Diet-induced Obesity Impairs Murine B cell Development and Antibody Production Accompanied by a Defect in Production of SPMs

Abstract

Abstract Diet-induced obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. There is limited information about the effects of obesity on B cell function outside of the context of adipose tissue inflammation. Therefore, we studied B cell development and ex vivo B cell antibody production in a murine model of diet-induced obesity. Analysis of the bone marrow revealed that obese mice displayed a two-fold reduction in the number of CD19+ cells, resulting in decreased frequencies of various B cell subsets. Early lymphoid commitment markers such as IL7Rα, IL7R, and STAT5 were significantly decreased at the transcript level. In addition, obese mice had reduced mRNA expression of the B cell lymphopoiesis markers, PAX5 and Oct2, compared to controls. Functionally, splenic B cells from obese mice were hyperstimulated with elevated ex vivo IgM and IgG secretion in the absence of stimulation. When B cells from the obese mice were challenged with anti-TLR4 or anti-BCR/TLR9 in culture, IgM and IgG levels were diminished. Mechanistically, the levels of D-series specialized pro-resolving lipid mediators (SPMs), which are potent regulators of inflammation and adaptive immunity, were lowered in obese mice compared to controls. Furthermore, select enzymes involved in generation of SPMs were also decreased in obese mice. Overall, these findings demonstrate that obesity hinders B cell development and drives a dysregulated antibody response, which could contribute to impaired responses to infections and vaccinations.