REGULATION OF FATTY ACID METABOLISM
"Fatty acids are the major lipid fuel in humans. More than 95%
of all fatty acids are stored as triacylglycerol fatty acids within adipose tissue, which takes up circulating triacylglycerol fatty
acids from VLDL and chylomicron particles. Adipose tissue
releases fatty acids via lipolysis into the circulation, where the
NEFAs serve as the major circulating lipid fuel. Although they
are mostly bound to albumin, the circulating half-life of NEFAs
is only 3–4 min (1).
There is an extreme range of normal NEFA availability in
humans. Physiologic hyperinsulinemia can reduce plasma NEFA
concentrations from their normal concentration of <500 to
10–20 mmol/L (2). Under conditions of fasting or adrenergic
stimulation, plasma NEFAs may increase to concentrations
³3000 mmol/L (3). Although there is also a wide range of NEFA
flux, it is not as extreme as the 300-fold variation in plasma
NEFA concentrations. Under hyperinsulinemic conditions,
plasma NEFA flux may decrease to 0.5 mmol · kg21 · min21 (2),
whereas with insulin deficiency (such as during fasting), plasma
NEFA flux may increase to 12.5 mmol · kg21 · min21 (2, 3). During
exercise, plasma NEFA flux may increase to as much as 25
mmol · kg21 · min21.
This wide range of plasma NEFA availability is possible
because of the exquisite sensitivity of adipose tissue lipolysis to
both insulin (2) and catecholamines (4). Small changes in plasma
insulin concentrations have dramatic effects on adipose tissue
lipolysis, and therefore NEFA availability. The insulin doseresponse
characteristics of NEFA flux were measured in normal
humans by using the pancreatic clamp technique to examine
plasma free insulin concentrations ranging from 0 to <130 pmol/L
(2). At plasma insulin concentrations near zero, NEFA flux is about
double its baseline value; half-maximal suppression of NEFA flux
occurs at plasma free insulin concentrations of <12 pmol/L (total
plasma insulin concentrations of <25 pmol/L). Thus, overnight
postabsorptive plasma insulin concentrations are a significant
restraint to basal NEFA flux. Maximal suppression of NEFA flux in
normal humans occurs at plasma insulin concentrations < 100
pmol/L, easily within the range observed after the ingestion of a
small, carbohydrate-containing meal (5). Catecholamines are
important stimulators of NEFA release under conditions of stress
and during exercise (6, 7). Growth hormone and cortisol also stimulate
lipolysis, but appear to be much less potent than catecholamines
(8, 9). Elevated plasma ketone body concentrations restrain lipolysis (10).
Basal NEFA availability, as measured with isotope-dilution
techniques, exceeds fatty acid oxidation as measured by indirect
calorimetry by <100% (1). Basal NEFA flux exceeds fatty acid
oxidation to a greater extent in individuals with upper-body obesity
(11) and to a lesser extent in trained athletes (12, 13).
Splanchnic tissues account for <40% of basal NEFA uptake
(14). The NEFAs taken up in the splanchnic bed (primarily the
liver) may be oxidized, released as ketone bodies, and released
as VLDL triacylglycerol (15). These VLDL triacylglycerol fatty
acids are then available for reuptake by adipose tissue.
Appropriate regulation of NEFA availability is important for
optimal human health. Excess NEFAs can induce insulin resistance
with respect to muscle glucose uptake (16) and suppression
of endogenous glucose production (17). Other associations with
increased NEFAs include hypertriglyceridemia (18), reduced
hepatic insulin clearance (19, 20), and impaired b-cell insulin
secretion (21). These abnormalities are also commonly associated
with obesity. Thus, it is not surprising that abnormalities of NEFA
flux may be present in some forms of obesity."-Am J Clin Nutr 1998;67(suppl):531S–4S. Printed in USA. © 1998 American Society for Clinical Nutrition