Adipose triglyceride lipase (ATGL) is the primary enzyme that initiates the breakdown of fat stored within the body’s adipose tissue (fat cells). It controls the release of stored energy, particularly when the body requires fuel during periods of fasting or exercise. ATGL performs the first step in mobilizing the body’s largest energy reserve, making its function important to metabolic balance.
The Primary Role of ATGL in Fat Metabolism
The main form of stored energy in the body is triglycerides, housed within lipid droplets inside fat cells. The process of breaking down these stored fats is called lipolysis, and ATGL initiates this sequence. It performs the first cut on a triglyceride molecule, hydrolyzing it into a diglyceride and one free fatty acid. This initial action is the rate-limiting step, meaning the overall speed of fat breakdown is dictated by ATGL’s activity.
Once ATGL has acted, other enzymes continue the process. Hormone-sensitive lipase (HSL) then breaks down the diglyceride into a monoglyceride and a second fatty acid. Finally, monoglyceride lipase (MGL) completes the process, yielding glycerol and the last fatty acid. This cascade releases the fatty acids into the bloodstream.
These liberated fatty acids serve as a fuel source for various tissues throughout the body. The heart and skeletal muscles, in particular, rely on fatty acids to meet their high energy demands. This is especially true during physical activity or when other energy sources like glucose are scarce.
How ATGL Activity is Controlled
The activity of ATGL is precisely managed to match the body’s immediate energy requirements through hormonal signals and specialized proteins. This regulation ensures that fat is stored when energy is plentiful and broken down only when it is needed.
Hormones serve as the primary on-and-off switches. During fasting, stress, or exercise, the body releases hormones like epinephrine and glucagon that activate ATGL. This ramps up the breakdown of triglycerides to supply the body with energy. Conversely, after a meal, the pancreas releases insulin, which inhibits ATGL’s activity to promote the storage of triglycerides.
ATGL’s function is also fine-tuned by helper and blocker proteins. A co-activator protein called comparative gene identification-58 (CGI-58) must bind to ATGL to enable its full enzymatic power. A protein known as G0/G1 switch gene 2 (G0S2) acts as a direct inhibitor, binding to ATGL to pause lipolysis.
The Health Consequences of ATGL Dysfunction
When ATGL does not function correctly due to genetic mutations, it can lead to a condition known as Neutral Lipid Storage Disease with Myopathy (NLSDM). This disorder results from the inability to initiate triglyceride breakdown, causing them to accumulate as abnormal lipid droplets in tissues throughout the body.
This lipid accumulation is particularly damaging to tissues with high energy needs. The heart muscle is one of the most affected, leading to a progressive weakening known as cardiomyopathy. The heart is simultaneously starved of energy and physically damaged by the toxic buildup of fat.
Skeletal muscles are also significantly impacted, resulting in myopathy, or muscle weakness. Patients with NLSDM often experience fatigue and reduced exercise tolerance as their muscles are deprived of their primary energy source.
ATGL’s Broader Impact on Disease and Therapeutic Potential
The regulation of ATGL plays a part in several common metabolic diseases. In obesity and type 2 diabetes, insulin resistance prevents insulin from effectively “turning off” ATGL. This leads to high levels of fatty acids being released into the bloodstream, which can worsen insulin resistance in other tissues.
ATGL is also implicated in cancer cachexia, the severe wasting of muscle and fat tissue that occurs in many advanced cancer patients. Some tumors can trigger an inflammatory response that puts ATGL into overdrive, causing an uncontrolled breakdown of stored fat. This continuous lipolysis is a driver of the weight loss seen in cachexia.
The enzyme’s activity also influences conditions like non-alcoholic fatty liver disease (NAFLD). The rate at which ATGL breaks down fat in adipose tissue controls the flow of fatty acids to the liver. If this process is dysregulated, an excessive flux of fatty acids can overwhelm the liver, promoting fat accumulation and damage.
These connections have opened the door to exploring ATGL as a therapeutic target. Drugs that could activate ATGL might offer a strategy for treating obesity by increasing energy expenditure. Conversely, inhibitors of ATGL could provide a way to combat cachexia in cancer patients.