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Uncovering an Adipocyte’s Perspective of Inflammation and Immunity in Obesity

Chan, Calvin
http://orcid.org/0000-0002-9933-3061
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1560866472579872

Abstract Details

2019, PhD, University of Cincinnati, Medicine: Immunology.
Adipocytes, traditionally perceived to be simple energy storing cells, are highly complex biosynthetic factories that regulate overall metabolic health. Among their multi-potent capacities, evidence hints at an intertwined relationship between adipocytes and inflammation. Like immune cells, adipocytes are highly plastic and consists of different subsets, including white, brown, beige and pink adipocytes. Adipocytes can conduct themselves in an “immune-like” manner and inflammation can influence adipocyte lipid metabolism. However, mechanisms underpinning adipocyte inflammatory potential and inflammatory regulation of adipocyte homeostasis remain critical gaps in knowledge. As long underappreciated cells, elucidating this complex connection holds promise to uncover how adipocyte-inflammation integrates within human health and disease. In this dissertation, we have identified two inflammatory pathways (type I interferon (IFN)/interferon aß receptor (IFNAR) and BAFF/APRIL axes) that regulate adipocyte functional potential. Our data define the role of type I IFN/IFNAR axis in unleashing dormant adipocyte inflammatory capacity. Notably, activation of IFNAR promotes an “immune-like” transcriptome and amplifies a glycolysis-associated inflammatory vigor in adipocytes. We posited that type I IFN/IFNAR-driven adipocyte inflammatory vigor could impact disease pathogenesis, including obesity. Indeed, obesity not only augments the type I IFN axis in adipocytes but also enhanced their responsiveness to type I IFN effects. Notably, non-hematopoietic (e.g., adipocytes) IFNAR expression contributed to obesity-associated metabolic dysfunction. These findings highlight for the first time a mechanism revealing adipocyte pathogenic inflammatory potential and its potential contribution in the context of obesity. As adipocytes and inflammation are recognized pathogenic agents in the context of obesity, we initially sought to define whether deletion of a negative regulator of TLR activity, radioprotective 105 (RP105), would exacerbate adipocyte and inflammation pathogenic effects. This pursuit led to the serendipitous discovery of the B cell activating factor (BAFF)/A proliferation inducing ligand (APRIL) axis-mediated protection from obesity development. Multiple transgenic mouse lines exhibiting increased systemic BAFF levels were protected from diet-induced obesity (DIO). While genetic deletion of BAFF or APRIL alone was insufficient to reverse resistance to DIO, removal of both BAFF and APRIL fully exacerbated diet-driven weight gain. Dissection of the source of this protection revealed that both BAFF and APRIL modified white adipocyte lipolysis, the breakdown of fat, increased brown adipocyte thermogenesis, and total body energy expenditure. Higher systemic BAFF or APRIL levels were directly correlated with greater weight loss after bariatric surgery. Thus, these findings highlight BAFF/APRIL as beneficial and multifaceted inflammatory mediators that may play a vital role in obesity development. Overall, our findings shed light on an intricate balance between inflammation and adipocyte function. Harnessing our understanding of how to modulate the detrimental (inflammatory vigor) and beneficial (lipid/energy handling) aspects of the adipocyte-inflammation axis may yield insights into previously hidden therapeutic avenues for human health and disease.
Senad Divanovic, Ph.D. (Committee Chair)
George Deepe, M.D. (Committee Member)
Kasper Hoebe, Ph.D. (Committee Member)
Thomas Inge, M.D. (Committee Member)
Ian Lewkowich, Ph.D. (Committee Member)
265 p.
Immunology
Obesity; Interferon; BAFF; APRIL; Adipocyte; Inflammation

Recommended Citations

Citations

  • Chan, C. (2019). Uncovering an Adipocyte’s Perspective of Inflammation and Immunity in Obesity [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1560866472579872

    APA Style (7th edition)

  • Chan, Calvin. Uncovering an Adipocyte’s Perspective of Inflammation and Immunity in Obesity. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1560866472579872.

    MLA Style (8th edition)

  • Chan, Calvin. "Uncovering an Adipocyte’s Perspective of Inflammation and Immunity in Obesity." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1560866472579872

    Chicago Manual of Style (17th edition)

ucin1560866472579872
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© 2019, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.