Impaired Ca signaling due to hepatic steatosis mediates hepatic insulin resistance in Alström syndrome mice that is reversed by GLP-1 analog treatment.

Ca signaling plays a critical role in the regulation of hepatic metabolism by hormones including insulin. Changes in cytoplasmic Ca regulate synthesis and posttranslational modification of key signaling proteins in the insulin pathways. Emerging evidence suggests that hepatocyte intracellular Ca signaling is altered in lipid-loaded liver cells isolated from obese rodent models. The mechanisms of altered Ca-insulin and insulin-Ca signaling pathways in obesity remain poorly understood. Here, we show that the kinetics of insulin-initiated intracellular (initial) Ca release from endoplasmic reticulum is significantly impaired in steatotic hepatocytes from obese Alström syndrome mice. Furthermore, exenatide, a glucagon-like peptide-1 (GLP-1) analog, reversed lipid-induced inhibition of intracellular Ca release kinetics in steatotic hepatocytes, without affecting the total content of intracellular Ca released. Exenatide reversed the lipid-induced inhibition of intracellular Ca release, at least partially, via lipid reduction in hepatocytes, which then restored hormone-regulated cytoplasmic Ca signaling and insulin sensitivity. This data provides additional evidence for the important role of Ca signaling pathways in obesity-associated impaired hepatic lipid homeostasis and insulin signaling. It also highlights a potential advantage of GLP-1 analogs when used to treat type 2 diabetes associated with hepatic steatosis.