Fatty acids, insulin resistance, and protein metabolism.

Accretion and maintenance of lean body mass, because of its fundamental role in health and disease, continues to be an area of intense investigation. By using sophisticated tracer isotopic methods, organ balance techniques, and molecular analysis of tissue samples in humans and animal models, a detailed analysis of the signaling pathway and metabolic fluxes has been possible. Despite these, understanding the regulatory mechanism of nitrogen/protein accretion and maintenance of lean body mass in vivo continues to be challenging. This is particularly difficult because of the adaptation of metabolism to various modifying influences, and because of the multiple levels of regulation in vivo. Yet, by careful studies, a number of investigators have systematically examined the influence of diverse modifiers on the physiology of protein synthesis and breakdown in humans in vivo. In this issue of JCEM, Katsanos et al. have examined, in healthy humans, the impact of elevated plasma fatty acids levels, induced by iv infusion of intralipid and heparin, on the responsiveness of the skeletal muscle protein synthesis and balance to an enterally administered essential amino acid mixture. By using isotopic tracers in combination with arteriovenous balance measurements across the leg and by quantifying tracer incorporation into muscle proteins, Katsanos et al. (1) have presented a detailed analysis of protein kinetics in the skeletal muscle. As anticipated, increase in plasma free fatty acids resulted in the development of insulin resistance (2). Their data show that in the basal state, in the presence of elevated plasma fatty acids levels and insulin resistance, there was a decrease in the rate of appearance of phenylalanine across the leg, suggesting a lower rate of protein breakdown. The rate of disappearance of phenylalanine was not affected, resulting in an improved or less negative amino acid balance. Essential amino acid administration resulted in no change in protein breakdown and caused an increase in phenylalanine rate of disappearance (increase in protein synthesis) and an increase in the fractional rate of protein synthesis. Of significance, fattyacids and/or fattyacid-induced insulin resistancedid not impact the rate of protein synthesis by skeletal muscle in response to the amino acid load. Fatty acids are critical oxidative substrates that are mobilized during fasting and result in sparing of glucose and amino acids. Elevated fatty acid levels during fasting are associated with decreased glucose uptake by skeletal muscle, decreased protein breakdown, and a lower rate of protein oxidation and urea synthesis (3). The cause and effect relating fatty acids to changes in fasting metabolism has been examined in a large number of studies.These studieshavebeendoneeitherduring fastingwhen there is a spontaneous increase in plasma fatty acid concentration or by infusing intralipid with heparin, resulting in an increase in the plasma fatty acid levels in the high physiological range. Fatty acids could impact glucose and protein metabolism (protein synthesis and breakdown) either directly or via their effect on insulin secretion and/or insulin action (insulin sensitivity/resistance). In studies in healthy humans, exogenously infused fatty acids have been shown to result in a decrease in the rate of protein breakdown by the skeletal muscle, evidenced by a decrease in the rate of net release of amino acids across the limb (4), and by a decrease in the rate of appearance of essential amino acids leucine and phenylalanine as measured by isotopic tracer methods (5, 6). Although the mechanism of the observed effect of fatty acids on protein breakdown has not been identified, it does not appear to be related to hepatic oxidation of fatty acids and consequent increase in ketone levels. In addition, fatty acids have been shown to cause a decrease in the rate of oxidation of leucine and of urea synthesis (protein sparing) (5, 6). The critical role of fatty acids in inhibiting protein breakdown was confirmed by Nørrelund et al. (7) in subjects who fasted for 37 h. Their data showed that acute suppression of lipolysis by acipimox resulted in an approximately 50% increase in muscle protein breakdown. Stoichiometric calculation of protein synthesis (synthesis breakdown loss) from these data suggests that fatty acid infusion resulted in a decrease in the rate of protein synthesis. The lower rate of protein synthesis could be the result of a decrease in