Adipocyte lipolysis is a tightly regulated process that plays a critical role in energy homeostasis by releasing fatty acids (FAs) and glycerol from white adipose tissue (WAT) stores. This process is controlled by hormonal and biochemical signals that modulate the activity of lipolytic enzymes and accessory proteins, allowing adipose tissue to respond to changes in energy needs. Recent discoveries have expanded our understanding of adipocyte lipolysis, including the identification of novel triacylglyceride (TAG) lipases such as desnutrin/ATGL and hormone-sensitive lipase (HSL), as well as nonenzymatic proteins like perilipin that regulate TAG breakdown. These enzymes and proteins work together to ensure efficient mobilization of energy substrates and the synthesis of very-low-density lipoproteins (VLDLs). HSL is the primary enzyme responsible for TAG and DAG hydrolysis in adipocytes, but recent studies have shown that desnutrin/ATGL also plays a significant role in TAG lipolysis, particularly under fasting conditions. Desnutrin/ATGL is induced by fasting and suppressed by refeeding, and its activity is regulated by glucocorticoids. In HSL-null mice, desnutrin/ATGL contributes to FA release, although it is not sufficient to maintain normal energy substrate levels. Other TAG lipases, such as triacylglycerol hydrolase (TGH) and CGI-58, also play roles in TAG hydrolysis, with TGH being primarily expressed in the liver and CGI-58 involved in lipolysis and ATGL activation. Lipolysis is also regulated by nonenzymatic proteins such as perilipin, which coats lipid droplets and modulates the access of lipases to TAG substrates. Perilipin is phosphorylated by protein kinase A (PKA) in response to beta-adrenergic stimulation, which facilitates HSL translocation to lipid droplets and enhances lipolysis. Adipose fatty acid-binding protein (aFABP) and caveolin-1 also play roles in lipolysis by facilitating fatty acid transport and regulating lipase activity. Nutritional regulation of lipolysis occurs at multiple levels, with fasting stimulating lipolysis through catecholamines and glucagon, while refeeding inhibits it through insulin. Dietary compounds such as calcium and caffeine can also influence lipolysis, with calcium increasing fat oxidation and caffeine stimulating lipolysis through cAMP production. Ethanol, on the other hand, has antilipolytic effects. Obesity is associated with increased basal lipolysis and decreased catecholamine-stimulated lipolysis, which may contribute to insulin resistance and metabolic disorders. Understanding the regulation of adipocyte lipolysis is crucial for developing strategies to combat obesity and related metabolic diseases.Adipocyte lipolysis is a tightly regulated process that plays a critical role in energy homeostasis by releasing fatty acids (FAs) and glycerol from white adipose tissue (WAT) stores. This process is controlled by hormonal and biochemical signals that modulate the activity of lipolytic enzymes and accessory proteins, allowing adipose tissue to respond to changes in energy needs. Recent discoveries have expanded our understanding of adipocyte lipolysis, including the identification of novel triacylglyceride (TAG) lipases such as desnutrin/ATGL and hormone-sensitive lipase (HSL), as well as nonenzymatic proteins like perilipin that regulate TAG breakdown. These enzymes and proteins work together to ensure efficient mobilization of energy substrates and the synthesis of very-low-density lipoproteins (VLDLs). HSL is the primary enzyme responsible for TAG and DAG hydrolysis in adipocytes, but recent studies have shown that desnutrin/ATGL also plays a significant role in TAG lipolysis, particularly under fasting conditions. Desnutrin/ATGL is induced by fasting and suppressed by refeeding, and its activity is regulated by glucocorticoids. In HSL-null mice, desnutrin/ATGL contributes to FA release, although it is not sufficient to maintain normal energy substrate levels. Other TAG lipases, such as triacylglycerol hydrolase (TGH) and CGI-58, also play roles in TAG hydrolysis, with TGH being primarily expressed in the liver and CGI-58 involved in lipolysis and ATGL activation. Lipolysis is also regulated by nonenzymatic proteins such as perilipin, which coats lipid droplets and modulates the access of lipases to TAG substrates. Perilipin is phosphorylated by protein kinase A (PKA) in response to beta-adrenergic stimulation, which facilitates HSL translocation to lipid droplets and enhances lipolysis. Adipose fatty acid-binding protein (aFABP) and caveolin-1 also play roles in lipolysis by facilitating fatty acid transport and regulating lipase activity. Nutritional regulation of lipolysis occurs at multiple levels, with fasting stimulating lipolysis through catecholamines and glucagon, while refeeding inhibits it through insulin. Dietary compounds such as calcium and caffeine can also influence lipolysis, with calcium increasing fat oxidation and caffeine stimulating lipolysis through cAMP production. Ethanol, on the other hand, has antilipolytic effects. Obesity is associated with increased basal lipolysis and decreased catecholamine-stimulated lipolysis, which may contribute to insulin resistance and metabolic disorders. Understanding the regulation of adipocyte lipolysis is crucial for developing strategies to combat obesity and related metabolic diseases.