Fatty Acids, Obesity, and Insulin Resistance: Time for a Reevaluation

  1. Keith N. Frayn1
  1. 1Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, U.K.
  2. 2National Institute for Health Research, Oxford Biomedical Research Centre, Oxford Radcliffe Hospitals Trust, Oxford, U.K.
  1. Corresponding author: Fredrik Karpe, fredrik.karpe{at}

There is a widespread acceptance in the literature that plasma nonesterified fatty acids (NEFA), also called free fatty acids (FFA), can mediate many adverse metabolic effects, most notably insulin resistance. Elevated NEFA concentrations in obesity are thought to arise from an increased adipose tissue mass. It is also argued that the process of fatty acid mobilization from adipose tissue, normally suppressed by insulin, itself becomes insulin resistant—thus, lipolysis is further increased, potentially leading to a vicious cycle. Although we have also accepted this model for many years (1,2), recently there has been a steady accumulation of data, both in the literature and from our own research, that has forced us to realize that this simple story is not always true. Here we review the background to the idea of “fatty acids as metabolic villains,” together with data from the literature and from our own studies, which tend to show another side to the fatty acids/insulin resistance story.

We will first examine the relationship between systemic concentrations of NEFA and obesity/insulin resistance and then study adipose tissue in the obese state with regard to its adaptation for NEFA release.


NEFA circulate in the plasma bound to plasma albumin. Their function was largely elucidated in the 1950s through the work of Vincent Dole (3) at the Rockefeller Institute in New York and Robert Gordon (4,5) at the National Institutes of Health. Gordon demonstrated the origin of plasma NEFA from adipose tissue and their use by tissues such as the liver and myocardium, but not the brain.

We now recognize that NEFA are the vehicle by which triacylglycerol (TG) stored in adipose tissue is transported to its sites of utilization. NEFA turnover is rapid, with a plasma half-life around 2–4 min (6). The only significant site of NEFA liberation …

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