Clinical SciencePostprandial changes in plasma acylcarnitine concentrations as markers of fatty acid flux in overweight and obesity
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.
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Human subjects
Sixteen nondiabetic, nonsmoking, sedentary, and overweight or obese subjects were recruited from health fairs and physician referral and gave their written informed consent. This study was a subproject of a larger postprandial study in which our goal was to recruit Hispanic (H) or African American (AA) men or women (aged 20-70 years) with a wide range of insulin sensitivities, stable body weight, and maintenance of pre-enrollment physical activity. The study was approved by the Institutional
Results
The sex/ethnic distribution was 12 women (7 H and 5 AA) and 4 men (3 H and 1 AA). As part of the project, each subject was screened on one occasion and then was admitted to the CTRC to study fatty acid metabolism (Fig. 1). Clinical and laboratory values obtained during screening procedures revealed that the subjects were overweight to obese (body mass index 35.4 ± 7.4 kg/m2, mean ± SD); were aged 45.8 ± 8.5 years; and had total body weight of 92.9 ± 22.7 kg, fat mass of 38.6 ± 16.1 kg, lean
Discussion
Acylcarnitines are carnitine esters derived from fatty acids or amino acids transferred into the mitochondria [1]. Elevated AC production can occur when β-oxidation rates are in excess of complete oxidation to CO2 through the tricarboxylic acid cycle [1], [23]. Previous studies have shown that AC concentrations increase with duration of fasting in humans [8], [32]. By contrast, glucose-stimulated insulin secretion during an oral glucose tolerance test [10] and hyperinsulinemia during a
Funding
This study was funded with support from National Institutes of Health grants 5RL1DK081187-04 (PI: EJ Parks), 5PL1DK081183-04 (PI: E Livingston), and UL1DE019584-04 (PI: J Horton) and Clinical and Translational Science Awards National Institutes of Health grant UL1-RR02498.
Conflict of Interest
No conflicts of interest exist for any of the 4 authors.
Acknowledgment
The authors would like to express their appreciation to the research subjects for their time and enthusiasm, to the staff of the CTRC and to Dora Bradford at University of Texas Southwestern Medical Center for their excellent care of the research subjects. We thank Dr Manisha Chandalia for early support with methodology and Dr Robert Phair for insightful discussions of the data.
References (42)
- et al.
Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid β-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African American women
J Nutr
(2009) - et al.
A branched-chain amino acid–related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance
Cell Metab
(2009) - et al.
Fatty acid metabolism in human obesity
J Lipid Res
(2006) - et al.
Differential oxidation of individual dietary fatty acids in humans
Am J Clin Nutr
(2000) - et al.
Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance
Cell Metab
(2008) - et al.
New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle
J Physiol (Lond)
(2007) - et al.
Tandem mass spectrometry: a new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism
J Inherit Metab Dis
(1990) - et al.
Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity
Obesity
(2010) - et al.
Relationship between plasma free fatty acid, intramyocellular triglycerides and long-chain acylcarnitines in resting humans
J Physiol (Lond)
(2009) - et al.
Short-term effects of dietary fatty acids on muscle lipid composition and serum acylcarnitine profile in human subjects
Obesity
(2011)
Carnitine metabolism in normal-weight and obese human subjects during fasting
Am J Physiol
Effect of caloric restriction with and without exercise on metabolic intermediates in nonobese men and women
J Clin Endocrinol Metab
Changes of the plasma metabolome during an oral glucose tolerance test: is there more than glucose to look at
Am J Physiol
Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease
J Clin Invest
Dietary carbohydrate's effects on lipogenesis and the relationship of lipogenesis to blood insulin and glucose concentrations
Br J Nutr
Plasma triglyceride as a risk factor for cardiovascular disease
Can J Cardiology
Triglyceride-rich lipoprotein remnant particles and risk of atherosclerosis
Circulation
AHA Conference Proceedings. Prevention conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: executive summary. American Heart Association
Circulation
Quantitative estimation of insulin sensitivity
Am J Physiol
MINMOD Millennium: a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test
Diabetes Technol Ther
Biometric study of basal metabolism in man
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2023, Food ChemistryCitation Excerpt :Acylcarnitine can be used as a marker of fatty acid flux in overweight and obese individuals. By intravenous infusing potassium [1,2,3,4-13C4]-palmitate in overweight or obese subjects and determining the tracer isotopes in the acylcarnitines pool, Ramos-Romana et al. (2012) concluded that conditions that impact fatty acid flux contribute to the control of postprandial plasma acylcarnitines concentrations. Polyunsaturated fatty acids (HUFAs), including fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are beneficial for preventing and modulating the risk of obesity.
- 1
Collected insulin sensitivity data, analyzed all results, performed statistical analysis, and wrote the manuscript.
- 2
Assisted with study design, performed sample analysis, and contributed essential interpretation of the data.
- 3
Contributed to the conduct of the study, and collected and analyzed dietary data.
- 4
Designed the study, analyzed the data, and contributed to manuscript writing.