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

Tian Su, Yue He, Yan Huang, Mingsheng Ye, Qi Guo, Ye Xiao, Guangping Cai, Linyun Chen, Changjun Li, Haiyan Zhou () and Xianghang Luo ()
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Tian Su: Xiangya Hospital of Central South University
Yue He: Xiangya Hospital of Central South University
Yan Huang: Xiangya Hospital of Central South University
Mingsheng Ye: Xiangya Hospital of Central South University
Qi Guo: Xiangya Hospital of Central South University
Ye Xiao: Xiangya Hospital of Central South University
Guangping Cai: Xiangya Hospital of Central South University
Linyun Chen: Xiangya Hospital of Central South University
Changjun Li: Xiangya Hospital of Central South University
Haiyan Zhou: Xiangya Hospital of Central South University
Xianghang Luo: Xiangya Hospital of Central South University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract The crosstalk between the bone and adipose tissue is known to orchestrate 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 considerable 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 causes 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, we show that GCA-neutralizing antibodies improve adipose tissue inflammation and insulin sensitivity in obese male mice. Together, these observations define a mechanism whereby bone marrow factor GCA initiates adipose tissue inflammation and insulin resistance, showing that GCA could be a potential target to treat metainflammation.

Date: 2024
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DOI: 10.1038/s41467-023-43787-x

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