Lnk/Sh2b3 Regulates Adipose Inflammation and Glucose Tolerance through Group 1 ILCs

Lnk/Sh2b3 is an adaptor protein that negatively regulates cytokine signaling in lymphohematopoiesis. A missense variant within the LNK/SH2B3 gene has been reported to be a risk variant for several autoimmune diseases, including diabetes. We found that glucose tolerance and insulin responses were impaired in Lnk−/− mice. Moreover, immune cells such as group 1 innate lymphoid cells (G1-ILCs), CD8+ T cells, and M1 macrophages accumulated in adipose tissue. When Lnk−/− mice were crossed with Il15−/− mice or depleted of G1-ILCs but not CD8+ T cells, glucose intolerance and adipose inflammation were ameliorated. Lnk−/− G1-ILCs showed activated phenotypes as well as enhanced reactivity for IL-15, and administration of a JAK inhibitor improved glucose tolerance. Accordingly, a high-fat diet greatly worsened glucose intolerance in Lnk−/− mice. Thus, Lnk/Sh2b3 controls homeostasis in adipose tissue and reduces the risk of onset of diabetes by regulating the expansion and activation of IL-15-dependent adipose G1-ILCs. [Display omitted] •Loss of Lnk leads to adipose inflammation and impaired glucose tolerance•Lnk impairs the proliferation and activation of adipose G1-ILCs•Depletion of G1-ILCs relieves insulin resistance in Lnk-deficient mice•Obesity reduces Lnk expression in immune cells It remains unknown how immune cells contribute to the progression of insulin resistance. Mori et al. identify a mechanism whereby Lnk/Sh2b3 regulates adipose tissue homeostasis and reduces the risk of diabetes by regulating the expansion and activation of adipose G1-ILCs, leading to insulin resistance.