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Sex-dependent Effects of Adipocyte STAT3 Inhibition on the Inflammatory Response during Sepsis

Davis, Xenia
http://orcid.org/0000-0002-5014-0197
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1668637450577416

Abstract Details

2022, PhD, University of Cincinnati, Medicine: Molecular, Cellular and Biochemical Pharmacology.
Sepsis is a dysregulated inflammatory response induced by an infection that can lead to life-threatening organ dysfunction. Clinical and animal studies consistently demonstrate that females are less susceptible to the adverse effects of sepsis, demonstrating the importance of understanding how sex influences sepsis outcomes. Obesity is a global health problem characterized by excessive fat accumulation in the white adipose tissue (WAT). Outcomes in obese patients with sepsis are inconsistent in the literature, with some studies showing that obesity is harmful and other studies showing that obesity is protective during sepsis. The signal transducer and activator of transcription 3 (STAT3) pathway facilitates inflammation in sepsis and obesity. STAT3 is abundantly expressed in the WAT, however little is known about the contribution of WAT STAT3 during sepsis. In a pilot study, polymicrobial sepsis was induced in 17-week-old C57BL/6 mice by cecal ligation and puncture (CLP). Non-septic control mice did not undergo CLP. We demonstrated that STAT3 is activated/phosphorylated at tyrosine 705 and serine 727 in the WAT during sepsis. We hypothesize that adipocyte STAT3 inhibition during sepsis will exaggerate the inflammatory response and impact organ injury, in a sex-dependent manner. To investigate the role of adipocyte STAT3 activation during sepsis, studies were done in 20-week-old male wild-type (WT) and adipocyte STAT3 knockout (A-STAT3 KO) mice. Polymicrobial sepsis was induced at a low severity by CLP (23-gauge needle, 2x cecum puncture). Non-septic control mice did not undergo CLP. Adipocyte STAT3 inhibition did not alter body weight in non-septic mice or cause body weight loss in septic mice. Polymicrobial sepsis increased plasma TNF-a, IL-6, and leptin levels, as well as lung and liver neutrophil infiltration and liver injury in WT and A-STAT3 KO mice. Adipocyte STAT3 inhibition increased plasma leptin levels but did not alter organ injury during sepsis. In clinical settings, organ injury occurs when sepsis is severe. We utilized a high severity sepsis model in 12-14-week-old WT and A-STAT3 KO mice. To determine if sex differences exist, we used both male and female mice. Polymicrobial sepsis was induced at a high severity by CLP (21-gauge needle, 2x cecum puncture). Non-septic mice did not undergo CLP. Body composition nor energy metabolism were altered with adipocyte STAT3 inhibition in male or female mice, under normal conditions (non-septic). Sepsis was associated with reduced adipocyte size in female WT and A-STAT3 KO mice. Sepsis was associated with increased plasma TNF-a and IL-6 in both male and female mice but the adipokine leptin was only increased in male mice. Adipocyte STAT3 inhibition did not affect cytokine expression. Adipocyte STAT3 inhibition reduced lung neutrophil infiltration and lung injury during sepsis in male, but not female mice. On the contrary, liver neutrophil infiltration and liver injury was not altered by adipocyte STAT3 inhibition in male or female mice. This dissertation demonstrates that female sex influences WAT morphology during sepsis, independent of adipocyte STAT3 activation. Furthermore, adipocyte STAT3 contributes to a diverse inflammatory response and organ injury during sepsis, in a sex-dependent manner.
Jennifer Kaplan, MD MS (Committee Member)
Guo-Chang Fan, Ph.D. (Committee Member)
Basilia Zingarelli, M.D. (Committee Member)
Juan Sanchez-Gurmaches, Ph.D. (Committee Member)
Jo El Schultz, Ph.D. (Committee Member)
Phillip Owens, Ph.D. (Committee Member)
179 p.
Physiology
Sepsis; Inflammation; STAT3; White adipose tissue; Sex-differences

Recommended Citations

Citations

  • Davis, X. (2022). Sex-dependent Effects of Adipocyte STAT3 Inhibition on the Inflammatory Response during Sepsis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1668637450577416

    APA Style (7th edition)

  • Davis, Xenia. Sex-dependent Effects of Adipocyte STAT3 Inhibition on the Inflammatory Response during Sepsis. 2022. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1668637450577416.

    MLA Style (8th edition)

  • Davis, Xenia. "Sex-dependent Effects of Adipocyte STAT3 Inhibition on the Inflammatory Response during Sepsis." Doctoral dissertation, University of Cincinnati, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1668637450577416

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.