Plasma acylcarnitine profiling indicates increased fatty acid oxidation relative to tricarboxylic acid cycle capacity in young, healthy low birth weight men

Abstract

We hypothesized that an increased, incomplete fatty acid beta‐oxidation in mitochondria could be part of the metabolic events leading to insulin resistance and thereby an increased type 2 diabetes risk in low birth weight (LBW) compared with normal birth weight (NBW) individuals. Therefore, we measured fasting plasma levels of 45 acylcarnitine species in 18 LBW and 25 NBW men after an isocaloric control diet and a 5‐day high‐fat, high‐calorie diet. We demonstrated that LBW men had higher C2 and C4‐OH levels after the control diet compared with NBW men, indicating an increased fatty acid beta‐oxidation relative to the tricarboxylic acid cycle flux. Also, they had higher C6‐DC, C10‐OH/C8‐DC, and total hydroxyl‐/dicarboxyl‐acylcarnitine levels, which may suggest an increased fatty acid omega‐oxidation in the liver. Furthermore, LBW and NBW men decreased several acylcarnitine levels in response to overfeeding, which is likely a result of an upregulation of fatty acid oxidation due to the dietary challenge. Moreover, C10‐OH/C8‐DC and total hydroxyl‐/dicarboxyl‐acylcarnitine levels tended to be negatively associated with the serum insulin level, and the total hydroxyl‐/dicarboxyl‐acylcarnitine level additionally tended to be negatively associated with the hepatic insulin resistance index. This indicates that an increased fatty acid omega‐oxidation could be a compensatory mechanism to prevent an accumulation of lipid species that impair insulin signaling.

Plasma amino acid levels are elevated in young, healthy low birth weight men exposed to short-term high-fat overfeeding

“…Taken together, we proposed that the acetyl‐CoA generation from in particular the increased fatty acid oxidation exceeds its oxidation in the TCA cycle in LBW individuals (Ribel‐Madsen et al. ), possibly due to a depletion of TCA cycle intermediates. In the state of a high intracellular acetyl‐CoA concentration, as seems to be the case in LBW individuals (Ribel‐Madsen et al.…”

“…Previously, we have shown that LBW men have a higher plasma acetylcarnitine level after the control diet and a tendency to this after the high‐fat, high‐calorie diet compared with NBW men (Ribel‐Madsen et al. ), and in addition, an increased fatty acid oxidation and a decreased glucose oxidation at night during intake of both diets (Brons et al. , ).…”

“…In the state of a high intracellular acetyl‐CoA concentration, as seems to be the case in LBW individuals (Ribel‐Madsen et al. ), pyruvate dehydrogenase is inhibited and pyruvate carboxylase is activated, favoring pyruvate carboxylation to oxaloacetate, the four‐carbon unit TCA cycle intermediate that condenses with acyl‐CoA to form citrate, and as well favoring pyruvate transamination to alanine (Hue and Taegtmeyer ). This promotes anaplerosis and gluconeogenesis, respectively (Hue and Taegtmeyer ).…”

“…These analyses included a semiquantitative determination of 45 acylcarnitine species or sets of species and were performed as described previously (Ribel‐Madsen et al. ).…”

“…Furthermore, LBW men have a higher relative contribution of fatty acid oxidation to the total energy expenditure at night and throughout 24 h when studied on the high-fat, high-calorie diet (Brons et al 2015). Recently, we have extended our understanding of the LBW prediabetic phenotype with the finding of elevated fasting plasma acetylcarnitine levels in LBW men, pointing toward an increased acetyl-CoA generation relative to its oxidation in the tricarboxylic acid (TCA) cycle (Ribel-Madsen et al 2016). An accumulation of acetyl-CoA may theoretically lead to mitochondrial stress responses and the activation of serine kinases, which in turn may impair skeletal muscle insulin signaling and glucose transporter 4 (GLUT4) translocation (Muoio and Newgard 2008).…”