Myeloid-derived grancalcin instigates obesity-induced insulin resistance and metabolic inflammation

The crosstalk between the bone and adipose tissue orchestrates the metabolic homeostasis, but the underlying mechanisms are largely unknown. Herein, we find that GCA+(grancalcin) immune cells accumulate in the bone marrow and release a sufficient amount of GCA into circulation during obesity. Genetic deletion of Gca in myeloid cells attenuates metabolic dysfunction in obese male mice, whereas injection of recombinant GCA into male mice cause adipose tissue inflammation and insulin resistance. Mechanistically, we found that GCA binds to the Prohibitin-2 (PHB2) receptor on adipocytes and activates the innate and adaptive immune response of adipocytes via the PAK1-NF-κB signaling pathway, thus provoking the infiltration of inflammatory immune cells. Moreover, GCA-neutralizing antibodies improve adipose tissue inflammation and insulin sensitivity in obese male mice. Together, these observations uncover a novel mechanism whereby bone marrow factor GCA initiates adipose tissue inflammation and insulin resistance, implicating GCA could be a potential target to treat metainflammation.