Infusion of tumor necrosis factor/cachectin promotes muscle catabolism in the rat. A synergistic effect with interleukin 1.

To improve our understanding of the metabolic role of cytokines in protein wasting, we estimated the rates of protein synthesis and degradation in muscle and liver tissues in intact rats treated with several doses of recombinant IL 1 and/or tumor necrosis factor (TNF)/cachectin. Protein breakdown in muscle and liver were derived in vivo from the relationship between [14C]leucine distribution and tissue dilution in reference to circulating leucine. Synthesis was derived from the relationship between [14C]leucine appearance in the protein-bound and free-tissue leucine pools. To specifically relate changes in leucine tracer metabolism to protein dynamics, we separately measured the effect of these cytokines on blood flow to different tissues. The increase in dilution of the tissue-free [14C]leucine by TNF and TNF/IL 1 mixture, but not by IL 1 alone, could not be explained by a hemodynamic effect of these cytokines. Rather, this finding indicated that muscle proteolysis is enhanced by TNF and synergistically augmented by the addition of IL 1. Compatible with these data was the finding that more prolonged infusions of recombinant TNF/cachectin and the combination with IL 1 increased urinary nitrogen excretion. Changes in [14C]leucine dilution in the liver were less pronounced than those in skeletal muscle and consistent with net anabolic effect of TNF on liver protein. We conclude that rats exposed systemically to sublethal doses of TNF respond with increasing muscle and decreasing liver proteolysis, similar to that observed in inflammation and in cancer.

1alpha,25-Dihydroxyvitamin D and fish oil synergistically inhibit G1/S-phase transition in prostate cancer cells.

Laboratory and epidemiological studies have indicated that 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] and dietary omega3-polyunsaturated fatty acids (PUFAs) are capable of inhibiting prostate cancer at the initiation and progression stages. The objective of this study is to investigate the influence of 1alpha,25(OH)(2)D(3) and PUFAs in the form of fish oil applied alone or in combination on cell cycle kinetics in the exponentially growing androgen-dependent and -independent prostate cancer cells. Our data indicate that the high passage androgen-independent cell line, LNCaP-c115 had a much greater inhibitory response at the level of the G(1)/S-phase transition in response to fish oil treatment than androgen-dependent low passage LNCaP-c38 cells. When LNCaP-c38 and LNCaP-c115 cells were treated with fish oil (50mug/ml), 1alpha,25(OH)(2)D(3) (10(-8)M) or fish oil (50mug/ml)+1alpha,25(OH)(2)D(3) (10(-8)M), a synergistic growth inhibitory effect was observed with 1alpha,25(OH)(2)D(3)+fish oil group in LNCaP-c115 cell line at the levels of the G(1)/S-phase transition and cell division. This interaction appears to be specific for androgen-independent prostate cancer cell lines. Based on these results, we hypothesize that dietary components, such as omega3PUFAs and Vitamin D, have the potential to delay the progression of prostate cancer cells to an aggressive and un-treatable state.

Influence of the Walker 256 carcinosarcoma on muscle, tumor, and whole-body protein synthesis and growth rate in the cancer-bearing rat.

The in vivo rates of protein synthesis were assessed in tumor tissue, skeletal muscle, and whole body of rats bearing the Walker 256 carcinosarcoma. Estimates of protein synthesis in the nontumorous tissues were compared to tumor-free controls. Changes in size of the whole animal and tumor (i.e., growth) were measured, and fractional rates of growth, synthesis, and breakdown were estimated. Muscle protein synthesis and whole-body growth were significantly reduced in rats bearing larger tumors, and both were negatively correlated with tumor size (r = -0.723 and -0.825, respectively; P less than 0.01). Furthermore, whole-body and muscle protein synthesis were positively correlated with body growth (r = 0.380 and 0.563, respectively; P less than 0.05). Tumor growth followed first-order kinetics between days 7 and 13 following implantation, with a mean rate constant of 34.3%/day for the larger tumors and 27.7%/day for the small tumors. The difference in tumor growth became statistically significant over the final 3 days of tumor volume measurements. Fractional protein synthesis was significantly lower in the larger compared to the smaller tumors (48.6 versus 84.8%/day; P less than 0.05) as measured on day 14. This finding indicates a lower protein breakdown rate for the larger tumors (14.3 versus 59.0%/day; P less than 0.01) and suggests that the process of protein breakdown could play a significant role in determining tumor size, leading support to the theory of tumors acting as nitrogen traps.

Effects of branched chain amino acid-enriched total parenteral nutrition on amino acid utilization in rats bearing Yoshida sarcoma.

We have studied the ability of branched chain amino-acid enriched total parenteral nutrition solutions to improve nutritional status without stimulating tumor growth. Protein kinetics, nitrogen balance, tumor kinetics, fractional synthetic rates of individual tissues, and albumin synthesis were compared in male Sprague-Dawley rats (125-145 g) that had either s.c. Yoshida sarcoma (n = 15) or sham implantations (n = 18). Ten days postinjection, rats were randomly assigned to 2 diet groups and given parenteral infusions of 4 days at 170 kcal/kg.body wt.day as dextrose and 2 g N/kg.body wt.day as either 19 or 50% branched chain amino acid-enriched diet. During the last 4 h of feeding, protein kinetic values were studied using a constant infusion of [14C]tyrosine. Plasma tyrosine appearance, synthesis, and breakdown were unchanged by branched chain amino acid infusion. Percentage of tyrosine flux oxidized and tyrosine oxidation decreased (P less than 0.05) and net tyrosine balance improved (P less than 0.05) in rats receiving the branched chain amino acid-enriched diet. Greater nitrogen balance and lower tumor growth rates were also found in branched chain amino acid-infused rats although not statistically significant. Tumor intracellular specific activity was significantly higher in tumor animals receiving crystalline infusions, suggesting greater tumor protein breakdown with branched chain amino acid-enriched infusion. Fractional synthetic rates of liver, muscle, and tumor were unchanged. Hence, branched chain amino acid-enriched total parenteral nutrition increases amino acid utilization for net protein synthesis principally by reducing oxidation without stimulating tumor growth.

Influence of interleukin-2 infusion on cell cycle kinetics in the Walker-256 carcinosarcoma.

The effect of recombinant human interleukin-2 (IL-2) on tumor cell cycle kinetics was evaluated in rats bearing the Walker-256 carcinosarcoma. Seven days after implantation, tumor-bearing rats were infused intravenously with IL-2 at a dose of 500 mg/kg body weight or 5% dextrose for 6 h. Tumor cell mean DNA synthesis time (TDNA), labeling index, potential doubling time (Tpot), and growth fraction (GF) were determined in vivo by use of bromodeoxyuridine (BrdUrd) pulse labeling and bivariate BrdUrd/DNA analysis using flow cytometry. IL-2 treatment significantly reduced the relative number of S-phase cells by 11.9% and increased the number of cells in the G0/G1 phase by 9.4%. The labeling index was reduced from 41.3 +/- 2.5% to 32.7 +/- 1.2% (P < .01). Estimates of TDNA derived from the change in BrdUrd movement relative to DNA content were not affected by IL-2 treatment. Based on these cytokinetic changes, IL-2 infusion significantly increased tumor Tpot from 15.3 +/- 0.3 h to 21.5 +/- 0.2 h (P < .001) and reduced GF from 1.01 +/- 0.07 to 0.83 +/- 0.01 (P < 0.001). The inhibitory effect of IL-2 infusion on tumor cell growth, which may be either direct or secondarily mediated by other factors, contrasts with other stimulatory effects of this cytokine on lymphoid cell proliferation.

Insulin resistance versus insulin secretion in the hypertension of obesity.

We measured the degree of association between obesity, blood pressure, insulin resistance, and insulin secretion in 72 male and female obese hypertensive, obese nonhypertensive, and normal weight control subjects. Baseline weight, body mass index, percent body fat, waist/hip ratio, and systolic and diastolic blood pressures were obtained. Insulin sensitivity was assessed according to Bergman's minimal model. Twelve-hour urinary c-peptide was measured after a standard liquid meal. Insulin action was inversely associated with blood pressure status, obesity status, and age. Meal-stimulated c-peptide excretion significantly correlated with systolic blood pressure and percent fat but not with body mass index or age. Multivariate regression analysis indicated that, of the measures of body composition, percent fat and waist/hip ratio had the strongest correlation with insulin action either alone or in combination with c-peptide excretion. Obese hypertensive patients had an index of insulin action (10(-4).min-1/[microunits/ml]) of 1.34 +/- 0.19, which was significantly (p less than 0.003) lower than in the obese nonhypertensive patients (index, 2.26 +/- 0.10) or the nonobese subjects (index, 5.41 +/- 0.26, p less than 0.001). Meal-stimulated c-peptide excretion (nmol/kg lean body mass) was increased only in the obese hypertensive group (0.32 +/- 0.01) and was significantly higher (p less than 0.001) than in the obese nonhypertensive (0.16 +/- 0.01) or the nonobese subjects (0.14 +/- 0.01). These results support the hypothesis that abnormalities in blood pressure regulation, insulin-stimulated glucose uptake, and insulin secretion coexist.

Absorption of stable70 Zn in healthy young men in relation to zinc intake.

Zinc absorption was measured in two groups of four healthy young men using the method of stable tracer isotope neutron activation analysis. All absorption measurements were made using a test dose of ZnCl2 in subjects who participated in an overnight fast and also in subjects from whom food was withheld for 5 h after ingestion of tracer. In one group of experimental subjects, dietary zinc intake was held constant (approximately 15 mg/day), and three different test doses of the tracer were administered at weekly intervals. Fractional absorption was 81% from a 4.52-mg dose, 67% from a 6.47 mg dose and 61% for a 24.52-mg dose. In the other group of subjects, dietary zinc was reduced from approximately 15 mg to less than 2 mg/day. This was accompanied by a significant increase in fractional zinc absorption of a fixed tracer zinc dose (1.19 mg), from 81 to 92%. This increase, which occurred within 6 days, was also measurable when the tracer zinc dose was increased to 4.76 mg. These data indicate that there is a significant effect of the dose level of stable zinc isotope on its fractional absorption. They also demonstrate that a restriction in dietary zinc intake results in a prompt increase in the absorption of a fixed pulse dose of zinc in healthy young men.

Measurement of 68Zn and 70Zn in human blood in reference to the study of zinc metabolism.

A method based on radiochemical neutron activation analysis has been developed for measurement of the stable isotopes 68Zn and 70Zn in human plasma and red cells. The method has been applied to measure the extent of 70Zn enrichment in plasma samples from four healthy adult volunteers who had each consumed a single 3.2 mg dose of 70ZnCl2 in fasting state. It is shown that measurements of 70Zn/68Zn ratio in plasma and red cell sample sizes of 2 ml can be made with precisions of 10% or less depending on the degree of enrichment achieved. The limiting factor in the precision of these measurements appears to be related to the counting statistics of the 386 kev photopeak (71mZn) which improves with increased enrichment. Clinical feasibility trials on these subjects with regard to plasma and red cell 70Zn enrichment have been carried out over a 24-h postadministration period. The results are consistent with kinetic studies reported in literature with radiozinc, and show that this method can be used to study kinetics of plasma appearance of 70Zn after oral administration of the isotope under physiological intake conditions. The present results further indicate that under these experimental conditions, enrichment of red cells can be measured after 24 h or longer postadministration periods, but short-term measurements yield marginal results. This new method provides an alternative approach to the use of radiolabeled zinc for the study of human zinc metabolism and appearance of isotopic zinc in plasma after oral administration under physiological intake conditions. It can be applied to all human population groups as a noninvasive and safe method which does not require safety considerations arising from human use of radiotracers. However, its application is both more expensive and limited in terms of sample throughput as compared with the radiotracer technique.

Absorption of dietary zinc in man: comparison of intrinsic and extrinsic labels using a triple stable isotope method.

Determination of true absorption of dietary minerals in human subjects using "extrinsic-tag" approach with stable isotopes requires establishment of its validity. The present study was conducted to test with quantitative aspects absorption of an extrinsic-tag of zinc labeled with 70Zn as compared with an "intrinsic-tag" of the mineral as 68Zn-labeled chicken meat given simultaneously to health male subjects. Three diet periods were used in which diet modulation with respect to zinc dialy intake and nature of protein source (chicken/soy protein isolate) was also examined. Absorption was measured via quantitative fecal isotope balance of 64Zn, 68Zn, 70Zn. For the three diet period 1 (protein: chicken; Zn intake: ZN intake: 10 to 11 mg/day), 2 (protein: chicken/soy protein isolate, 50/50; Zn intake: 10 to 11 mg/day), and 3 (protein: chicken; Zn intake: 7 mg/day), fractional absorption of the extrinsic tag (mean +/- 1 SEM) was 0.46 +/- 0.06, 0.46 +/- 0.06, and 0.66 +/- 0.04 respectively. The comparable values for intrinsic 68Zn were 0.57 +/- 0.06, 0.57 +/- 0.06, and 0.72 +/- 0.04. There was a highly significant correlation (r=0.91), between zinc absorption from the two labels. However, absorption of intrinsic 68Zn was significantly higher (p less than 0.02) during all periods than that for the extrinsic 70Zn. A 50% replacement of protein from chicken meat with the soy protein isolate did not later fractional absorption of zinc from either tag. The ratio of fractional absorption of the extrinsic/intrinsic tag (mean +/- 1 SEM) was 0.79 +/- 0.06, 0.79 +/- 0.04, and 0.92 +/- 0.03 for periods 1, 2, 3, respectively.

IGF-I alters energy expenditure and protein metabolism during parenteral feeding in rats.

In this study, 20 micrograms.kg.-1.h-1 of recombinant human insulin-like growth factor I (IGF-I) was infused into normal healthy rats to examine the effects of IGF-I on glucose, protein, and energy metabolism in either overnight-fasting or parenteral-feeding states. The fed state was maintained by continuous intravenous feeding of a complete diet containing 838 kJ.kg-1.d-1, 2 g N.kg-1.d-1, and no fat. At each nutritional state, one-half of the animals received IGF-I infusion while the other half received saline as control. [14C-1]leucine and [3H-6]glucose were used to determine the effects of IGF-I on protein and glucose kinetics during fed and fasting states. The results showed that 1) infusion of IGF-I at this amount did not alter plasma glucose appearance and only marginally decreased plasma glucose concentrations in both nutritional states; 2) during fasting, IGF-I did not show anabolic effects on protein metabolism either at the whole-body level or in individual tissues. However, during feeding, IGF-I significantly stimulated exogenous nitrogen utilization by the whole body; and 3) IGF-I reduced the thermogenic effect of feeding. The results suggest that parenteral feeding may be an important variable in the response of protein anabolism to IGF-I in vivo.

Structured lipid made from fish oil and medium-chain triglycerides alters tumor and host metabolism in Yoshida-sarcoma-bearing rats.

The effects of structured lipid composed of fish oil and medium-chain triglycerides (Fish/MCT) on tumor and the host metabolism was compared with conventional long-chain triglycerides (LCTs) in Yoshida-sarcoma-bearing rats receiving TPN for 3 d. The two parenterally fed groups were divided into two treatments, saline or tumor necrosis factor (TNF), given intravenously at 20 micrograms/kg body wt. Changes in tumor volume, body weight, urinary nitrogen, whole-body and tissue protein kinetics, and fatty acid composition were measured. The study revealed that Fish/MCT feeding inhibited tumor growth, which could be attributed to decreased tumor protein synthesis. Body weight and nitrogen were better maintained by Fish/MCT feeding. In addition, the effects of Fish/MCT on tumor growth were synergistic with TNF treatment. The results demonstrate that dietary fat composition can influence fatty acid compositions of tumor tissue as well as tumor protein kinetics after a short period of TPN feeding.

Enteral nutrition with structured lipid: effect on protein metabolism in thermal injury.

The effect of total enteral nutrition with structured and conventional lipids on protein and energy metabolism was assessed in gastrostomy-fed burned rats (30% body surface area) by measuring nitrogen balance, serum albumin, energy expenditure, and rectus muscle and liver fractional synthetic rates of protein (FSRs). Male Sprague-Dawley rats weighing 200 +/- 10 g received isovolemic diets that provided 50 kcal/d, 2 g/d amino acids, and 40% nonprotein calories as lipid for 3 d. The lipid source was either long-chain triglycerides (LCTs), medium-chain triglycerides (MCTs), structured lipid (SL), or a physical mix (PM) of the oils used in SL. Burned rats enterally fed either SL (p less than 0.01) or PM (p less than 0.05) yielded significantly higher daily and cumulative nitrogen balances and rectus muscle and liver FSRs than those fed either LCTs or MCTs. Rats fed SL or MCTs maintained higher serum albumin concentrations than rats fed either PM or LCTs. This study shows that the enteral administration of a mixed fuel system containing SL or its PM improves protein anabolism and attenuates net protein catabolism after thermal injury.

DNA replication time accounts for tumor growth variation induced by dietary fat in a breast carcinoma model.

Female Fischer rats were pair-fed on diets containing either safflower oil (SO) or fish oil (FO) for 6 weeks. Implanted breast 13762 MAT tumors had a doubling times of 35.4 and 55.5 h in SO and FO rats, respectively (P < 0.001). Proliferation kinetics were measured in vivo by bromedeoxyuridine (BrdUrd) labeling and bivariate DNA/BrdUrd analysis by flow cytometry. After 1 h of pulsing, the labeling index was similar in both groups. However, 6 h later, tumor cells from FO rats had significantly lower relative movement of BrdUrd-labeled cells (0.78 vs. 0.91, P < 0.001). These results reflected a significantly longer S phase duration (15.0 vs. 9.1 h, P < 0.001) in FO rats and accounted for all the difference in tumor growth rates. This mechanism, which has not previously been reported, implies a significant role for fatty acids in DNA replication.

Cell-cycle kinetics of permanent glioma-cells measured by pulse labeling with bromodeoxyuridine.

Cell phase distribution and cycle kinetics of six human glioblastoma cell lines were characterized after labelling with 5-Bromo-2-deoxyuridine (BrdUrd). Cycle time (T(c)), DNA synthesis time (T(s)), and potential doubling time (T(pot)) were compared with the actual doubling time (T(d)) of the growing cell population. Mathematical estimates closely correlated with T(d). Low labelling index (LI) correlated with short T(s) and vice versa. T(s) and LI allowed grouping of the cell lines in two clusters. The mean number of silver stained nucleolar organizer regions (mAgNORs) and percentage of cells with more than five AgNORs (pAgNOR) were counted. AgNORs closely related to LI. Low mAgNORs and pAgNORs correlated with fast T(s) among the clustered cell lines.

Disparate effects of weight loss on insulin sensitivity and erythrocyte sodium-lithium countertransport activity.

Previous investigations have demonstrated an association between impaired insulin sensitivity and elevated erythrocyte sodium-lithium countertransport (Na(+)-Li+ CT) activity. It has been speculated that insulin resistance and endogenous hyperinsulinemia are causally related to the development of elevated Na(+)-Li+ CT activity. To test this hypothesis, we measured insulin sensitivity (euglycemic insulin clamp technique) and Na(+)-Li+ CT activity in eight obese women before (weight = 102 +/- 5 kg) and after (weight = 88 +/- 5 kg; P < .001) a 10 week weight reduction program. Maximal velocity of Na(+)-Li+ CT activity did not change (0.50 +/- 0.09 v 0.49 +/- 0.10 mmol/L red blood cells/h; P = NS) despite the significant improvement in insulin sensitivity (73 +/- 12 vs 110 +/- 7 mg/m2/min; P < .0025) and reduction in fasting insulin levels (17 +/- 2 v 10 +/- 2 microU/mL; P < .05) that accompanied weight loss. These results suggest that insulin resistance and hyperinsulinemia are not linked pathophysiologically to the development of elevated Na(+)-Li+ CT activity.

Effect of fish oil on glucose metabolism in the interleukin-1 alpha-treated rat.

Fish oil has been demonstrated to ameliorate many of the responses to infection. This study was conducted to determine whether fish oil feeding could modify the alterations of glucose metabolism induced by interleukin-1 alpha (IL-1 alpha) infusion in the rat. Male Sprague-Dawley rats were pair-fed for 5 weeks on two experimental diets in which the source of fat was either fish oil or soybean oil and provided 20% of calories; the diets were isonitrogenous and isocaloric. After 5 weeks of feeding, rats from both diet regimens were further divided into two subgroups to receive a 3-hour infusion of either 0.1% albumin in saline or 0.1% albumin in saline containing IL-1 alpha. A total of 20 micrograms/kg IL-1 alpha was administered, and half the dose of IL-1 alpha was given as a bolus and the remaining portion (10 micrograms/kg) was continuously infused into the jugular vein. During the last 2 hours of IL-1 alpha infusion, a primed constant infusion of D-(6-3H)glucose and D-(U-14C)glucose was combined to determine the effects of IL-1 alpha and diet on glucose kinetics. Plasma levels of glucose and insulin, energy expenditure, and respiratory quotient were also measured. IL-1 alpha significantly increased concentrations of plasma insulin and the percentage of glucose carbon recycling, confirming previous findings. Concentrations of glucose and insulin with IL-1 alpha treatment were significantly higher in soybean oil- fed animals compared with fish oil-fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of systemic infusions of endotoxin, tumor necrosis factor, and interleukin-1 on glucose metabolism in the rat: relationship to endogenous glucose production and peripheral tissue glucose uptake.

This study was performed to characterize and compare the actions of insulin on hepatic glucose production and peripheral glucose utilization during infusions of endotoxin, tumor necrosis factor (TNF), interleukin-1 (IL-1), and a combination of IL-1 and TNF in the rat. The euglycemic hyperinsulinemic clamp technique was combined with a primed-constant tracer infusion of high-performance liquid chromatography (HPLC)-purified 3H-3-glucose for estimation of whole-body glucose appearance and utilization rates; 14C-deoxyglucose (14C-DG) uptake was also measured in specific tissues following intravenous bolus administration. As expected, acute endotoxemia resulted in a significant reduction of glucose infusion during the clamp procedure (insulin concentration, 100 microU/mL), suggesting decreased insulin action. Similarly, infusion of TNF decreased the rate of glucose infusion necessary to maintain euglycemia. However, differences between endotoxin- and cytokine-treated rats were noted in whole-body glucose appearance (or disappearance) rates. Whereas endotoxin infusion predominantly decreased whole-body glucose uptake, suggesting diminished utilization in skeletal muscles, cytokine infusions were associated with a measurable hepatic glucose output despite hyperinsulinemia. In contrast, both cytokine and endotoxin administration decreased the rate of 14C-DG uptake by muscle tissue. These results demonstrate that TNF, IL-1, and endotoxin can induce a state of insulin resistance when infused continuously; the results also emphasize the complexity of regulation of glucose homeostasis during infection and sepsis.

Fish oil feeding improves muscle glucose uptake in tumor necrosis factor-treated rats.

This study was conducted to characterize the effects of fish oil and sunflower oil on hepatic glucose production and peripheral glucose utilization during infusion of saline or tumor necrosis factor (TNF), using the euglycemic-hyperinsulinemic clamp technique combined with a primed-constant tracer infusion of high-performance liquid chromatography-purified 3H-3-glucose for estimation of whole-body glucose appearance and utilization rates. Insulin 10 mU/kg.min was infused to reach a plasma insulin level of 200 microU/mL. 14C-1-deoxyglucose (14C-DG) uptake was also measured in specific tissues following intravenous bolus administration. The results showed that during a hyperinsulinemic-euglycemic clamp, infusion of TNF 20 micrograms/kg for 3 hours resulted in a significant reduction of glucose infusion and a significant increase of hepatic glucose production in both dietary groups as compared with saline infusion, indicating a state of insulin resistance induced by TNF. The results also showed that TNF infusion significantly decreased the rate of 14C-DG uptake in muscle in the sunflower oil group but not in the fish oil group, suggesting that fish oil is able to restore to normal the glucose utilization impaired by TNF. These observations suggest that in hyperinsulinemic and euglycemic conditions, prefeeding with fish oil significantly improves glucose uptake in muscle tissue, but does not alter the increase in hepatic glucose production during TNF infusion.

Insulin modulates circulating endothelin-1 levels in humans.

Recent data indicate that insulin stimulates synthesis of the vasoconstrictor peptide endothelin-1 (ET-1) by cultured vascular endothelial cells in vitro. To determine whether insulin modulates ET levels in vivo and whether this effect is important in the pathogenesis of obesity-associated hypertension, we measured circulating immunoreactive ET-1 levels during euglycemic hyperinsulinemic clamps (20 mU/m2.min-1 for 120 minutes) in eight obese women (body mass index, 36 +/- 1 kg/m2) before and after 10 weeks on an 800-kcal/d protein-sparing liquid diet. During the clamp that preceded weight loss, insulin levels were increased from 17 +/- 2 to 51 +/- 3 mU/L and this was associated with an increment in ET-1 level from 28 +/- 3 to 33 +/- 3 pg/mL (P < .05). After weight loss, insulin levels were increased from 10 +/- 2 to 47 +/- 3 mU/L during the clamp, and there was a corresponding increase in ET-1 levels from 24 +/- 3 to 30 +/- 3 pg/mL (P < .025). The reduction in basal ET-1 level (from 28 +/- 3 to 24 +/- 3 pg/mL) with weight loss correlated strongly with the reduction in fasting immunoreactive insulin level (from 17 +/- 2 to 10 +/- 2 mU/L; r = .92, P < .01). The decrease in blood pressure with weight loss (from 130 +/- 6/73 +/- 3 to 118 +/- 4/72 +/- 3 mm Hg) did not correlate with the corresponding reduction in circulating ET-1 levels. These results indicate that insulin modulates ET-1 levels in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative effects of omega-3 and omega-6 polyunsaturated fatty acids on protein metabolism in rats bearing the mammary adenocarcinoma.

The comparative effects of diets containing 20% (wt/wt) of either fish oil (FO) or safflower oil (SO) on protein synthesis and catabolism were determined in rats bearing the 7,12-dimethylbenz(a)anthracene (DMBA) 13762 mammary adenocarcinoma in vivo using a 6-hour constant infusion of L-(1-14C)-leucine. Tumor-bearing animals fed FO had significantly lower tumor growth rate (36 +/- 0.5 v 53 +/- 0.7%/d, P less than .05), total tumor protein synthesis (Ts) (1.25 +/- 0.1 v 1.85 +/- 0.1 mumol/h, P less than .05), and tumor protein concentration (12.0 +/- 0.5 v 14.0 +/- 0.7%/d, P less than 0.01). Tumor fractional synthetic rate and total protein breakdown rate of the tumor were unaffected by FO feeding. Both tumor-bearing and saline-control animals fed FO had significantly (P less than .01) lower liver fractional synthetic rate and total protein breakdown rate, and higher liver total protein compared with SO-fed rats. Muscle protein kinetics were unaffected by either treatment or diet. Whole body protein kinetics were not affected by dietary treatment, but the presence of tumor significantly (P less than .001) reduced whole body flux, synthesis, breakdown, and oxidation. Chronic FO feeding for 7 weeks significantly (P less than .001) lowered omega-6 polyunsaturated fatty acids (omega-6 PUFAs) and significantly elevated omega-3 polyunsaturated fatty acids (omega-3 PUFAs) (P less than .001) in both plasma phospholipid and triglycerides. The present study indicates that dietary FO can modulate mammary tumor growth in a manner that reflects changes in protein metabolism in both host and tumor tissues.