Free fatty acids (NEFA)

Free fatty acids (NEFA, non-esterified fatty acids) are long-chain fatty acids in plasma bound to albumin, released by lipolysis of adipose triglycerides via hormone-sensitive lipase. Fasting concentrations range from 0.3 to 0.8 mmol/L. Insulin suppresses lipolysis; impaired antilipolytic signalling — as in adipose insulin resistance — causes chronically elevated NEFA flux. In liver, skeletal muscle, myocardium, and pancreatic β-cells, excess NEFA undergo incomplete oxidation, generating ceramides, diacylglycerols, and acylcarnitines that impair mitochondrial function, activate inflammatory kinases (IKKβ, JNK), and blunt insulin signalling — collectively termed lipotoxicity. Karpe, Dickmann, and Frayn (Diabetes, 2011) concluded that physiological postprandial NEFA swings are insufficient to cause insulin resistance per se, but chronic basal NEFA excess in visceral obesity contributes causally to hepatic and muscle insulin resistance. In the Baltimore Longitudinal Study of Aging (Carlson et al., 2007), elevated NEFA were linked to post-challenge dysglycaemia despite normal fasting glucose. Evidence for NEFA as a modifiable longevity biomarker remains associational; exercise and caloric restriction reduce NEFA flux, but long-term trials targeting NEFA specifically are lacking.