Obesity-associated systemic and intrinsic IR dysregulates B cell metabolism and function

• Author / Creator

  Zhu, Mengyi

• Obesity and associated insulin resistance (IR) represent a significant global health burden. Emerging evidence suggests that obesity is accompanied by impaired adaptive immunity. B cells contribute significantly to adaptive immunity, and the dysregulation of B cell function in obese individuals has been demonstrated. Insulin is a crucial hormone governing glucose homeostasis, which is essential for cell survival, growth, activation, and function. Our laboratory previously
  observed that B cells can express the insulin receptor (InsR), and diet-induced obesity (DIO) impaired insulin signaling in B cells. However, the specific role of insulin signaling and IR in B
  cells remains unknown. Therefore, my research aims to elucidate the impact of insulin signaling and IR on the regulation of B cell activation and function during both a healthy state and dietinduced obesity.
  Here, I present my findings that the activation and disruption of insulin signaling may have no effect on the activation of B cells but regulated the metabolism in B cells stimulated with LPS or
  CpG. Several studies have mentioned that vaccinations for overweight or obese individuals may be less effective than lean individuals. Thus, to determine whether and how obesity-associated IR regulates B cell-mediated immunity under vaccination, I utilized an OVA/CFA-induced primary
  immunization model. I observed that obesity-induced IR altered the antibody production by B cells and impaired the antigen-specific germinal center reaction. To further isolate the effect of IR specifically on B cells, by using a mouse model with genetic InsR ablation in B cells, I observed that B cell-intrinsic IR dampened the antigen-specific germinal center reaction and altered antibody production by B cells during OVA/CFA-induced primary immune responses. These changes may be associated with the loss of help from CD4+ T cells and TFH cells, as well as impaired metabolism in B cells. Next, to assess the role of B cell-intrinsic IR in B cell-mediated memory responses, I employed
  an OVA/CFA/IFA-induced prime/boost protocol in B cell-specific InsR-deficient mice. I observed that B cell-intrinsic IR negatively regulated the re-entry of memory B cells into the germinal center
  and the differentiation of plasma cells from memory B cells upon re-exposure to the same antigen. Prompted by the clinical observations that obese individuals are at an increased risk of severe respiratory infections, including H1N1, I subjected mice with InsR ablation in B cells to intranasal infection with the H1N1/PR8 influenza virus. I observed that B cell-intrinsic IR impaired the B cell-mediated anti-viral immunity by impairing virus-specific germinal center reaction, altering antibody production, and weakening immune-dominant T cell responses.
  Altogether, my findings highlight the significant role of insulin signaling and IR in modulating B cells functionality. Conducting further investigations to better understand the mechanisms by
  which insulin signaling and IR modulate B cell-mediated immunity will be important to decipher whether the insulin signaling pathway can be manipulated to bolster protective immunity in individuals with IR.

• Subjects / Keywords

  • B cells
  • insulin resistance
  • Obesity

• Graduation date

  Fall 2024

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-g6xz-1b90

• License

  This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.