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David DiSilvestro PhD Dissertation.pdf (7 MB)

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Encapsulation of Genetically Modified Preadipocytes for Potential Treatment of Metabolic Disorders

DiSilvestro, David Joel
http://orcid.org/0000-0001-8382-8193
http://rave.ohiolink.edu/etdc/view?acc_num=osu1449090087

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Ohio State University Nutrition.
Obesity is a worldwide epidemic that affects millions of people. The location of the excess fat dictates the health risk. Excess visceral fat increases the risk of fatal diseases like type II diabetes and certain cancers. Not all forms of obesity can be treated with traditional methods like diet, exercise, and drugs because of physiological differences between individuals. There is a need for new treatments that directly target visceral fat as well as treat the biochemistry that comprises the obesity disease. This dissertation is designed to investigate potential treatments for obesity and metabolic diseases by using genetically modified adipocytes. Cell lines can be engineered to be thermogenic or to overproduce hormones that regulate metabolism. However, there is not currently a safe way to genetically modify preexisting adipocytes and transplantations of modified adipocytes require immunosuppression. We developed a solution to these problems by encapsulating engineered fibroblasts in an immunoprotective poly-L-lysine membrane, allowing for controlled delivery of genetically modified cells into the host’s tissue. We hypothesized that encapsulating stably transduced preadipocytes, designed to be more thermogenic or overproduce hormones that regulate metabolism, could attenuate weight gain and improve metabolic markers when injected into the visceral fat pads of mice. For this reason, we investigated encapsulated genetically modified cells’ ability to improve glucose metabolism, metabolic rate, and attenuate weight gain in mouse models of obesity. Chapter one is a literature review of the obesity epidemic, the difference between fat depots, and how microencapsulation technology could be applied to treating obesity related diseases. In chapter two, we hypothesize that encapsulated Rptor deficient preadipocytes will have a thermogenic phenotype in vivo and improve symptoms of diet induced obesity. We find that these capsules attenuated weight gain briefly, but improved glucose metabolism and possibly fat metabolism through increased production of ATGL. In chapter three, we hypothesized that increasing the ability of Rptor deficient fibroblasts to up take nutrients could increase the rate of thermogenesis. These cells could be engineered to overproduce appetite suppressing hormones, amylin and leptin to compensate for increased appetite that comes with increased thermogenesis. The in vivo effects of these encapsulated cells were studied in mice fed a high fat diet. In chapter four, we hypothesized that encapsulated adipocytes overproducing leptin could secrete leptin, improve metabolism, and attenuate weight gain in ob/ob mice, an obese mouse model lacking leptin. We discovered that cells constitutively produced leptin and were able to secrete leptin when encapsulated. In vivo, these capsules improve metabolic rate, glucose metabolism, and reduce resistin. We previously showed that Aldh1a1-/- fibroblasts derived from subcutaneous fat are much more thermogenic than wild type fibroblasts from the same depot. In chapter five, we isolated these fibroblasts from subcutaneous fat, immortalized the cells, and stably transduced them to overexpress a fluorescence protein in order for these cells to be used for a future encapsulation experiment in obese dogs. Our preliminary data provides evidence, for the first time, that encapsulation of engineered preadipocytes may be a viable treatment option for metabolic diseases.
Ouliana Ziouzenkova (Advisor)
Steven Clinton (Committee Member)
Kichoon Lee (Committee Member)
Martha Belury (Committee Member)
118 p.
Biochemistry; Nutrition
encapsulation; alginate poly-L-lysine; obesity; type 2 diabetes; leptin; obesity therapy; rptor; regulatory associated protein of mTOR; weight loss; nutrition; microcapsule; resistin; thermogenesis; ob ob mice; Aldh1a1; obese gene

Recommended Citations

Citations

  • DiSilvestro, D. J. (2015). Encapsulation of Genetically Modified Preadipocytes for Potential Treatment of Metabolic Disorders [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449090087

    APA Style (7th edition)

  • DiSilvestro, David. Encapsulation of Genetically Modified Preadipocytes for Potential Treatment of Metabolic Disorders. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1449090087.

    MLA Style (8th edition)

  • DiSilvestro, David. "Encapsulation of Genetically Modified Preadipocytes for Potential Treatment of Metabolic Disorders." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1449090087

    Chicago Manual of Style (17th edition)

osu1449090087
445
© 2015, some rights reserved.Creative Commons License Encapsulation of Genetically Modified Preadipocytes for Potential Treatment of Metabolic Disorders by David Joel DiSilvestro is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.