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 the liver of fasting animals; these changes are reversed by subsequent refeeding. Furthermore, in global G0S2 knockout mice, basal as well as stimulated lipolytic rates are increased in adipose tissue and hepatic TG content are decreased. Consequently, G0S2−/− mice are resistant to diet-induced obesity and exhibit accelerated hepatic lipolysis and ketogenesis. A considerable impact of G0S2 on hepatic glucose metabolism and substrate partitioning in the fasting state was also demonstrated with liver-specific knockdown in wild-type mice. Thus, on top of an increase in FFA oxidation and ketogenesis, G0S2 ablation also enhanced gluconeogenesis and reduced glycogen breakdown. Conversely, liver-specific overexpression of G0S2 generally had opposite effects that resulted in steatosis and reduced rates of lipolysis, FFA oxidation, and ketogenesis. Finally, whole-body glucose tolerance and insulin sensitivity was improved in high-fat diet–fed mice with global or hepatic loss of G0S2. In other words, the authors elegantly exploit loss‐of‐function and gain‐of‐function experiments to demonstrate the physiologic relevance of G0S2 in the control of lipolysis and energy homeostasis. These findings clearly suggest a role for G0S2 in the pathogenesis of hepatic steatosis and of insulin resistance and type 2 diabetes and the metabolic phenotypes of ATGL loss‐ and gain‐of‐function mutants supports this. Thus, analogous to reduced G0S2 expression, hepatic ATGL overexpression is associated with reduced TG accumulation and increased lipolysis, FFA oxidation, and ketogenesis (12,13), suggesting that the effects of G0S2 on hepatic metabolism is linked to the impact of this protein on lipolysis.
By now it is fairly well established that G0S2 acts as an important inhibitor of lipolysis in fat and liver and that it is reciprocally regulated during fasting, thus leading to decreased hepatic and increased peripheral adipose tissue lipolysis (Fig. 1B). The novel results in Zhang et al. reflect a very comprehensive and sophisticated study without major limitations or concerns. It should be noted that the findings were made in rodents and therefore do not necessarily extrapolate to a clinical setting. However, these results add support to the concept of G0S2 as a “master regulator” of basal and stimulated lipolytic rates. Indeed, it has previously been shown in humans that elevated FFA mobilization during prolonged fasting is associated with a substantial decrease in G0S2 in adipose tissue (14). Similarly, increased FFA mobilization was found in type 2 diabetic patients following 16 h of hypoinsulinemia (15). Notably, no change was found in adipose tissue HSL phosphorylation while G0S2 was decreased, clearly suggesting a distinct increase in basal lipolysis (15). Importantly, G0S2 does indeed regulate ATGL activity in human fat cells (9), and fasting-induced reductions in G0S2 expression have also been found in adipose tissue from birds (16) and pigs (17), indicating that this regulatory mechanism is highly conserved.
In conclusion, the discoveries by Zhang et al. (11) have brought us much closer to a proof of concept regarding the understanding of the role of ATGL and G0S2 in the regulation of lipolysis and partitioning of metabolic fuels. Returning to a clinical setting, the current findings cement a role for ATGL and G0S2 as key regulators of lipolysis and, by extension, key components in the genesis of acute metabolic stress, diabetic ketoacidosis, and insulin resistance and type 2 diabetes. In addition, the data suggest a specific role for increased G0S2 expression in promoting hepatic steatosis. It remains to be assessed which hormonal mechanisms are involved and whether ATGL and G0S2 constitute new therapeutic targets for prevention of nonalcoholic hepatic steatosis, the metabolic syndrome, and type 2 diabetes.
See accompanying article, p. 934.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.