The body stores energy primarily as triacylglycerol (TG) molecules, packed into specialized intracellular structures called lipid droplets. Accessing this stored energy requires initiating fat breakdown, known as lipolysis. Adipose Triglyceride Lipase (ATGL) is the enzyme responsible for this first step. ATGL’s activity dictates the rate at which stored fat is mobilized, making it a central regulator of whole-body energy balance and metabolic adaptation.
ATGL’s Role in Initiating Fat Breakdown
ATGL performs a specific biochemical action that initiates cellular fat mobilization. Triacylglycerol (TG) molecules consist of a glycerol backbone linked to three fatty acid chains. ATGL acts as the primary hydrolase, cleaving the first fatty acid chain from the TG molecule to produce diacylglycerol (DAG) and one free fatty acid (FFA). This initial reaction is the rate-limiting step of lipolysis, determining the overall speed of fat breakdown.
The subsequent steps in the complete breakdown rely on other enzymes. Hormone-Sensitive Lipase (HSL) targets the resulting DAG, cleaving the second fatty acid to yield monoacylglycerol (MAG). Monoacylglycerol lipase (MGL) then hydrolyzes the MAG into a final free fatty acid and a glycerol molecule. While HSL and MGL are necessary for the full release of all three fatty acids, ATGL’s initial cleavage is mandatory to unlock the stored energy.
ATGL exhibits a strong preference for the triacylglycerol substrate, unlike HSL which prefers diacylglycerol. This substrate specificity reinforces ATGL’s function as the dedicated initiator of lipolysis. The enzyme contains a conserved patatin domain, which houses its catalytic site and facilitates the hydrolysis reaction that generates the first available fatty acid for the rest of the body to use as fuel.
How the Body Controls ATGL Activity
The activity of ATGL must be tightly regulated to prevent the uncontrolled release of fatty acids. Control occurs through a complex molecular dialogue between ATGL and other proteins on the surface of the lipid droplet. In a resting or fed state, ATGL is suppressed by the coating protein Perilipin 1 (PLIN1). PLIN1 sequesters Comparative Gene Identification-58 (CGI-58), which is ATGL’s most potent co-activator.
When the body enters a fasted state or experiences high energy demand, hormones like catecholamines signal the need for fat release. This signal activates protein kinase A (PKA), which phosphorylates PLIN1 and HSL. Phosphorylation of PLIN1 causes a conformational change that forces it to release the sequestered CGI-58. The freed CGI-58 then binds directly to ATGL, increasing its enzymatic activity up to twenty-fold, which dramatically accelerates the rate of lipolysis.
Insulin, released after a meal, inhibits ATGL activity, signaling that energy is plentiful and fat storage should resume. Another layer of control involves the protein G0/G1 switch gene 2 (G0S2), which functions as a direct inhibitor of ATGL. G0S2 binds to ATGL and physically blocks its lipase activity, suppressing fat breakdown when energy demand is low.
ATGL’s Central Role in Energy Supply
The fundamental consequence of ATGL’s action is the sustained supply of energy substrates to the entire body. By initiating the release of free fatty acids (FFAs) from adipose tissue, ATGL ensures these molecules are available to circulating blood for uptake by other organs. These FFAs are the primary fuel source for many tissues, especially during periods like prolonged fasting or intense exercise. The heart, skeletal muscles, and liver all rely heavily on ATGL-mediated lipolysis to fuel their energy-intensive functions.
In the absence of sufficient ATGL activity, the body’s energy metabolism is shifted dramatically. Tissues that should be oxidizing fat are forced to depend more on glucose, altering overall systemic energy homeostasis. The liver uses the released FFAs not only for its own energy but also to synthesize lipoproteins for transport to other tissues. ATGL activity is therefore directly linked to maintaining stable blood lipid levels, balancing fat storage with its necessary mobilization.
In addition to providing bulk energy, the FFAs and diacylglycerol molecules produced by ATGL also serve as important signaling molecules. These lipid-derived ligands can activate nuclear receptors, such as the peroxisome proliferator-activated receptors (PPARs), which regulate the expression of genes involved in energy metabolism. By governing the release of these molecules, ATGL plays a far-reaching role in cellular communication and metabolic adaptation.
ATGL Dysfunction and Metabolic Health
When the finely tuned process of ATGL activity is disrupted, significant health problems can emerge. A genetic deficiency in ATGL leads to a rare disorder called Neutral Lipid Storage Disease with Myopathy (NLSDM). Patients with NLSDM cannot efficiently break down fat, resulting in the massive accumulation of triacylglycerol droplets in virtually all tissues. This accumulation is particularly damaging in muscle tissues, causing progressive skeletal myopathy and severe cardiomyopathy (heart muscle disease).
The pathological accumulation of fat in the heart, known as lipotoxic cardiomyopathy, can lead to heart failure and often necessitates heart transplantation. The lack of ATGL impairs the heart’s ability to use its stored fat for energy and disrupts the PPAR signaling pathways essential for mitochondrial function and fat oxidation.
Dysregulation of ATGL is also implicated in common metabolic disorders where its activity is unbalanced. In conditions like insulin resistance and type 2 diabetes, decreased ATGL protein levels in fat cells contribute to dysfunctional fat storage and release. Conversely, excessive ATGL activity in non-adipose tissues like the liver can contribute to ectopic lipid accumulation and Non-Alcoholic Fatty Liver Disease (NAFLD).