Ca²⁺ signaling plays a critical role in the regulation of hepatic metabolism by hormones including insulin. Changes in cytoplasmic Ca²⁺ regulate synthesis and posttranslational modification of key signaling proteins in the insulin pathways. Emerging evidence suggests that hepatocyte intracellular Ca²⁺ signaling is altered in lipid-loaded liver cells isolated from obese rodent models. The mechanisms of altered Ca²⁺-insulin and insulin-Ca²⁺ signaling pathways in obesity remain poorly understood. Here, we show that the kinetics of insulin-initiated intracellular (initial) Ca²⁺ 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 Ca²⁺ release kinetics in steatotic hepatocytes, without affecting the total content of intracellular Ca²⁺ released. Exenatide reversed the lipid-induced inhibition of intracellular Ca²⁺ release, at least partially, via lipid reduction in hepatocytes, which then restored hormone-regulated cytoplasmic Ca²⁺ signaling and insulin sensitivity. This data provides additional evidence for the important role of Ca²⁺ 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.