Aberrant Ca 2+ signaling by IP 3 Rs in adipocytes links inflammation to metabolic dysregulation in obesity

Chronic metabolic inflammation is a key feature of obesity, insulin resistance, and diabetes. Here, we showed that altered regulation of the Ca²⁺ channel inositol trisphosphate receptor (IP₃R) was an adipocyte-intrinsic event involved in the emergence and propagation of inflammatory signaling and the resulting insulin resistance. Inflammation induced by cytokine exposure in vitro or by obesity in vivo led to increases in the abundance and activity of IP₃Rs and in the phosphorylation of the Ca²⁺-dependent kinase CaMKII in adipocytes in a manner dependent on the kinase JNK. In mice, adipocyte-specific loss of IP₃R1/2 protected against adipose tissue inflammation and insulin resistance, despite the mice exhibiting substantial diet-induced weight gain. Thus, this work suggests that increased IP₃R activity is a key link between obesity, inflammation, and insulin resistance. These data also suggest that approaches to target IP₃R-mediated Ca²⁺ homeostasis in adipocytes may offer new therapeutic opportunities against metabolic diseases, especially because GWAS studies also implicate this locus in human obesity.