Lori A. Kurth

Utilization of intracellular acylcarnitine pools by mononuclear phagocytes

Carnitine is essential for the metabolism of long-chain fatty acids and has both direct and indirect roles in the metabolism of short-chain and medium-chain acyl-CoAs. The purpose of this study was to quantitate and identify the individual acylcarnitines that occur in human mononuclear phagocytes (MNP) after activating them with phorbol-12-myristate 13-acetate (PMA). Mononuclear phagocytes were isolated from healthy adults and the levels of free carnitine and individual acylcarnitines were determined in unactivated and activated cells. The degree of activation of MNP was assessed by following hydrogen peroxide production. In unactivated cells, acetyl-L-carnitine represented more than 80% of the total acylcarnitine pool. Small amounts of 3-carbon and 4-carbon acylcarnitines were present, with less than 10% of the carnitine pool being long-chain acylcarnitine. Free carnitine in unactivated cells represented 7% of the total carnitine pool, which remained essentially unchanged in unactivated cells when monitored for a period of 60 min. However, free carnitine rose to more than 50% of the total pool in PMA-activated cells. Similarly, after 1 h of activation, the acetylcarnitine level in activated cells decreased by more than 50%. These data suggest that acetylcarnitine plays a key metabolic role as MNP initiate an immune response. It was further shown that MNP contain both carnitine acetyltransferase and malonyl-CoA-sensitive carnitine palmitoyltransferase in mitochondrial-enriched fractions, as well as in post-mitochondrial supernatant fractions.

Increased reproductive tract tumors in the female offspring of mice fed a high fat diet during the fetal stage of pregnancy

In a previous study, female offspring of mice consuming a high fat diet throughout pregnancy developed reproductive system tumors and tumor metastases with a frequency significantly higher than offspring of mice on a low fat diet. To test for the sensitive period more specifically, the feeding of a high fat diet was restricted to the fetal period of pregnancy in the present experiment. The offspring were raised to terminal illness and autopsied. The total number of ovarian, uterine and mammary tumors was 14 among 74 mice exposed prenatally to low fat and 34 among 75 mice exposed prenatally to high fat (P < 0.002). In mice exposed to high fat during the fetal period 13 tumors produced metastases, but no metastases were identified after exposure to low fat (P < 0.001). Thus, a maternal diet high in fat during the fetal period of pregnancy was sufficient to increase reproductive system tumors and metastases in the female offspring.

Effects of fostering on the increased tumor incidence produced by a maternal diet high in fat

Previous work has shown that female offspring of mice fed a diet high in fat during pregnancy developed more reproductive system tumors and metastases than offspring of pregnant mice fed a low-fat diet. The purpose of the current experiment was to use fostering to test whether the sensitive period for this cancer effect involved the early postnatal period. Strain CD-1 female mice were placed on a diet of 2.6% fat or 29% fat from corn oil at 4 weeks of age and bred at 6-10 weeks of age. The special diets were discontinued at birth, and litters from dams that had been fed the low-fat diet were fostered to dams previously fed the high-fat diet, and vice versa. The offspring were raised to terminal illness and autopsied. There was no difference in age at terminal illness or in the number of the common nonreproductive system tumors between the two fostered groups. Tumor metastases appeared in both groups. However, the combined frequency of reproductive tract tumors and mammary tumors was significantly higher in mice exposed prenatally to a low-fat diet and fostered to dams that had consumed a high-fat diet during pregnancy than in mice exposed prenatally to a high-fat diet and fostered to a dam fed a low-fat diet. Thus the most sensitive period for a cancer effect from high fat was early postnatal, even though the special diets had been discontinued at birth. This matches the period of greatest sensitivity for sex differentiation of the hypothalamus.