Free Fatty Acids Flux and Insulin Resistance

The hepatic portal system provides a close association between visceral fat and the liver and has played a key role in explaining one of the possible mechanisms by which visceral fat may exert distant metabolic effects. Thus, increased lipolysis from this site is associated with release of FFA that have local direct access to the prime metabolic organ of the body, the liver. It is reasoned that FFA from other adipose tissue sites, which may be less susceptible to lipolysis, deliver less FFA, and then only indirectly, to the liver, thus having less potential for harmful influence. This might explain the apparently less deleterious role of peripheral adiposity. Supportive data for a FFA hypothesis to link abdominal obesity with morbidity has been forthcoming in various forms:

  • FFA inhibits glucose utilization. Competition between FFA and glucose as substrates for cellular energy needs has been known for some time, as formulated in the Randle hypothesis. FFA are thought to reduce sensitivity to insulin action by virtue of preferential use of FFA over glucose by muscle tissue, the major site of insulin action in the body.
  • FFA stimulate hepatic glucose production. The products of lipolysis enhance gluconeogenesis. Excess glucose production by the liver has been shown to occur in diabetes mellitus and also in patients with impaired glucose tolerance and contributes to elevated blood glucose levels in both conditions. In diabetes, enhanced glucose production occurs in both fasting and postprandial states; in persons with impaired glucose tolerance, failure to normally suppress hepatic glucose production after a glucose load contributes to elevated plasma glucose concentrations diagnostic of this condition.
  • FFA stimulate insulin secretion and thus may contribute to the finding of hyperinsulinemia in these subjects. Hyperinsulinemia also appears to be due to decreased clearance of insulin by the liver in abdominal obesity.
  • FFA are also a substrate for triglyceride and VLDL production by the liver, when available during insulin excess, synthesis is enhanced.

All of the above suggest that elevated FFA, arising from the abdominal adipose tissue source that is both sensitive to adrenergically-induced lipolysis and also resistant to insulin-induced inhibition of lipolysis, may be responsible, directly or indirectly, for many of the disorders associated with visceral obesity, i.e., that abdominal obesity is a primary abnormality.

However, recently published data have created some difficulty for this hypothesis and introduce a chicken and egg situation - which came first? Prospective studies of Japanese-Americans who are at risk for Type II diabetes suggest that the primary lesion may be hyperinsulinemia and insulin resistance, not abdominal obesity. After long-term follow-up, investigators in Seattle demonstrated that the risk for later appearance of visceral adiposity was predictable by initial serum insulin concentrations and measures of insulin resistance. Other data, implicating visceral fat tissue with preferential susceptibility to insulin-stimulated lipogenesis, (for example increased levels of adipose tissue lipoprotein lipase activity), fit with the concept that this location might accumulate fat more easily than peripheral fat depots in predisposed individuals. This sets up the possibility for a vicious cycle; abdominal obesity, insulin resistance, hyperinsulinemia, visceral obesity, without a clear indication which is the initial lesion.