Fatty Acids, Insulin Resistance, and Protein Metabolism

Abstract

A ccretion 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, fatty acids and/or fatty acid-induced insulin resistance did 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 studies have been done either during fasting when 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 an...

Obesity-Dependent Metabolic Signatures Associated with Nonalcoholic Fatty Liver Disease Progression

“…Similar increases in serum essential amino acids have previously been related to a higher rate of whole-body protein turnover in NASH, modulated by co-factors such as cytokines, inflammation and insulin resistance 38 . While in the morbidly obese cohort of patients the clearest NASH metabolic abnormalities seem to be associated with the overloading of oxidative free fatty acid disposal routes, NASH is reflected in the lean cohort by significant alterations of a series of potentially lipotoxic intermediates that have been previously associated with NAFLD progression.…”

Methionine and protein metabolism in non-alcoholic steatohepatitis: evidence for lower rate of transmethylation of methionine

“…This is in contrast to the acutely induced insulin resistance by intravenous fatty acid infusion, where a decrease in the rate of appearance of phenylalanine across the leg was observed [37]. The fatty acid induced decrease in proteolysis may be a direct inhibitory effect of fatty acids on protein breakdown [38, 39]. The negative correlation between plasma insulin levels and phenylalanine Ra is consistent with the effect of insulin on whole body rate of protein breakdown [40].…”

Plasma metabolomic profile in nonalcoholic fatty liver disease

“…The increase in essential amino acids suggests a higher rate of whole body protein turnover. In addition, the lack of increase in essential amino acids in individuals with steatosis suggests that changes in protein turnover may be a late event in the progression of steatosis to NASH, and may be modulated by other factors such as cytokines and inflammation, in addition to insulin resistance (33–36). …”