Fatty acids, stored as triglyceride, constitute the largest energy depot in the human body. It has been estimated that fat mass comprises around 20–30% of the entire body mass in Western populations (1). In terms of energy regulation, release of substrates from this huge energy reservoir may be viewed as one of the—if not the—principal metabolic process in the body. Clearly, mechanisms regulating mobilization of fatty acids—those regulating lipolysis—are of seminal interest. In line with this concept, free fatty acids (FFAs) in the circulation have decisive actions. Under conditions of stress, such as prolonged fasting, lipolysis is stimulated and FFAs are released into the blood. This response diverts the body from use of carbohydrate and protein fuels, and directs it to use fat, thereby preserving vital protein stores (2). Under postprandial conditions, which are habitual in modern societies, insulin secretion is stimulated and lipolysis is restricted. This leads to low levels of FFAs and increased utilization of carbohydrate and protein fuels. However, when insulin fails to reduce lipolysis adequately, increased FFA levels induce insulin resistance and lead to development of the metabolic syndrome and eventually type 2 diabetes (3–6). Mobilization of fat involves the sequential action of three lipases (7)(Fig. 1A). The rate-limiting step is cleavage of the first ester bond in triglycerides (TGs) by adipose triglyceride lipase (ATGL), producing diacylglycerol (DG) and releasing one FFA. Subsequently, hormone sensitive lipase (HSL) and monoglyceride lipase (MGL) hydrolyze DG to monoacylglycerol (MG) and MG to glycerol and FFA, respectively. Thus, for each TG molecule, one glycerol and three FFA molecules can be exported to the circulation and delivered to recipient tissues where they can serve as metabolic substrates. In the acute phase, protein kinase A (PKA) stimulates adipocyte lipolysis through phosphorylation of HSL and the lipid droplet–associated protein PLIN1. This activates HSL and disrupts the association between PLIN1 and comparative gene identification-58 (CGI-58), which is a potent coactivator of ATGL (7). Recently, the protein product of G0/G1 switch gene 2 (G0S2) has been shown to be a dominant inhibitor of ATGL in adipocytes (8). Interestingly, G0S2 suppresses ATGL activity in a dose-dependent manner, and this effect appears to be independent of the activation state of PKA (8, 9). However, expression of G0S2 is highly modifiable by hormonal stimuli and sustained adrenergic and insulin action causes G0S2 levels to decrease and increase, respectively (8, 10). Hence, in contrast to the role of CGI-58 in the acute lipolytic response, it seems that G0S2 predominantly acts as a long-term regulator of ATGL. It provides adipocytes with a mechanism to adapt to altered nutrient demands by changing the overall capacity, or dynamic range, of basal and stimulated lipolysis. In a clinical context, ATGL and G0S2 have the potential to increase lipolysis and circulating FFA concentrations as part of both an acute general metabolic stress response and more specifically in the pathogenesis of diabetic ketoacidosis and also during low-grade chronic inflammation, which may precede the metabolic syndrome and type 2 diabetes. In this issue, Zhang et al.(11) provide convincing in vivo evidence supporting this model. They demonstrate that murine G0S2 acts decisively in the coordination of lipid metabolism in liver and adipose tissue during the fasting-refeeding cycle and under high-fat feeding. The authors studied the role of ATGL and G0S2 in mice under a variety of conditions and show that G0S2 protein expression decreases in adipose tissue and increases in …