Obesity-associated systemic and intrinsic IR dysregulates B cell metabolism and function
Creators: Zhu, Mengyi
Publisher: name: University of Alberta Library
Year: 2024

<p>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<br>
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<br>
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.<br>
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<br>
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<br>
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<br>
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<br>
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.<br>
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<br>
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.</p>