Free fatty acids (NEFA)

Free fatty acids (NEFA, or non-esterified fatty acids) are long-chain fats floating in your blood. They ride on the protein albumin. They are released when an enzyme (hormone-sensitive lipase) breaks down stored fat. Fasting levels run about 0.3 to 0.8 mmol/L. Insulin normally suppresses that fat release. When that brake fails, as in fat-tissue insulin resistance, NEFA flow stays chronically high. Then your liver, muscle, heart, and pancreatic β-cells get flooded with fat. Excess NEFA there get burned incompletely. That generates toxic byproducts: ceramides, diacylglycerols, and acylcarnitines. Those harm your mitochondria. They switch on inflammatory kinases (IKKβ, JNK). And they blunt insulin signaling. The whole state is called lipotoxicity. Karpe, Dickmann, and Frayn (Diabetes, 2011) drew a careful line. Normal post-meal NEFA swings alone do not cause insulin resistance. But a chronically high baseline, as in belly-fat obesity, does help cause liver and muscle insulin resistance. In the Baltimore Longitudinal Study of Aging (Carlson et al., 2007), high NEFA were linked to high blood sugar after a glucose challenge. That held even when fasting glucose looked normal. As a modifiable longevity marker, the evidence is still associational. Exercise and caloric restriction lower NEFA flow. But long-term trials aimed at NEFA specifically are lacking.

Last reviewed: June 22, 2026

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