The study investigates the mechanisms underlying chronic endoplasmic reticulum (ER) stress in obesity, focusing on the liver. It compares proteomic and lipidomic profiles of hepatic ER from lean and obese mice, revealing a shift from protein synthesis to lipid synthesis and metabolism in the obese ER. Specifically, the obese ER shows increased lipid synthesis, particularly monounsaturated fatty acids (MUFA) and phosphatidylcholine (PC), leading to an elevated PC/PE ratio. This imbalance impairs the activity of the SERCA protein, which is crucial for calcium homeostasis in the ER. Reduced SERCA activity results in impaired calcium transport, contributing to ER stress and insulin resistance. The study demonstrates that correcting the PC/PE ratio by suppressing *Pemt* expression or over-expressing *Serca* in the liver can alleviate ER stress, improve glucose homeostasis, and reduce hepatic steatosis. These findings suggest that abnormal lipid metabolism and calcium homeostasis are key contributors to ER stress in obesity and provide potential therapeutic targets for managing obesity-related metabolic disorders.The study investigates the mechanisms underlying chronic endoplasmic reticulum (ER) stress in obesity, focusing on the liver. It compares proteomic and lipidomic profiles of hepatic ER from lean and obese mice, revealing a shift from protein synthesis to lipid synthesis and metabolism in the obese ER. Specifically, the obese ER shows increased lipid synthesis, particularly monounsaturated fatty acids (MUFA) and phosphatidylcholine (PC), leading to an elevated PC/PE ratio. This imbalance impairs the activity of the SERCA protein, which is crucial for calcium homeostasis in the ER. Reduced SERCA activity results in impaired calcium transport, contributing to ER stress and insulin resistance. The study demonstrates that correcting the PC/PE ratio by suppressing *Pemt* expression or over-expressing *Serca* in the liver can alleviate ER stress, improve glucose homeostasis, and reduce hepatic steatosis. These findings suggest that abnormal lipid metabolism and calcium homeostasis are key contributors to ER stress in obesity and provide potential therapeutic targets for managing obesity-related metabolic disorders.