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ORIGINAL RESEARCH article

Front. Immunol.
Sec. B Cell Biology
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1436900

BAFF neutralization impairs the autoantibody-mediated clearance of dead adipocytes and aggravates obesity-induced insulin resistance

Provisionally accepted
Melissa D. Lempicki Melissa D. Lempicki 1Jake A. Gray Jake A. Gray 1Gabriel Abuna Gabriel Abuna 1Ramiro M. Murata Ramiro M. Murata 1Senad Divanovic Senad Divanovic 2Coleen A. Mcnamara Coleen A. Mcnamara 3Akshaya K. Meher Akshaya K. Meher 1*
  • 1 East Carolina University, Greenville, United States
  • 2 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • 3 University of Virginia, Charlottesville, Virginia, United States

The final, formatted version of the article will be published soon.

    B cell-activating factor (BAFF) is a critical TNF-family cytokine that regulates homeostasis and peripheral tolerance of B2 cells. BAFF overproduction promotes autoantibody generation and autoimmune diseases. During obesity, BAFF is predominantly produced by white adipose tissue (WAT), and IgG autoantibodies against adipocytes are identified in the WAT of obese humans. However, it remains to be determined if the autoantibodies formed during obesity affect WAT remodeling and systemic insulin resistance. Here, we show that IgG autoantibodies are generated in high-fat diet (HFD)-induced obese mice that bind to apoptotic adipocytes and promote their phagocytosis by macrophages. Next, using murine models of obesity in which the gonadal WAT undergoes remodeling, we found that BAFF neutralization depleted IgG autoantibodies, increased the number of dead adipocytes, and exacerbated WAT inflammation and insulin resistance. RNA sequencing of the stromal vascular fraction from the WAT revealed decreased expression of immunoglobulin light-chain and heavy-chain variable genes suggesting a decreased repertoire of B cells after BAFF neutralization. Further, the B cell activation and the phagocytosis pathways were impaired in the WAT of BAFF-neutralized mice. In vitro, plasma IgG fractions from BAFFneutralized mice reduced the phagocytic clearance of apoptotic adipocytes. Altogether, our study suggests that IgG autoantibodies developed during obesity, at least in part, dampens exacerbated WAT inflammation and systemic insulin resistance.

    Keywords: BAFF, B2 cell, IgG autoantibodies, Obesity-induced insulin resistance, white adipose tissue, Inflammation

    Received: 22 May 2024; Accepted: 22 Jul 2024.

    Copyright: © 2024 Lempicki, Gray, Abuna, Murata, Divanovic, Mcnamara and Meher. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Akshaya K. Meher, East Carolina University, Greenville, United States

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