What Causes Free Fatty Acids in the Body?

November 25, 2025 •

4 min read

While plasma fatty acid levels are normally low during fasting, they increase significantly with increased energy demand or exercise. Understanding the causes of free fatty acids in the body is crucial, as their levels reflect energy mobilization and are tightly regulated by hormonal, metabolic, and neural signals.

Quick Summary

Free fatty acids are produced through the breakdown of stored fat (lipolysis) and from dietary fat. Hormones like adrenaline and insulin, and metabolic states like fasting and obesity, are key regulators of their release and uptake.

Key Points

Lipolysis is the core mechanism: The primary cause of FFAs is the breakdown of stored triglycerides in fat tissue, a process called lipolysis.
Hormones regulate release: Insulin is an antilipolytic hormone, promoting storage, while catecholamines and glucagon stimulate FFA release for energy.
Metabolic state dictates levels: FFA levels are high during fasting and low after meals. This reflects the shift between mobilizing and storing energy.
Obesity disrupts regulation: Enlarged fat mass and insulin resistance in obesity lead to perpetually elevated FFAs, creating a vicious metabolic cycle.
Diabetes exacerbates the issue: Type 2 diabetes involves both insulin resistance and insufficient insulin, causing high FFAs and contributing to further dysfunction.
Exercise affects levels dynamically: Exercise acutely increases FFAs, but chronic training improves the body's efficiency in using and clearing them.

The Primary Source: Lipolysis

The main cause of free fatty acids (FFAs) in the body is lipolysis, the process by which stored triglycerides within fat cells (adipocytes) are broken down. Triglycerides are large molecules made of a glycerol backbone with three fatty acid chains attached. When the body needs energy, enzymes called lipases hydrolyze these triglycerides, releasing FFAs and glycerol into the bloodstream.

The Enzymatic Cascade

Lipolysis is a multi-step process involving several key enzymes:

Adipose Triglyceride Lipase (ATGL): This is the rate-limiting enzyme that initiates the breakdown of triglycerides into diacylglycerols and the first FFA.
Hormone-Sensitive Lipase (HSL): HSL primarily acts on the diacylglycerols produced by ATGL, hydrolyzing them into monoacylglycerols and the second FFA.
Monoglyceride Lipase (MGL): MGL performs the final step, breaking down monoacylglycerols into a third FFA and glycerol.

Hormonal Control

This enzymatic cascade is under strict hormonal control, particularly in response to the body's energy needs. Adipocyte lipolysis is activated by catecholamines (adrenaline and noradrenaline) and glucagon, which signal a need for energy, such as during fasting or stress. Insulin, conversely, is a potent inhibitor of lipolysis, promoting energy storage rather than release. This creates a delicate balance, where low insulin and high glucagon/catecholamine levels shift the body towards fat mobilization.

The Impact of Diet and Fasting

Nutritional state is a major driver of FFA levels. The concentration and flux of FFAs through the bloodstream can vary widely depending on whether a person is in a fasted or fed state.

Fasted State: After several hours without food, blood glucose levels fall. In response, the body switches to using fat as its primary energy source. Adipose tissue releases FFAs from stored triglycerides via lipolysis, increasing their circulating concentration.
Fed State: After a meal, especially one rich in fat, triglycerides are digested in the intestine and packaged into lipoproteins called chylomicrons. Capillaries, particularly in adipose and muscle tissue, contain an enzyme called lipoprotein lipase (LPL) that breaks down these lipoprotein-transported triglycerides, releasing FFAs for local uptake or storage. The hormone insulin is released, which suppresses lipolysis and promotes the uptake of these FFAs into adipocytes for storage.

Medical Conditions Affecting FFA Release

Several health conditions can disrupt the normal regulation of FFA release, leading to chronically elevated levels, which can be detrimental to metabolic health.

Obesity and Insulin Resistance: Obese individuals typically have enlarged fat tissue mass that releases more FFAs. This is compounded by insulin resistance, where cells fail to respond properly to insulin. Since insulin normally inhibits lipolysis, insulin resistance leads to a blunted anti-lipolytic effect, creating a cycle of high FFA release.
Type 2 Diabetes: In type 2 diabetes, the combination of insulin resistance and impaired insulin secretion results in significantly elevated FFA levels. The pancreas fails to produce enough insulin to overcome the resistance, leading to persistent hyperglycemia and excessive fat breakdown. Elevated FFAs themselves can further impair insulin signaling and secretion.
Other Factors: Other physiological stressors and medical conditions can increase FFA levels, including sleep deprivation (which raises lipolytic hormones like cortisol and norepinephrine), obstructive sleep apnea, and conditions involving increased sympathetic nervous system activity. Cigarette smoking also stimulates lipolysis and elevates FFAs through increased epinephrine and norepinephrine secretion.

Exercise and FFA Dynamics

During exercise, the body's energy demands increase, leading to a temporary rise in circulating FFAs. This process is stimulated by catecholamines. The timing of exercise relative to meals affects FFA dynamics:

Fasted Exercise: Exercising in a fasted state, such as before breakfast, leads to a greater and more rapid increase in plasma FFAs, as the body relies more heavily on stored fat for energy. This enhances fat oxidation during the exercise session.
Chronic Exercise: While a single session increases FFAs, chronic endurance training improves the body's metabolic handling of FFAs. Trained individuals demonstrate an enhanced ability to oxidize FFAs for energy, and during recovery, FFAs may return to lower levels compared to before the exercise bout. Chronic exercise can also improve insulin sensitivity, which indirectly helps regulate FFA levels by dampening excessive lipolysis.

Comparison of FFA Sources: Fasted vs. Fed State


Feature	Fasted State	Fed State
Primary FFA Source	Breakdown of stored triglycerides via lipolysis	Digestion of dietary triglycerides in the small intestine, released from chylomicrons by lipoprotein lipase (LPL)
FFA Levels	Elevated; FFA flux is outward from adipocytes	Suppressed lipolysis; FFA flux is inward to adipocytes for storage, and LPL-derived FFA is absorbed
Hormonal Regulation	High glucagon and catecholamines activate lipolysis; Low insulin inhibits fat storage	High insulin promotes fat storage and suppresses lipolysis
Energy Demand	High, utilizing stored fat	Replenishing fat stores, suppressing fat mobilization

Conclusion

Free fatty acids are essential energy substrates released into the circulation primarily through lipolysis from adipose tissue, a process intricately regulated by hormones like insulin, adrenaline, and glucagon. Their levels are significantly influenced by the body's metabolic state, rising during fasting and exercise to meet energy demands, and being suppressed after meals to promote storage. However, conditions like obesity and insulin resistance disrupt this balance, leading to chronically elevated FFAs that contribute to further metabolic dysfunction and chronic disease. Lifestyle factors such as chronic exercise can improve the body's metabolic handling of FFAs, demonstrating that these levels are a modifiable risk factor for metabolic health. Understanding the drivers behind FFA production is key to managing metabolic health and preventing related complications. Read more on the effects of FFAs on metabolic health at the NIH Library

Frequently Asked Questions

The main source is the breakdown of stored fat, or triglycerides, in adipose tissue through a process called lipolysis. FFAs are also absorbed from the digestion of dietary fats.

The release of FFAs is primarily controlled by adrenaline, noradrenaline, and glucagon, which stimulate lipolysis. Insulin has the opposite effect, acting as an anti-lipolytic hormone to promote fat storage.

During fasting, as blood glucose levels drop, the body increases its reliance on fat for energy. This triggers an increase in lipolysis, leading to elevated free fatty acid levels in the blood.

During a single bout of exercise, FFA levels increase significantly. However, chronic exercise training improves insulin sensitivity and the body's capacity to oxidize fat, leading to better long-term regulation of FFA levels.

Obesity, particularly with insulin resistance, leads to higher circulating FFA levels. The larger fat mass releases more FFAs, and the impaired insulin signaling further hinders the suppression of lipolysis.

While FFAs are a vital energy source, chronically high levels can be harmful. They are associated with insulin resistance, lipotoxicity in non-adipose tissues, inflammation, and increased risk for metabolic and cardiovascular diseases.

After digesting dietary fats (triglycerides), lipoprotein lipase breaks them down into FFAs. These FFAs are then transported into tissues. The proportion that ends up circulating depends on whether the body is in a fed or fasted state and hormonal signals.