Adipose Triglyceride Lipase and G₀/G₁ Switch Gene 2: Approaching Proof of Concept

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. …