACTOR ASSOCIATED WITH BROWN ADIPOSE TISSUE SILENCING TO COMBAT OBESITY AND METABOLIC DISEASE dissertation or thesis https://newcatalog.library.cornell.edu/catalog/16921927 application/pdf Biomedical and Biological Sciences Cornell University Doctor of Philosophy Ph. D., Biomedical and Biological Sciences https://hdl.handle.net/1813/59810.2 Publication Cornell Theses and Dissertations Cheng, Chloe 5893a6ea-7af3-41d7-abc6-04bcd26ab5df open.access open.access <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="062b597e-1c58-47cf-aa3e-f00dfba057d3"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>en</Language> <Title>AQP1—A REGULATORY FACTOR ASSOCIATED WITH BROWN ADIPOSE TISSUE SILENCING TO COMBAT OBESITY AND METABOLIC DISEASE</Title> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2024-12</PublicationDate> <DOI>http://doi.org/10.7298/6jhn-cx64</DOI> <Authors> <Author> <DisplayName>Cheng, Chloe</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <OrgUnit /> </Publisher> </Publishers> <License>https://creativecommons.org/licenses/by-nc-nd/4.0/</License> <Keyword>Aquaporin</Keyword> <Keyword>Brown Adipose Tissue</Keyword> <Keyword>Metabolic Dysfunction</Keyword> <Keyword>Negative Regulators</Keyword> <Keyword>Obesity</Keyword> <Keyword>Thermogenic Silencing</Keyword> <Abstract>The activation of non-shivering thermogenesis (NST) in brown adipose tissue (BAT) by environmental cold challenge yields strong metabolic benefit in the face of diet-induced obesity (DIO). Yet, a critical barrier to leveraging brown fat NST for therapeutic use against metabolic disease is that BAT is silenced and inactive at physiological ambient temperature conditions in humans and the mechanisms that govern this silencing process remain poorly understood. Here, I present a putative BAT-silencing factor, aquaporin-1 (AQP1), as a novel therapeutic target to protect subjects against DIO and metabolic dysfunction. Interrogation of in vivo metabolic parameters revealed BAT-specific AQP1 knockout mice (AQP1-KO) on high fat diet (HFD) experienced reduced diet-induced weight gain and fat mass, improved glucose tolerance, and increased whole body energy expenditure compared to control mice. Mechanistically, AQP1 ablation in mice on HFD had upregulated gene expression related to the electron transport chain (ETC) and mitochondrial translation. Thus, I demonstrate that ablation of AQP1 in BAT protects mice against DIO by increasing whole body energy expenditure through upregulation of the core ETC and mitochondrial translation gene program. My findings identify AQP1 as a novel regulatory factor that plays a potent role in modulating BAT metabolism and curbing the growing obesity epidemic in the United States.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>