The effects of dietary flaxseed on the Fischer 344 rat. III. Protection against CCl(4)-induced liver injury

The hepatotoxic effect of carbon tetrachloride (CCl(4)) administered by gavage at 0.25 ml CCl(4) (1:1 in olive oil) per 100 g body weight was examined 24 h later in regular chow fed (RC) and 10% flax chow fed (FC) male and female Fischer 344 rats. CCl(4)-treated RC rats were subdued, lethargic and unkempt. CCl(4)-treated FC rats were much less affected. CCl(4) treatment resulted in loss of weight in RC and FC rats. In males, the weight loss was 6.7% body mass in RC rats compared to 5.6% body mass in FC rats. In females, the weight loss was 7.5% body mass in both RC and FC rats. While CCl(4) treatment increased the level of the liver injury marker plasma alanine aminotransferase (ALT) in RC rats, this CCl(4) effect was significantly attenuated in FC rats. In male rats, the ALT increase was 435-fold in RC rats and 119-fold in FC rats, over that of their respective controls. In female rats, the ALT increase was 454-fold in RC rats and 381-fold in FC rats, over that of their respective controls. These results provide evidence that flax consumption protects the liver against injury and that the extent of the protection is sex dependent. CCl(4) had no effect on the plasma level of gamma-glutamyltranspeptidase (gammaGT) in RC and FC rats supporting the contention that plasma gammaGT is not a useful marker for acute liver injury which is seen in this model. The activity of gammaGT was increased in the livers of FC rats compared to RC rats: 2.7-fold in males and 1.5-fold in females. In RC rats, the activity of liver gammaGT was decreased by CCl(4) treatment: 70% in the male and 25% in the female. However, this CCl(4) effect was reversed or abolished by flax consumption. Compared to RC rats: in male FC rats, CCl(4) actually increased the activity of liver gammaGT 1.28-fold; while in female FC rats, the depressing effect of CCl(4) treatment was abolished. The flax-induced preservation of gammaGT in the liver in response to injury may be involved in the observed hepatoprotection through generation of GSH. In RC male rats, CCl(4) treatment effected a 25% reduction in plasma glucose levels. There was no decrease in CCl(4)-treated FC male rats. In female rats, CCl(4) treatment effected a 21% decrease in plasma glucose levels in both RC and FC rats. In conclusion, multiple parameters for acute CCl(4)-induced injury were attenuated in the FC compared to the RC rat. That flaxseed consumption conferred greater protection against liver injury in the male than in the female suggests an involvement of the estrogenic lignan component of flaxseed. We discuss the possibility that this hepatoprotection is through a flax lignan-induced increase in reduced glutathione related to a flax effect on the activity of liver gammaGT in the resting state and the maintenance of its activity in response to injury.     

Interleukin 1 pretreatment reduces the insulin response to glucose in chronic sucrose-fed rats.

The present studies were undertaken to determine whether interleukin 1 beta ([IL-1] 1.0 micrograms/kg, ip) pretreatment for 3 days impairs the adaptive response to sucrose feeding in rats. One week after the last IL-1 injection, when no differences in plasma glucose and serum immunoreactive insulin (IRI) levels were observed, sucrose feeding was started. Sucrose feeding for 4 weeks did not affect basal glucose levels, whereas basal IRI levels were increased in sucrose-fed rats without IL-1 pretreatment. Eight weeks later, plasma glucose levels were increased before and at 15 min after intravenous bolus of 0.5 g/kg of glucose in sucrose-fed rats with IL-1 pretreatment. Only in IL-1-treated sucrose-fed rats were basal and glucose-stimulated IRI levels significantly reduced, compared with those levels in sucrose-fed vehicle-treated rats. IL-1 decreased pancreatic IRI contents at 1 and 9 weeks after the injection. These data suggest that pancreatic damage by IL-1 attenuated insulin response to glucose stimulation after long-term sucrose feeding.     

Diethylnitrosamine-induced increase in gamma-glutamyltranspeptidase in rat liver: its association with thyroid hormone deficiency and its reversal by tri-iodothyronine.

1. The nodular phase of hepatic premalignancy was induced in male Fischer 344 rats by the administration of diethylnitrosamine, 200 mg/kg i.p., followed by promotion utilizing the Solt-Farber promoting regime. 2. Relative to the situation in normal non-treated control rats: the activity of gamma-glutamyltranspeptidase was found to be increased 9.42-fold in homogenate and 7.33-fold in plasma membrane fractions prepared from the livers of saline-injected control rats; and 81.37-fold in homogenates and 91.92-fold in plasma membranes prepared from the livers of diethylnitrosamine-injected rats; plasma levels of total T3 and total T4 were found to be decreased 42.06 and 47.45% in saline-injected control rats and 88.7 and 83.2% in diethylnitrosamine-injected rats, respectively. 3. An early pre-nodular phase of hepatic premalignancy was produced in young immature and mature adult male Fischer 344 rats by the administration of diethylnitrosamine, 75 mg/kg, without subsequent application of the promotion regime. 4. Relative to the situation in control rats: the activity of gamma-glutamyltranspeptidase was found to be increased in liver homogenates prepared from diethylnitrosamine-treated rats, 1.62-fold in young immature rats 1.20-fold in mature adult rats; plasma levels of total T3 were found to be reduced in diethylnitrosamine-treated rats, 28% in young immature rats 9% in mature adult rats. 5. Treatment of diethylnitrosamine-injected young immature male Fischer 344 rats at the prenodular phase of hepatic premalignancy with tri-iodothyronine at 0.005 micrograms/kg s.c. daily for 7 days reversed the diethylnitrosamine-induced increase in liver homogenate gamma-glutamyltranspeptidase activity and the decrease in plasma total T3, restoring these parameters to normal levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of sucrose addition to drinking water,that induces hypertension in the rats,on liver microsomal Δ9 and Δ5-desaturase activities

This study was undertaken with the aim of investigating the effect of sucrose addition to the drinking water of rats who were fed with the same diet as a control group, on Δ9- and Δ5-desaturase activities and on the fatty acid composition of serum and liver microsomes. Weanling male Wistar rats had 30% sucrose in their drinking water for 20 weeks. An increase in total calories consumed, visceral fat accumulation, insulin, triglycerides and blood pressure and a decrease in the food intake were observed in the sucrose-fed group as compared with the control group. A decrease in linoleic and α-linolenic acid (essential fatty acids) in all serum lipid fractions of sucrose-fed rats was found. This observation correlated with a low food intake by sucrose-fed rats. The conversion of [1 ¹⁴C]-palmitic to [1 ¹⁴C]-palmitoleic acid by Δ9-desaturase activity was increased in sucrose-fed compared with control rats, while the conversion of [1 ¹⁴C]-dihomo-γ-linolenic acids by Δ5-desaturase activity was depressed. In sucrose-fed as compared to control rats, the proportion of palmitoleic and oleic fatty acids was increased. Arachidonic acid was decreased in sucrose-fed rats. The 1,6-diphenylhexatriene fluorescence polarization of the microsomal membranes was significantly lower in the sucrose-fed group compared to the control group. These results indicate that the sucrose addition to the drinking water of the rats increased microsomal Δ9-desaturase activity and membrane disorder and decreased the activity of the Δ5-desaturase, a key enzyme in the biosynthesis of arachidonic acid, implicated in hypertension.     

Regulation of glucose transport and transporter 4 (GLUT-4) in muscle and adipocytes of sucrose-fed rats: effects of N-3 poly- and monounsaturated fatty acids.

The goal of this study was to compare the short-term effects of dietary n-3 polyunsaturated (fish oil) and monounsaturated (olive oil) fatty acids on glucose transport, plasma glucose and lipid controls in a dietary insulin resistance model using sucrose-fed rats. The underlying cellular and molecular mechanisms were also determined in the muscle and adipose tissue. Male Sprague-Dawley rats (5 weeks old) were randomized for diets containing 57.5 % (w/w) sucrose and 14 % lipids as either fish oil (SF), olive oil (SO) or a mixture of standard oils (SC) for 3 weeks. A fourth control group (C) was fed a diet containing 57.5 % starch and 14 % standard oils. After three weeks on the diet, body weight was comparable in the four groups. The sucrose-fed rats were hyperglycemic and hyperinsulinemic in response to glucose load. The presence of fish oil in the sucrose diet prevented sucrose-induced hyperinsulinemia and hypertriglyceridemia, but had no effect on plasma glucose levels. Insulin-stimulated glucose transport in adipocytes increased after feeding with fish oil (p < 0.005). These modifications were associated with increased Glut-4 protein (p < 0.05) and mRNA levels in adipocytes. In the muscle, no effect was found on Glut-4 protein levels. Olive oil, however, could not bring about any improvement in plasma insulin, plasma lipids or Glut-4 protein levels. We therefore conclude that the presence of fish oil, in contrast to olive oil, prevents insulin resistance and hypertriglyceridemia in rats on a sucrose diet, and restores Glut-4 protein quantity in adipocytes but not in muscle at basal levels. Dietary regulation of Glut-4 proteins appears to be tissue specific and might depend on insulin stimulation and/or duration of dietary interventions.     

Metabolic syndrome in the rat: females are protected against the pro-oxidant effect of a high sucrose diet

Metabolic syndrome is more prevalent in men than in women. In an experimental dietary model of metabolic syndrome, the high-fructose-fed rat, oxidative stress has been observed in males. Given that estradiol has been documented to exert an antioxidant effect, we investigated whether female rats were better protected than males against the adverse effects of a high-sucrose diet, and we studied the influence of hormonal status in female rats. Males and females were first fed a sucrose-based or starch-based diet for 2 weeks. In the males, the plasma triglyceride (TG)-raising effect of sucrose was accompanied by significantly lowered plasma alpha-tocopherol and a significantly lowered alpha-tocopherol/TG ratio (30%), suggesting that vitamin E depletion may predispose lipoproteins to subsequent oxidative stress. In males, after exposure of heart tissue homogenate to iron-induced lipid peroxidation, thiobarbituric reactive substances were significantly higher in the sucrose-fed than in the starch-fed rats. In contrast, in sucrose-fed females, neither a decrease in vitamin E/TG ratio nor an increased susceptibility of heart tissue to peroxidation was observed, despite both a significantly decreased heart superoxide dismutase activity (14%) and a significant 3-fold increase in plasma nitric oxide concentration compared with starch-fed females. The influence of hormonal status in female rats was then assessed using intact, ovariectomized, or estradiol-supplemented ovariectomized female rats fed the sucrose or starch diet for 2 weeks. After exposure of heart tissue to iron-induced lipid peroxidation, higher susceptibility to peroxidation was found only in ovariectomized females fed the sucrose diet compared with the starch group and not in intact females or ovariectomized females supplemented with estradiol. Thus, estrogens, by their effects on antioxidant capacity, might explain the sexual difference in the pro-oxidant effect of sucrose diet resulting in metabolic syndrome in rats.     

The effects of dietary flaxseed on the Fischer 344 rat: II. Liver gamma-glutamyltranspeptidase activity

The effect of 10% flax chow consumption from the 30th to the 130th day after birth was examined in male Fischer 344 rats. The effects of both the high lignan/high oil Norlin strain and a high lignan/low oil Solin strain of flaxseed were compared. Physically and behaviourally there were no differences in rats belonging to the three dietary groups at any time. At 50 and 100 days of dietary exposure, blood glucose levels were the same in Norlin and Solin flax chow-fed and as well as regular chow-fed rats; there were no signs of toxicity in the Norlin and Solin flax-fed rats since their plasma levels of alanine aminotransferase were the same and equal to those of regular chow-fed rats. The activity of gamma-glutamyltranspeptidase (gammaGT) displayed an increase in the liver homogenates of flax chow-fed rats. This increase was the same in Norlin and Solin flax-fed rats at 50 and 100 days. Thus the liver effect was not oil, but lignan, likely secoisolariciresinol diglucoside (SDG), induced and was effected early on, and sustained, after flax exposure. The degree of heat activation of liver homogenate gammaGT was the same in regular chow-fed and flax chow-fed rats. Compared to liver homogenate gammaGT activity, the soluble form of gammaGT was expressed at very low levels while the plasma membrane-bound form of gammaGT was expressed at very high levels in rat liver in both regular chow-fed and flax chow-fed rats. There was no effect of flax feeding on the soluble form of liver gammaGT which was expressed at a very low level. Flax feeding effected an increase in the activity of gammaGT in isolated plasma membrane fractions which mirrored that in liver homogenates: the same degree of increase was seen in Norlin flax chow-fed and Solin flax chow-fed rats. Flax consumption effects an increase in the activity of liver gammaGT at the level of the plasma membrane which is lignan dependent, physiologically relevant and may be linked to hepatoprotection against injury through an increase in reduced glutathione.     

The effects of elk velvet antler consumption on the rat: development, behavior, toxicity and the activity of liver gamma-glutamyltranspeptidase

The effect of exposure to, followed by consumption of, a diet containing 10% powdered elk velvet antler (EVA) from the 18th day of gestation to the 88th day after birth was examined in male and female Fischer 344 rats. There were no teratogenic effects of EVA exposure in utero or differences in birth outcomes between pups born to regular chow fed and EVA chow fed dams. Growth curves of the EVA fed rats were identical to those of regular chow fed rats, as were developmental milestones of pinna development and eye-opening. Acoustical startle and righting reflexes, developmental and behavioral indices, were identical. Blood glucose levels were comparable in EVA chow fed and regular chow fed rats, indicating that EVA is without effect on glucose balance. There were no signs of toxicity in the EVA chow fed compared to regular chow fed rats as judged from plasma enzyme markers of liver damage: plasma levels of alanine aminotransferase were 50% lower in EVA chow fed rats compared to regular chow fed rats; and plasma levels of gamma-glutamyltranspeptidase (gammaGT) were the same. The activity of gammaGT displayed a decrease in the livers of EVA chow fed rats, more so in the male (22%) than in the female (14%), suggestive of an androgenic effect. A possible hepatobeneficial effect of the EVA induced decrease in liver gammaGT is discussed. In summary, dietary10% EVA chow is without long term effect on growth, development and behavior is non-toxic and may be hepatobeneficial.     

Differential inhibitory effects of carbon tetrachloride on the hepatic plasma membrane, mitochondrial and endoplasmic reticular calcium transport systems: implications to hepatotoxicity

Mitochondrial, endoplasmic reticular and plasma membrane fractions were isolated by a new method from control male Fischer 344 rats and rats given CCl4 by gavage. After 1 h of CCl4 treatment, rats were in glucose and pancreatic hormone balance but plasma levels of T3 and T4 were decreased 29 and 22%, respectively. After 24 hours of CCl4 treatment, rats were: hypoglycaemic and insulin and glucagon levels were increased 33- and 35-fold, respectively; total T4 levels were decreased 62%; while total T3 levels were normalized. In liver fractions from CCl4-treated rats, 1 h after CCl4 administration: (i) calcium binding was decreased 65% in the mitochondrial fraction, 66% in the endoplasmic reticular fraction and 46% in the plasma membrane fraction; (ii) calcium uptake was decreased 59% in the mitochondrial fraction, 46% in the endoplasmic reticular fraction and 37% in the plasma membrane fraction. After 24 h of CCl4 administration: (i) calcium binding was decreased 57% in the mitochondrial fraction, 50% in the endoplasmic reticular fraction and 71% in the plasma membrane fraction; (ii). calcium uptake was decreased 55% in the mitochondrial fraction, 17% in the endoplasmic reticular fraction and 53% in the plasma membrane fraction. In vitro studies indicated the plasma membrane calcium transport system to be rapidly (within a minute) and strongly (>90%) inhibited by CCl4. We conclude that CCl4 produces a differential inhibitory effect on the hepatocyte calcium pumps that are implicated with hepatocellular damage.     

The effect of high-amylose cornstarch on lipid metabolism in OVX rats is affected by fructose feeding

We examined whether the effects of high-amylose cornstarch (HACS) on lipid metabolism in ovariectomized (OVX) rats were affected by high-fructose feeding. Sucrose (482 g/kg diet) was used as fructose source. OVX rats were fed one of the following four diets for 21 days: a sucrose-based or cornstarch-based cholesterol-free diet with or without HACS (150 g/kg diet). Body weight and food intake were increased by sucrose. Plasma total cholesterol and low-density lipoprotein cholesterol concentrations were increased by sucrose and decreased by HACS in cornstarch-fed rats, but not in sucrose-fed rats. Liver total lipids and concentrations of plasma and liver triacylglycerol (TAG) were increased by sucrose, whereas plasma TAG concentration was decreased by HACS, in sucrose-fed rats. However, liver cholesterol concentration was not affected by diet. The amount of cholesterol in small-intestinal contents was increased in sucrose-fed rats, but not in cornstarch-fed rats, but that of bile acids was not affected by diet. Fecal excretions of bile acids and neutral sterols were increased by HACS. The level of sterol-regulatory element-binding protein-1c mRNA was increased by sucrose and decreased by HACS in sucrose-fed rats, but not in cornstarch-fed rats. The level of farnesoid X receptor mRNA was decreased by sucrose and increased by HACS in cornstarch-fed rats, but not in sucrose-fed rats, as was the level of cholesterol 7α-hydroxylase mRNA. These results show that the effect of HACS on hyperlipidemia induced by ovarian hormone deficiency would be affected by the consumption of fructose-rich sweeteners such as sucrose and high-fructose syrup.     

Effects of high sucrose diet on insulin-like effects of vanadate in diabetic rats

The insulin-like effects of vanadate were compared in streptozotocin-induced diabetic rats fed on high starch control and high sucrose diets for a period of six weeks. Diabetic rats in both diet groups were characterized by hypoinsulinemia, hyperglycemia (6.8–7.0 fold increase) and significant decreases (p<0.001) in the activities of glycogen synthase, phosphorylase and lipogenic enzymes, ATP-citrate lyase, glucose 6-phosphate dehydrogenase and malic enzyme in liver. There were no diet-dependent differences in these abnormalities. However, the insulin-mimetic agent vanadate was more effective in diabetic rats fed sucrose diet as compared to animals fed control starch diet. Vanadate administration resulted in 30% and 64% decreases in plasma glucose levels in diabetic rats fed control and sucrose diets, respectively. The activities of glycogen synthase (active) and phosphorylase (active and total) were restored significantly by vanadate in control (p<0.05–0.01) and sucrose (p<0.001) diets fed diabetic rats. This insulin-mimetic agent increased the activities of hepatic lipogenic enzymes in control diet fed rats to 38–47% of normal levels whereas in sucrose fed group it completely restored the activities. Sucrose diet caused a distinct effect on the plasma levels of triacylglycerol (4-fold increase) and apolipoprotein B (2.8-fold increase) in diabetic rats and vanadate supplementation decreased their levels by 65–75%. These data indicate that vanadate exerts insulin-like effects in diabetic rats more effectively in sucrose fed group than the animals fed control diet. In addition, vanadate also prevents sucrose-induced hypertriglyceridemia.     

Modulation of gamma-glutamyltranspeptidase activity in rat liver plasma membranes by thyroid hormone

1. In adult male and female rats, liver plasma membrane gamma-glutamyltranspeptidase activities were 16-fold higher in the propylthiouracil (PTU)-induced hypothyroid state than in the control euthyroid state; thyroxine (T4)-replacement resulted in an 80% restoration to control levels. 2. Liver plasma membrane gamma-glutamyltranspeptidase activities were 6.7-fold higher in PTU-induced congenitally hypothyroid rats than in control euthyroid rats; T4-replacement reduced enzyme activities to 37% of control levels. 3. In adult rats, in response to the development and recovery from tri-iodothyronine (T3) excess, liver plasma membrane gamma-glutamyltranspeptidase activities were inversely related to, and out of phase by 12 hr, to the earlier changes in T3. 4. Liver gamma-glutamyltranspeptidase is a thyroid hormone-dependent enzyme.     

Running exercise increases tumor necrosis factor-alpha secreting from mesenteric fat in insulin-resistant rats.

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obese subjects, through its overexpression in fat tissue. However, how exercise can modify the expression of TNF-alpha is controversial. We examined TNF-alpha in adipose tissue using an animal model of insulin resistance that was produced by feeding rats a diet high in sucrose. The rats were allocated to one of three groups: those receiving a starch-based diet (control group): those fed a high-sucrose diet (sucrose-fed group): and those fed a high-sucrose diet and given wheel exercise (exercised group). The animals were allowed to eat and drink ad lib for 4 or 12 weeks (4 wk: control n=7, sucrose-fed n=7, exercised n=10; 12 wk: control n=5, sucrose-fed n=5, exercised n=9). The voluntary wheel exercise was initiated with the feeding of the high-sucrose diet. The rats in the exercise groups ran 15 +/- 3 km/week. We showed that 12-week voluntary running exercise significantly (P<0.05) increased both TNF-alpha protein (5-fold) and mRNA (1.4 fold) in the mesenteric fat of insulin-resistant rats compared to non-exercised sucrose-fed mice. Accordingly, in exercised group, plasma glucose (124 +/- 9 mEq/L vs 141 +/- 11 mEq/L). and free fatty acid (0.98 +/- 0.07 mEq/L vs 1.4 +/- 0.05 mEq/L) concentrating in portal vein blood were reduced compared to sucrose-fed group. The amounts of fatty tissue both in mesenteric and subcutaneous tissues were significantly (P<0.05) decreased through running exercise. We consider that up-regulation of TNF-alpha in mesenteric fat may be a compensatory mechanism for the reduction of fatty acid in adipose tissues and this change could control metabolic homeostasis during exercise to modulate a hyperinsulinemic state.     

Failure of chronic hyperinsulinemia to suppress pancreatic glucagon in vivo in the rat.

To determine the effects of chronic hyperinsulinemia on glucagon release, rats were made hyperinsulinemic for 14 days by supplementation of drinking water with sucrose (10%; sucrose-fed) to increase endogenous release or by implantation of osmotic minipumps (subcutaneous, s.c.; or intraperitoneal, i.p.) to deliver exogenous insulin (6 U/day). Both s.c. and i.p. rats also had sucrose in the drinking water to prevent hypoglycemia. Plasma insulin levels were significantly elevated in sucrose-fed, s.c., and i.p. rats. However, glucose levels were significantly elevated in sucrose-fed rats only. Surprisingly, plasma glucagon concentrations were elevated in i.p. and s.c. rats and were not suppressed in sucrose-fed rats. Inverse relationships were found between the plasma levels of insulin and glucose (n = 65; r = -0.42, p less than 0.0001) and between glucose and glucagon (n = 73; r = -0.46, p less than 0.0001). However, unexpectedly, a positive correlation between insulin and glucagon (n = 65; r = 0.47, p less than 0.0001) was established. As suppression of plasma glucagon levels below basal was not observed in any of the hyperinsulinemic or hyperglycemic rats, we wished to establish further whether pancreatic glucagon release could be suppressed below basal levels in the rat by another means. Thus, high doses of somatostatin (50-100 micrograms.kg-1.min-1) were infused for 45 min into normal rats without or with a concomitant hyperinsulinemic, hyperglycemic glucose clamp. Somatostatin fully suppressed insulin, but although plasma glucagon levels were decreased by somatostatin infusion relative to saline-infused animals, there was still no suppression below basal levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Running Exercise Improves Metabolic Abnormalities and Fat Accumulation in Sucrose-Induced Insulin-Resistant Rats

NARA, MAKOTO, MASAKI TAKAHASHI, TSUGIYASU KANDA, YOUNOSUKE SHIMOMURA, ISAO KOBAYASHI. Running exercise improves metabolic abnormalities and fat accumulation in sucrose-induced insulin-resistant rats. Insulin resistance and hyperinsulinemia are observed in rats fed a high sucrose diet. Insulin resistance is thought to be related to abnormal fat distribution. We previously reported the metabolic characteristics and the fat distribution in rats with sucrose-induced insulin resistance. This study was designed to examine the effects of exercise in these rats. The rats were divided into three groups: those receiving a starch-based diet (control), those receiving a high-sucrose diet (sucrose fed), and those receiving a high-sucrose diet and wheel-running exercise (exercised). Animals were killed after 4 weeks or 12 weeks. After 4 weeks, the three groups did not differ with respect to gain in adipose tissues. The portal vein (PV) insulin concentration was significantly increased in the sucrose-fed and the exercised rats compared with the control rats. The inferior vena cava (IVC) glucose concentration and the PV free fatty acid (FFA) were significantly lower in the exercised rats than in the sucrose-fed rats. After 12 weeks, the exercised rats had significantly lower mesenteric fat (MS) and subcutaneous fat (SC) and a lower MS:SC ratio than the sucrose-fed rats. The glucose levels in IVC, PV, and FFA in PV were significantly reduced in the exercised rats as compared with the sucrose-fed rats. These findings suggest that long-term exercise improves insulin resistance by reducing the accumulation of MS as well as SC. It is also suggested that short-term exercise improves glucose metabolism without change of fat accumulation.     

Diurnal variations of plasma lipoproteins and liver lipids in rats fed starch sucrose or fat

The incidence of the dietary source of energy on lipid transport and accumulation was investigated over a full nycthemeral cycle in adapted rats fed ad libitum. Starch, sucrose and lard were compared. Lipoprotein composition of the plasma, liver and plasma lipids and insulinemia were analyzed every 3 hours over 24 hours. The pattern of VLDL concentration was dependent on the nature of the energetic substrate. Feeding starch resulted in a remarkable stability of lipoproteins, liver and plasma lipids, despite clearcut diurnal variations in plasma non esterified fatty acids, insulinemia and liver glycogen. In sucrose-fed rats VLDL rose to a sharp maximum in the post prandial period (9-12:00) and were totally cleared by 18:00. In fat-fed rats, HDL were elevated during the night, suggesting a possible stimulation of their synthesis by dietary fat in the intestine. LDL were constantly elevated with peak values at 21:00 while VLDL were very low, even at night, despite elevated levels of non-esterified fatty acids. It is concluded that, in animals adapted to a high fat-diet, a high level of circulating non esterified fatty acids is not sufficient to promote the synthesis of VLDL. The main regulating factor appears to be the intensity of hepatic lipogenesis which is stimulated by sucrose and inhibited by lard. No correlation was found between variations in plasma VLDL and insulinemia.     

Protective effect of ascorbic acid against lipid peroxidation and oxidative damage in cardiac microsomes

Effects of feeding sucrose rich diet supplemented with and without the insulinmimetic agent vanadate for a period of six weeks were studied in rats. Sucrose diet caused hypertriglyceridemia (140% increase), hyperinsulinemia (120% increase) and significant elevations in the levels of glucose (p<0.001) and cholesterol (p<0.05) in plasma as compared to control starch fed rats. Activities of hepatic lipogenic enzymes, ATP-citrate lyase, glucose 6-phosphate dehydrogenase and malic enzyme increased by 100–150% as a result of sucrose feeding. However, glycogen content and the activities of glycogen synthase and phosphorylase in liver remained unaltered in these animals. The plasma levels of triacylglycerols and insulin in the rats fed on vanadate supplemented sucrose diet were 65% and 85% less, respectively as compared to rats on sucrose diet without vanadate. The concentrations of glucose and cholesterol in plasma and the activities of lipogenic enzymes in liver did not show any elevation in sucrose fed rats when supplemented with vanadate. These data indicate that the sucrose diet-induced metabolic aberrations can be prevented by the insulin-mimetic agent, vanadate.     

The effects of dietary flaxseed on the Fischer 344 rat: I. Development, behaviour, toxicity and the activity of liver gamma-glutamyltranspeptidase

The effect of exposure to, followed by consumption of, 10% flax chow from the 18th day of gestation to the 86th day after birth was examined in male and female Fischer 344 rats. Growth curves of the flax chow-fed rats were identical to those of regular chow-fed rats, as were such developmental milestones as pinna development, growth of hair and eye opening. Acoustical startle and the righting reflexes, developmental behavioural indices, were also the same. Blood glucose levels were comparable in flax chow-fed and regular chow-fed rats at all stages of development, indicating that flax is without effect on glucose balance. There were no signs of toxicity in the flax chow-fed rats since their plasma levels of alanine aminotransferase and gamma-glutamyltranspeptidase (gammaGT) were the same as those of regular chow-fed rats. The activity of gammaGT displayed an increase in the livers of flax chow-fed rats after puberty, more so in the male-four-fold-than in the female-1.38-fold. This is suggestive of an estrogenic effect which implicates an effect of an estrogenic flax lignan. An hepatobeneficial effect of the flax-induced increase in liver gammaGT is discussed. In summary, dietary 10% flax chow is without long-term effect on growth, development and behaviour, is non-toxic and may be hepatoprotective.     

Role of fatty acid composition in the development of metabolic disorders in sucrose-induced obese rats

Fatty acids have been shown to be involved in the development of insulin resistance associated with obesity. We used sucrose loading in rats to analyze changes in fatty acid composition in the progression of obesity and the related metabolic disorder. Although rats fed a sucrose diet for 4 weeks had body weights similar to those of control animals, their visceral fat pads were significantly larger, and serum triglyceride levels were higher; however, neither plasma glucose nor insulin levels were significantly higher. After 20 weeks of sucrose loading, body weight and visceral and subcutaneous fat pads had increased significantly compared with those in control rats. Moreover, plasma glucose, insulin, and triglyceride levels were significantly higher. An analysis of individual fatty acid components in the blood and peripheral tissues demonstrated phase- and tissue-dependent changes. After 20 weeks of sucrose loading, palmitoleic acid (16:1 n-7) and oleic acid (18:1 n-9), the major components of monounsaturated fatty acid, showed a ubiquitous increase in plasma and all tissues analyzed. In contrast, linoleic acid (18:2 n-6) and arachidonic acid (20:4 n-6), the major components of polyunsaturated fatty acid in the n-6 family, decreased in plasma and all tissues analyzed. After 4 weeks of sucrose loading, these changes in fatty acid composition were observed only in the liver and plasma and not in fat and muscle. This led us to conclude that elevation of plasma glucose and insulin develop at the late phase of sucrose-induced obesity, when changes in fatty acid composition appear in fat and muscle. Furthermore, changes in fatty acid composition in liver seen after 4 weeks of sucrose loading, when increases in neither plasma glucose nor insulin were detected, suggest that liver may be the initial site of fatty acid imbalance and that aberrations in hepatic fatty acid composition may lead to fatty acid imbalances in other tissues.     

Fatty acid metabolism and lipid secretion by perfused livers from rats fed laboratory stock and sucrose-rich diets

To assess the possible role of altered hepatic processing of free fatty acids in dietary sucrose-induced accumulation of triglyceride in the liver and blood plasma, livers from rats fed commercial laboratory stock and high sucrose diets were perfused both with and without oleic acid substrate. Consumption of the sucrose diet exerted a multiplicity of effects on oleic acid metabolism, characterized by decreased conversion to both ketone bodies and carbon dioxide, increased esterification into liver triglyceride, and increased secretion in triglyceride-rich lipoproteins. During the infusion of oleic acid, livers from sucrose-fed rats also exhibited decreased ketogenesis, and increased secretion of triglyceride from endogenous sources. Since oleic acid uptake from the perfusion medium was identical in both groups, the observed effects of sucrose feeding are ascribed to altered rates of intracellular metabolic processes. Mass and radiochemical analyses of perfusate ketone bodies and triglycerides were indicative of greater mobilization of triglycerides from hepatocellular lipid droplets in the livers from sucrose-fed rats. These livers contained more triglyceride and secreted more triglyceride even in the absence of infused oleic acid. In summary, the sucrose-rich diet increased the esterification:oxidation ratio of intracellular free fatty acids derived from both the circulation and endogenous sources within the hepatocyte. In response, secretion of triglyceride-rich lipoproteins by the liver and deposition of triglyceride within the liver were promoted. It is concluded that alterations in the processing of free fatty acids by the liver contribute significantly to the liver and plasma triglyceride accumulation following sucrose consumption.