AQP1—A REGULATORY FACTOR ASSOCIATED WITH BROWN ADIPOSE TISSUE SILENCING TO COMBAT OBESITY AND METABOLIC DISEASE

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.

Name thesis:degree_name

Ph. D., Biomedical and Biological Sciences

Level thesis:degree_level

Doctor of Philosophy

Discipline thesis:degree_discipline

Biomedical and Biological Sciences

Grantor

Cornell University

Year dc:date.issued

2024

Author dc:creator

• Cheng, Chloe

Committee members dc:contributor.committeemember

• Schimenti, John
• Sethupathy, Praveen
• Lujan, Marla

• Aquaporin
• Brown Adipose Tissue
• Metabolic Dysfunction
• Negative Regulators
• Obesity
• Thermogenic Silencing

Statement dc:rights

• Attribution-NonCommercial-NoDerivatives 4.0 International

Licence dc:rights.uri

• https://creativecommons.org/licenses/by-nc-nd/4.0/

Language dc:language.iso

en

DOI

http://doi.org/10.7298/6jhn-cx64

Dc Identifier Other

ProQuest Submission ID: 14725
ProQuest Publication ID: 31639364

OAI identifier oai:identifier

oai:ecommons.cornell.edu:1813/117122