The impact of epidermal growth factor receptor inhibition on energy homeostasis
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Weed, Melanie B. The Impact of Epidermal Growth Factor Receptor Inhibition On Energy Homeostasis. Chapel Hill, NC: University of North Carolina at Chapel Hill, 2010. https://doi.org/10.17615/rcat-ww81APA
Weed, M. (2010). The impact of epidermal growth factor receptor inhibition on energy homeostasis. Chapel Hill, NC: University of North Carolina at Chapel Hill. https://doi.org/10.17615/rcat-ww81Chicago
Weed, Melanie B. 2010. The Impact of Epidermal Growth Factor Receptor Inhibition On Energy Homeostasis. Chapel Hill, NC: University of North Carolina at Chapel Hill. https://doi.org/10.17615/rcat-ww81- Last Modified
- March 22, 2019
- Creator
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Weed, Melanie B.
- Affiliation: School of Medicine, Curriculum in Toxicology
- Abstract
- As a result of the worldwide rise in obesity and obesity-related complications such as diabetes, stroke, and cardiovascular disease, understanding the mechanisms associated with this disease and determining treatment options is necessary. A balance between food intake and energy expenditure, through a highly integrated multi-organ system, determines body weight regulation. Signals relaying energy storage and satiety from the periphery are sent to the central nervous system (CNS) where they, along with other neuronal signals, are used to maintain this balance. Accumulating evidence suggests signaling through the epidermal growth factor receptor (EGFR) is required for normal adipocyte development; therefore understanding how this signaling contributes to excess body fat mass is necessary to unravel the mechanisms associated with obesity. Our lab has previously shown that EGFR inhibition retards adipose deposition in a diet-induced obesity (DIO) model. To further delineate the role of EGFR in DIO, we performed two studies using pharmacological and genetic mouse models with either suppressed or conditionally deleted EGFR. In the first study, wild-type male C57BL/6J mice were chronically exposed to a high-fat western diet (WD) with or without a small molecule inhibitor to the EGFR tyrosine kinase, AG1478. In a separate experiment, mice homozygous for the Egfrwa2 mutation, a constitutionally impaired EGFR tyrosine kinase, and their control littermates were also challenged with this WD. The second study aimed to understand the role of EGFR in energy homeostasis in DIO. Mice with Egfr specifically deleted in peripheral tissues (intestines and adipocytes) and in the CNS using the Egfrtm1Dwt conditional allele and the Villin-Cre, aP2-Cre, and GFAP-Cre, transgenic lines, respectively, were chronically exposed to the WD. Significantly less body weight and fat mass were observed in mice with EGFR inhibition, either pharmacologically with AG1478 or genetically in the Egfrwa2 and GFAP-Cre genetic lines. Alterations in adipocyte size, adipocyte-specific factors, food intake, energy expenditure, and clinical parameters were also observed in these mice. We conclude that alterations in energy homeostasis account for this fat mass decrease. These studies should aid in our understanding of the role of EGFR in appetite and metabolism and provide potential avenues for the treatment of obesity.
- Date of publication
- May 2010
- DOI
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- Rights statement
- In Copyright
- Note
- "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Toxicology."
- Advisor
- Threadgill, David W.
- Language
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- Place of publication
- Chapel Hill, NC
- Access right
- Open access
- Date uploaded
- March 18, 2013
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