The effect of pivalate treatment of pregnant rats on body mass and insulin levels in the adult offspring.

Pivalic acid is used as a prodrug to increase gut absorption of a variety of different antibiotics. Pivalic acid is also known to induce a number of metabolic aberrations which may be in part explained by concurrent mild carnitine depletion. Rat pups (5 days old) born to mothers treated throughout their pregnancy and lactation period with sodium pivalate, showed an increase in liver and muscle triglycerides and elevated plasma ketone bodies, compared to controls. A reduction of free carnitine content in liver, muscle and plasma was also observed in the pivalate treated group. In a second study, pups were treated with either pivalate for 24 days (females), or pivalate for 120 days (males). Both groups were fed standard diets. In both groups (male and female), the pivalate treatment showed a statistically significant hyperinsulinaemia and an increase of body mass compared with that of age- and sex-matched control groups. In addition, after a glucose loading, significantly higher levels of insulin in the pivalate-treated group (male) with respect to controls were observed. In conclusion, our data suggest that maternal pivalate treatment may predispose adult offspring to developing insulin-resistance and obesity.

Entry of [(1,2-13C2)acetyl]-L-carnitine in liver tricarboxylic acid cycle and lipogenesis: a study by 13C NMR spectroscopy in conscious, freely moving rats.

The biochemical pathways involved in acetyl-L-carnitine utilization were investigated in conscious, freely moving rats by 13C NMR spectroscopy. Following 4-h [(1,2-13C2)acetyl]-L-carnitine infusion in fasted animals, the free carnitine levels in serum were increased, and an efflux of unlabelled acetyl-L-carnitine from tissues was observed. [(1,2-13C2)Acetyl]-L-carnitine was found to enter biosynthetic pathways in liver, and the acetyl moiety was incorporated into both cholesterol and 3-hydroxybutyrate carbon skeleton. In accord with the entry of [(1,2-13C2)acetyl]-L-carnitine in the mitochondrial acetylCoA pool associated with tricarboxylic acid cycle, the 13C label was also found in liver glutamate, glutamine, and glutathione. The analysis of the 13C-labelling pattern in 3-hydroxybutyrate and cholesterol carbon skeleton provided evidence that the acetyl-L-carnitine-derived acetylCoA pool used for ketone bodies synthesis in mitochondria was homogeneous, whereas cholesterol was synthesized from two different acetylCoA pools located in the extra- and intramitochondrial compartment, respectively. Furthermore, cholesterol molecules were shown to be preferentially synthesized by the metabolic route involving the direct channelling of CoA-activated mitochondria-derived ketone bodies into 3-hydroxy-3-methylglutarylCoA pathway, prior to equilibration of their acyl groups with extramitochondrial acetylCoA pool via acetoacetylCoA thiolase.

Role of acetyl-L-carnitine in rat brain lipogenesis: implications for polyunsaturated fatty acid biosynthesis.

This study was undertaken to explore the metabolic fate of acetyl-L-carnitine in rat brain. To measure the flux of carbon atoms into anabolic processes occurring at regional levels, we have injected [1-(14)C]acetyl-L-carnitine into the lateral brain ventricle of conscious rats. After injection of [1-(14)C]acetyl-L-carnitine, the majority of radioactivity was recovered as 14CO2 expired (60% of that injected). The percentage of radioactivity recovered in brain was 1.95, 1.60, 1.30, and 0.93% at 1, 3, 6, and 22 h, respectively. Radioactivity distribution in various lipid components indicated that the fatty acid moiety of phospholipid contained the majority of radioactivity. The radioactive profile of these fatty acids showed that the acetyl moiety of acetyl-L-carnitine was incorporated into saturated (60%), monounsaturated (15%), and polyunsaturated (25%) fatty acids [mainly present in 20:4 (5.2%) and 22:6 (7.8%)]. Injection in the brain ventricle of radioactive glucose, the major source of acetyl-CoA in the CNS, revealed that glucose was a precursor of saturated (85%) and monounsaturated (15%) but not of polyunsaturated fatty acids. Thus, this study demonstrated distinct fates of glucose and acetyl-L-carnitine following intracerebroventricular injection. In summary, these data implicate acetyl-L-carnitine as an important member of a complex acetate trafficking system in brain lipid metabolism.

Acetyl-L-carnitine modulates glucose metabolism and stimulates glycogen synthesis in rat brain.

The effects of acetyl-L-carnitine on cerebral glucose metabolism were investigated in rats injected with differently 14C- and 13C-labelled glucose and sacrificed after 15, 30, 45, and 60 min. Acetyl-L-carnitine was found to reduce total 14CO2 release from [U-14C]glucose along with the decrease in [1-13C]glucose incorporation into cerebral amino acids and tricarboxylic acid cycle intermediates. However the 13C labelling pattern within different carbon positions of glutamate, glutamine, GABA, and aspartate was unaffected by acetyl-L-carnitine administration. Furthermore, the cerebral levels of newly-synthesized proglycogen were higher in rats treated with acetyl-L-carnitine than in untreated ones. These results suggest that acetyl-L-carnitine was able to modulate cerebral glucose utilization and provide new insights on the mechanisms of action of this molecule in the central nervous system.