Autophagy is a critical process for maintaining cellular homeostasis by degrading damaged organelles and proteins. In obesity, both genetic and dietary models show severe downregulation of autophagy, particularly in the liver, with reduced Atg7 expression. This leads to impaired insulin signaling and increased ER stress. Restoring Atg7 expression in the liver of obese mice reduces ER stress, improves insulin action, and enhances glucose tolerance. The beneficial effects of Atg7 restoration are dependent on autophagy, as blocking Atg5, a downstream mediator, prevents these effects. The study demonstrates that autophagy is essential for regulating organelle function and insulin signaling, and its loss is a key factor in defective insulin action in obesity. Obesity leads to chronic energy and nutrient overload, which challenges cellular homeostasis and causes metabolic and oxidative stress, leading to inflammation and organelle dysfunction. Autophagy is involved in maintaining cellular homeostasis under nutrient-poor conditions and is linked to immune responses and ER stress. ER stress can induce autophagy, which helps in clearing misfolded proteins and maintaining ER homeostasis. Recent studies show that autophagy is important for preserving β-cell function in obesity, and autophagy is regulated by insulin and mTOR, both of which are altered in obesity. Thus, autophagy dysregulation may be a critical component of obesity and contribute to metabolic dysfunction. In obese mice, autophagy is downregulated, leading to ER stress and insulin resistance. The expression of Atg7 is significantly reduced in the liver of ob/ob and HFD models, and this is not due to hyperinsulinemia. Excess lipid accumulation in nonadipose tissues impairs autophagic clearance, and lipid exposure leads to defective autophagy in the liver. Calpain 2 expression is increased in the liver of ob/ob mice, and its inhibition restores Atg7 expression, suggesting that calpain-mediated depletion of Atg7 is a key mechanism in obesity. Suppression of autophagy results in insulin resistance and ER stress. In cultured cells, Atg7 deficiency leads to reduced insulin signaling and severe insulin resistance. In vivo, suppression of Atg7 in lean mice leads to insulin resistance and ER stress, indicating the physiological relevance of the relationship between autophagy and insulin action. Restoration of Atg7 in the liver of obese mice improves systemic glucose homeostasis, insulin action, and reduces ER stress. The beneficial effects of Atg7 restoration are dependent on autophagy, as blocking Atg5 negates these effects. The study shows that defective autophagy in obesity leads to ER stress and insulin resistance. Restoration of autophagy improves insulin action and reduces ER stress. The findings highlight the importance of autophagy in maintaining metabolic homeostasis and suggest that autophagy dysregulation is a critical factor in obesity-related metabolic disorders. TheAutophagy is a critical process for maintaining cellular homeostasis by degrading damaged organelles and proteins. In obesity, both genetic and dietary models show severe downregulation of autophagy, particularly in the liver, with reduced Atg7 expression. This leads to impaired insulin signaling and increased ER stress. Restoring Atg7 expression in the liver of obese mice reduces ER stress, improves insulin action, and enhances glucose tolerance. The beneficial effects of Atg7 restoration are dependent on autophagy, as blocking Atg5, a downstream mediator, prevents these effects. The study demonstrates that autophagy is essential for regulating organelle function and insulin signaling, and its loss is a key factor in defective insulin action in obesity. Obesity leads to chronic energy and nutrient overload, which challenges cellular homeostasis and causes metabolic and oxidative stress, leading to inflammation and organelle dysfunction. Autophagy is involved in maintaining cellular homeostasis under nutrient-poor conditions and is linked to immune responses and ER stress. ER stress can induce autophagy, which helps in clearing misfolded proteins and maintaining ER homeostasis. Recent studies show that autophagy is important for preserving β-cell function in obesity, and autophagy is regulated by insulin and mTOR, both of which are altered in obesity. Thus, autophagy dysregulation may be a critical component of obesity and contribute to metabolic dysfunction. In obese mice, autophagy is downregulated, leading to ER stress and insulin resistance. The expression of Atg7 is significantly reduced in the liver of ob/ob and HFD models, and this is not due to hyperinsulinemia. Excess lipid accumulation in nonadipose tissues impairs autophagic clearance, and lipid exposure leads to defective autophagy in the liver. Calpain 2 expression is increased in the liver of ob/ob mice, and its inhibition restores Atg7 expression, suggesting that calpain-mediated depletion of Atg7 is a key mechanism in obesity. Suppression of autophagy results in insulin resistance and ER stress. In cultured cells, Atg7 deficiency leads to reduced insulin signaling and severe insulin resistance. In vivo, suppression of Atg7 in lean mice leads to insulin resistance and ER stress, indicating the physiological relevance of the relationship between autophagy and insulin action. Restoration of Atg7 in the liver of obese mice improves systemic glucose homeostasis, insulin action, and reduces ER stress. The beneficial effects of Atg7 restoration are dependent on autophagy, as blocking Atg5 negates these effects. The study shows that defective autophagy in obesity leads to ER stress and insulin resistance. Restoration of autophagy improves insulin action and reduces ER stress. The findings highlight the importance of autophagy in maintaining metabolic homeostasis and suggest that autophagy dysregulation is a critical factor in obesity-related metabolic disorders. The