Non-esterified fatty acids, or NEFAs, are a type of fat that circulates freely in the bloodstream. Unlike most fats in the body, they are not attached, or esterified, to a glycerol molecule. The body’s largest fat reserve, known as triglycerides and stored in adipose tissue, is the primary source of these molecules. When the body needs energy, it breaks down these stored triglycerides, releasing NEFAs into the blood for tissues to use as fuel.
Generation and Mobilization of NEFAs
The release of NEFAs is a regulated process centered on lipolysis, the breakdown of fat stores. This occurs within fat cells, where triglycerides are broken into glycerol and three fatty acid chains. This reaction is managed by an enzyme called hormone-sensitive lipase. Once freed, these NEFAs exit the fat cell and travel through the bloodstream to tissues in need of fuel.
Hormones are the primary controllers of this process. Insulin, released after a meal when blood sugar is high, suppresses the activity of hormone-sensitive lipase. This signals that energy is plentiful, which halts the release of NEFAs from adipose tissue and promotes fat storage.
In contrast, other hormones stimulate NEFA release during fasting, exercise, or stress. Catecholamines, such as adrenaline, are released during stress and activate hormone-sensitive lipase to mobilize energy reserves. Glucagon, a hormone released when blood glucose is low, also promotes lipolysis. This hormonal balance ensures NEFAs are available when needed but stored when energy from food is sufficient.
Essential Functions of NEFAs in the Body
NEFAs serve as an energy source for many tissues, particularly those with high energy demands like skeletal muscle and the heart. During physical activity or between meals when glucose is less available, these tissues shift their metabolism to use NEFAs for fuel. The heart, for example, can derive up to 70% of its energy from the oxidation of these fatty acids.
This metabolic flexibility allows the body to function under varying nutritional states. In the liver, NEFAs can be converted into ketones, which are useful for the brain during extended fasting. The liver can also use NEFAs for its own energy or repackage them into triglycerides to be transported and stored elsewhere.
Beyond their role as fuel, NEFAs also function as building blocks for complex lipid molecules. They are precursors for substances like phospholipids and glycolipids, which are components of cell membranes. They can also be converted into signaling molecules that participate in regulating inflammation and other cellular processes.
Elevated NEFAs and Associated Health Risks
When the release of NEFAs into the bloodstream chronically exceeds the body’s ability to use or store them, health problems can arise. Persistently high levels can lead to lipotoxicity, a condition where fatty acids accumulate in tissues not specialized for fat storage, such as the liver, skeletal muscle, and pancreas. This buildup can disrupt cellular function and even trigger cell death.
A significant consequence of chronically elevated NEFAs is the development of insulin resistance. In skeletal muscle, excess NEFAs impair the cell’s ability to take up glucose from the blood. In the liver, high NEFA levels promote glucose production, further raising blood sugar levels. This dual effect forces the pancreas to produce more insulin, a cycle that can lead to type 2 diabetes.
The liver is vulnerable to damage from excess NEFAs. When the liver takes up more fatty acids than it can use for energy or export, the surplus is converted back into triglycerides and stored. This accumulation leads to non-alcoholic fatty liver disease (NAFLD), a condition that can progress to more severe liver inflammation. High NEFA concentrations are also linked to an increased risk of cardiovascular problems by promoting inflammation in blood vessels.
Factors Modifying NEFA Concentrations
Diet plays a substantial role in regulating NEFA levels. Prolonged fasting or a very low-carbohydrate, high-fat ketogenic diet increases lipolysis. This elevates circulating NEFAs to ensure a consistent energy supply in the absence of dietary carbohydrates.
Physical activity has a dual effect on NEFA levels. During exercise, NEFA mobilization increases to provide fuel for working muscles. However, regular physical activity improves metabolic health over time, leading to better insulin sensitivity and more efficient use of fatty acids by muscle cells.
Chronic stress is another factor that can lead to high NEFA levels. The continuous release of stress hormones like cortisol and adrenaline keeps hormone-sensitive lipase activated, causing a steady release of NEFAs from fat stores. Obesity also disrupts NEFA regulation, as enlarged fat cells can leak fatty acids into the bloodstream, contributing to associated metabolic complications.