Postprandial changes in plasma acylcarnitine concentrations as markers of fatty acid flux in overweight and obesity

Abstract

This study determined whether reductions in postprandial plasma nonesterified fatty acid (FFA) flux would lead to reductions in plasma acylcarnitine (AC) concentrations. Plasma AC was measured by liquid chromatography with tandem mass spectrometry in the fasting state and over 6 hours after a high-fat (50% energy) meal was fed to 16 overweight and obese subjects with a wide range of insulin sensitivities. Body composition was measured by dual-energy x-ray absorptiometry; insulin sensitivity by insulin-modified, frequently sampled intravenous glucose tolerance test; substrate oxidation by indirect calorimetry; blood metabolite and hormone concentrations biochemically; and fatty acid flux by using stable isotope tracers. Lean body mass and fasting fat oxidation correlated positively (r > 0.522, P < .05), whereas glucose oxidation correlated negatively (r < −0.551, P < .04), with fasting AC. Postprandially, plasma glucose, insulin, and triglyceride concentrations increased; and FFA concentrations decreased significantly. The responses of plasma AC species depended on chain length and saturation, with C14:0, C16:0, and C18:0 remaining unchanged, and unsaturated species (eg, C14:1, C14:2) falling significantly (21%-46%, P < .03). Postmeal nadir AC concentrations were positively associated with lean body mass, postprandial fatty acid flux, and FFA concentrations (r > 0.515, P < .05). By contrast, nadir AC correlated negatively with insulin sensitivity and spillover of meal-derived fatty acids (r < −0.528, P < .04). Conditions that impact fatty acid flux contribute to the control of postprandial plasma AC concentrations. These data underscore the need for a better understanding of postprandial fatty acid oxidation and dietary fat delivery in the setting of adipose insulin resistance to determine how postprandial lipemia contributes to chronic disease risk.

Introduction

Acylcarnitines (ACs) are carnitine esters of fatty acids that have entered the mitochondria [1], and their quantitation has been used for more than 20 years to diagnose inborn errors of fatty acid metabolism [2]. Recently, plasma ACs have been proposed as biomarkers of insulin resistance and metabolic inflexibility in adults [3], [4]. Although the plasma nonesterified fatty acid (FFA) pool is the original precursor of intracellular tissue fatty acids, Kanaley et al [5] determined that the intramyocellular triglyceride (TG) pool is the immediate fatty acid precursor of intramyocellular long-chain AC (LCAC) in fasted humans. With respect to the role of dietary fatty acids, one report by Kien et al [6] demonstrated that a dietary change as brief as 7 days can result in similarities between the dietary fatty acid composition and muscle TG and AC species, again assessed in the fasting state. Thus, both endogenous and dietary fatty acids have the potential to impact the composition of AC species, varying in chain length and saturation.

Fasting plasma AC concentrations have been shown to be elevated in obese individuals with either impaired glucose tolerance or diabetes [3], [7], and these findings support incomplete fat oxidation in these subjects. However, AC concentrations increase in the plasma of lean, insulin-sensitive subjects during long-term fasting [8] and relatively healthy overweight subjects during caloric restriction [9]. These observations suggest that the AC increase in obesity may not only be due to an impairment of metabolism but also be a natural response to an excess supply of lipid. Thus, increased production of AC could result from excess fatty acid flux emanating from lipid stored either intracellularly or peripherally. Indeed, plasma AC concentrations are reduced during an oral glucose tolerance test and during a euglycemic-hyperinsulinemic clamp, both procedures that reduce plasma FFA concentrations significantly [4], [10]. Yet, under these conditions, obese and diabetic subjects maintained higher AC concentrations than lean controls [4].

Metabolic dysfunction can be uncovered by the challenge of food consumption [11], [12]. Given that elevations in postprandial lipemia pose an independent risk for the development of chronic disease [13], [14], [15], it is important to understand how the metabolic transitions from fasting to feeding can be reflected in changes in plasma AC. The present study was designed to determine whether AC concentrations would fall when subjects were fed a high-fat, mixed meal, which produced a physiologic pattern of postprandial elevations in glucose and insulin and reductions in FFA, concurrent with significant increases in plasma TG-rich lipoproteins. We sought to (1) compare the dynamic responses of different AC species and (2) identify subject characteristics associated with changes in postmeal concentrations of plasma AC. Our goal was to test the hypothesis that a fall in plasma AC after a standardized mixed meal would be positively related to measures of insulin sensitivity. We hypothesized that the concentrations of all plasma AC would fall after consumption of a meal that induces a significant reduction in adipose fatty acid release and plasma FFA concentration.