NK cell-activating receptor NKp46 does not participate in the development of obesity-induced inflammation and insulin resistance

Abstract

Recent evidence establishes a pivotal role for obesity -induced inflammation in precipitating insulin resistance and type -2 diabetes. Central to this process is the proinflammatory M1 adipose -tissue macrophages (ATMs) in epididymal white adipose tissue (eWAT). Notably, natural killer (NK) cells are a crucial regulator of ATMs since their cytokines induce ATM recruitment and M1 polarization. The importance of NK cells is shown by the strong increase in NK-cell numbers in eWAT, and by studies showing that removing and expanding NK cells respectively improve and worsen obesity -induced insulin resistance. It has been suggested that NK cells are activated by unknown ligands on obesity -stressed adipocytes that bind to NKp46 (encoded by Ncr1 ), which is an activating NK-cell receptor. This was supported by a study showing that NKp46knockout mice have improved obesity -induced inflammation/insulin resistance. We therefore planned to use the NKp46knockout mice to further elucidate the molecular mechanism by which NKp46 mediates eWAT NK-cell activation in obesity. We confirmed that obesity increased eWAT NKp46 + NK-cell numbers and NKp46 expression in wild -type mice and that NKp46-knockout ablated these responses. Unexpectedly, however, NKp46-knockout mice demonstrated insulin resistance similar to wild -type mice, as shown by fasting blood glucose/insulin levels and glucose/insulin tolerance tests. Obesityinduced increases in eWAT ATM numbers and proinflammatory gene expression were also similar. Thus, contrary to previously published results, NKp46 does not regulate obesity -induced insulin resistance. It is therefore unclear whether NKp46 participates in the development of obesity -induced inflammation and insulin resistance. This should be considered when elucidating the obesity -mediated molecular mechanisms that activate NK cells.