Spleen supports a pool of innate-like B cells in white adipose tissue that protects against obesity-associated insulin resistance

Significance The rise in obesity-associated diseases has led to increased efforts to identify new therapeutic targets. Lipid accumulation in obesity triggers a low-grade inflammation that links obesity to its associated diseases, notably insulin resistance and type 2 diabetes. In this report, we have studied a group of innate-like B lymphocytes in visceral white adipose tissue (VAT) of mice that are ( i ) capable of producing the anti-inflammatory mediator IL-10; ( ii ) replenished from precursor cells in spleen during diet-induced obesity (DIO); and ( iii ) impaired in VAT of DIO mice, resulting in diminished protection against obesity-associated insulin resistance that can be ameliorated by supplementation of these cells. These findings identify spleen-supplied innate-like B cells in VAT as previously unidentified therapeutic targets for obesity-associated diseases. Lipid accumulation in obesity triggers a low-grade inflammation that results from an imbalance between pro- and anti-inflammatory components of the immune system and acts as the major underlying mechanism for the development of obesity-associated diseases, notably insulin resistance and type 2 diabetes. Innate-like B cells are a subgroup of B cells that respond to innate signals and modulate inflammatory responses through production of immunomodulatory mediators such as the anti-inflammatory cytokine IL-10. In this study, we examined innate-like B cells in visceral white adipose tissue (VAT) and the relationship of these cells with their counterparts in the peritoneal cavity and spleen during diet-induced obesity (DIO) in mice. We show that a considerable number of innate-like B cells bearing a surface phenotype distinct from the recently identified “adipose natural regulatory B cells” populate VAT of lean animals, and that spleen represents a source for the recruitment of these cells in VAT during DIO. However, demand for these cells in the expanding VAT outpaces their recruitment during DIO, and the obese environment in VAT further impairs their function. We further show that removal of splenic precursors of innate-like B cells through splenectomy exacerbates, whereas supplementation of these cells via adoptive transfer ameliorates, DIO-associated insulin resistance. Additional adoptive transfer experiments pointed toward a dominant role of IL-10 in mediating the protective effects of innate-like B cells against DIO-induced insulin resistance. These findings identify spleen-supplied innate-