Increased hepatic activity of inducible nitric oxide synthase in rats fed on a high-fat diet

The effects were examined of the dietary level of fat on the activity of inducible nitric oxide synthase (iNOS) in the liver of rats. In experiment 1, rats were fed on a diet containing 5% or 20% beef tallow or safflower oil for 32 d. The animals were given a subcutaneous injection of the carcinogen, 1,2-dimethylhydrazine (DMH), on d 4. The activity of hepatic iNOS was significantly elevated by the high-fat diet, but was unaffected by the dietary source of the fat examined. In experiment 2, rats were fed on a 5% or 20% beef tallow diet for 11 d or 32 d with or without the DMH treatment. Feeding the high-fat diet and DMH treatment caused higher activity of hepatic iNOS. In experiment 3, the high-fat diet elevated hepatic iNOS activity and the amount of its protein in the lipopolysaccharide-treated rats. The results suggest that hepatic NO production is enhanced by a high-fat diet.     

Long-term consumption of a diet with moderate medium chain triglyceride content does not inhibit the activity of enzymes involved in hepatic lipogenesis in the rat

The activities of glucose 6-phosphate dehydrogenase (EC 1.1.1.49), malic enzyme (EC 1.1.1.40), ATP-citrate lyase (EC 4.1.3.8), acetyl-CoA carboxylase (EC 6.4.1.2) and fatty acid synthetase were lower (-25 to -60%) in liver of rats fed during 45 days with a moderate long-chain triglycerides (LCT) content diet (32% of metabolizable energy, ME), than in control rats fed with a low fat diet (LCT, 10% of ME). However, the fall in malic enzyme activity was not significant. In contrast, these activities were higher (+40 to +160%) in rats fed with a diet with a moderate medium-chain triglycerides (MCT) content (32% of ME), than in control rats. Nevertheless, the increase in activity of malic enzyme and ATP-citrate lyase was more important. Contrary to LCTs, MCTs had no inhibitory effect on the activity of enzymes involved in hepatic lipogenesis.     

Comparative studies on lipogenic enzyme activities in brown adipose tissue and liver of the rat during starvation-refeeding transition and cold exposure

1. The effect of starvation-refeeding transition and cold exposure on the activity of lipogenic enzymes in brown adipose tissue (BAT) and liver from rats was compared. 2. Starvation caused a decrease of lipogenic enzyme activities in BAT and liver. 3. Refeeding of the animals with a high carbohydrate diet caused an increase of lipogenic enzymes in these tissues. 4. Cold exposure (4 degrees C for 30 days) led to the increase of BAT enzyme activities to the values observed in rats fed a high carbohydrate diet. 5. Under the same conditions the activity of hepatic lipogenic enzymes also increased but never reached the values observed in the liver of rats fed with a high carbohydrate diet. 6. Therefore BAT and liver lipogenic enzymes showed, in general, a similar pattern of variation under identical nutritional conditions, but substantial differences between these two organs occurred as far as the response to cold exposure was concerned. 7. The experiments also revealed that in the control animals BAT displayed a higher lipogenic potential than the liver.     

Role of Glucose-6-phosphatase in Hepatic and Renal Gluconeogenesis

Comparison of the effects of a high fat and high protein diet on the capacity for glucose formation from pyruvate and glycerol was investigated in vivo and in vitro. Ratios of radioactivity incorporated from either pyruvate-3-¹⁴C or glycerol-l-¹⁴C into blood glucose to those into expired CO₂ were higher in both groups fed the high fat and the high protein diet than those in a group fed a high carbohydrate diet. Gluconeogenesis from pyruvate and glycerol by liver slices were both increased significantly in rats fed the high fat diet, while feeding the high protein diet caused increase of renal gluconeogenesis from pyruvate and glycerol. The activities of hepatic and renal glucose-6-phosphatase(s) were changed in a similar fashion to changes in hepatic and renal gluconeogenesis, respectively.

In addition, the response of the activity of hepatic glucose-6-phosphatase with high dietary fat was more rapid than that of the activity of renal glucose-6-phosphatase with high dietary protein. Furthermore, the intraperitoneal injection of actinomycin-D to rats resulted in decrease of the activities of renal glucose-6-phosphatase of both groups fed the high fat and the high protein diet, but no significant change of the activity of hepatic glucose-6-phosphatase was observed among dietary groups.

These findings suggested that the increases in the overall flow of metabolites towards glucose formation by feeding the high fat and the high protein diet might be based on the action of different mechanisms which regulate the activities of glucose-6-phosphatase(s) of the liver and kidney.     

Effect of dietary fat on whole body fatty acid synthesis in weanling rats

The effect of dietary fat on body composition, whole body lipogenesis, and enzyme activity was measured in rats over the first 16 weeks post-weaning. Rats were fed either a low fat (5% w/w fat) or high fat (20% w/w fat) diet for the first 4 weeks. After this time all rats were fed the low fat diet. The results showed no significant effect of diet on the rate of fat synthesis over the first 8 weeks of the experiment. However, the activities of the enzymes of fatty acid synthesis [glucose 6-phosphate dehydrogenase, malic enzyme, adenosine triphosphate-citrate lyase, acetyl-coenzyme A carboxylase (ACCX), fatty acid synthetase] were dependent on the age and dietary status of the animals. The exact pattern depended on the specific enzyme and the tissue source. No significant differences in pyruvate dehydrogenase (PDH) activity were observed. Mathematical analysis of the enzyme activities suggested that ACCX and PDH were the most likely sites of fat synthesis regulation. In addition, an examination of body composition and overall weight retention showed that the "weight increasing" effect of a high fat diet could be completely reversed by subsequent feeding of a low fat diet. However, the reversal required an additional 12 weeks. Interestingly, at this time the rats switched from a high fat to a low fat diet had a lower body weight and lower body fat content than rats fed a low fat diet throughout the course of the experiment.     

Purification and Characterization of the Main Isozyme of Polyphenol Oxidase in Mung Bean (Vigna mungo) Seedlings

The induction of NADPH-generating enzymes by polychlorinated biphenyls (PCB) in rats was investigated. The administration of PCB to rats for 3 and 14 days increased the activities of malic enzyme (ME, EC 1.1.1.40), glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49), and 6-phosphogluconate dehydrogenase (6PGD, EC 1.1.1.44) about 2-fold above the control level in the liver. Hepatic mRNA levels of ME, G6PD, and 6PGD, except for G6PD mRNA of the 14-day group, were also elevated to the same degree as the enzyme activities in PCB-treated rats. In rats fed a PCB-containing diet for 1 day, the hepatic mRNA levels of ME and G6PD were elevated prior to the induction of enzyme activity. In the kidney, lung, spleen, heart, and testis, the mRNA levels of ME, G6PD, and 6PGD were not affected by PCB. The induction of hepatic NADPH-generating enzymes would imply an increased demand of NADPH in the liver of rats fed with a PCB-containing diet.     

Weaning and metabolic regulation in the rat

Premature weaning of rats to high carbohydrate diets causes a variety of short- and long-term changes in lipid metabolism, but the mechanisms involved are unclear. It is likely that interaction of diet with certain emerging hormonal control patterns during weaning might condition metabolic control and (or) subsequent adaptations in the adult organism. This implies that the adaptive responses of infant animals to diet may differ from those of the mature organism. For example, premature weaning leads to early appearance of rat liver malic enzyme (ME), even when fat supplies as much as 65% of the dietary energy; the same diet suppresses ME activity in 45-day-old rats. The levels of plasma glucagon and thyroid hormones are elevated during the weaning period. Several studies have shown that triiodothyronine evokes hepatic ME in suckling rats. Conversely, glucagon infusion into prematurely weaned rats suppresses the early appearance of the enzyme. Premature weaning, regardless of fat intake, leads to a rapid decline in plasma glucagon levels. Since glucagon is known to antagonize the actions of triiodothyronine on liver ME, the interaction of diet with glucagon and thyroid hormones is conceivably part of the mechanism responsible for the early appearance of hepatic malic enzyme, whereby the decline of plasma glucagon permits triiodothyronine to act on liver ME. Insulin probably exerts a permissive action subsequently. The manner in which these events relate to the long-term consequences of premature weaning is unknown.     

Influence of capsaicin,curcumin and ferulic acid in rats fed high fat diets

Three compounds capsaicin, curcumin and ferulic acid showing hypolipidemic activity have been tested in adult Wistar rats fed high fat diets. Capsaicin (0.20 mg%) fed to female rats along with a 30% saturated fat diet lowered the rate of weight gain, liver and serum triglycerides. In male rats it lowered only the liver and serum total and very low density and low density lipoprotein triglycerides whether fed continuously for 13 or 8 weeks after interchanging the control and test diets from the 5th week onwards. Capsaicin fed to female rats in 30% mixed fat diet increased the rate of weight gain, lowered liver and serum triglycerides, lowered adipose tissue lipoprotein lipase, elevated the hormone sensitive lipase and serum free fatty acids. Capsaicin in 30% saturated fat diet lowered both the enzyme activities to a much lesser extent. Curcumin and ferulic acid (both at 25 mg%) in 30% saturated fat diet tended to lower the rate of weight gain, liver total lipids and serum triglycerides. It is of significance that a common dietary compound ‘capsaicin’ in the range of human intake triggers lipid lowering action in rats fed high fat diets. This paper was presented at the 55th Annual Meeting of the Society of Biological Chemists (India) held at Trivandrum during December 15–17th, 1986.     

Plasma arginine and ornithine levels and selected enzyme activities in uremic rats fed various amounts of arginine

Rats weighing 100 g were made chronically uremic by partial left renal artery ligation and contralateral nephrectomy. Rats with urea clearances below 0.30 ml/min and sham-operated controls were pair-fed arginine-free diets, diets containing normal amounts of arginine or diets with high levels of arginine. After 4 to 8 weeks, rats were killed and plasma levels of arginine, ornithine and lysine were measured. In addition, activities of various urea cycle enzymes in liver and kidney and renal transamidinase were determined. Plasma amino acid levels and enzyme activities of the urea cycle remained constant in control rats fed diets differing in arginine content. However, renal transamidinase activity was elevated in control rats fed arginine-free diets. In plasma of uremic as compared with control rats, arginine levels varied with the arginine intake, and lysine levels were elevated when arginine supplements were fed. With all diets, plasma ornithine remained constant in uremic rats at slightly but not significantly increased levels. Hepatic carbamoyl phosphate synthetase activity and renal arginine synthetase activity were reduced in uremic as compared to control rats. Renal transamidinase activity, expressed per g of kidney, was elevated in uremic rats with all diets except arginine-free. When amino acid diets were fed, hepatic arginase activity was higher in uremic rats and this increase was enhanced by arginine-free diets. Other enzyme activities in uremic rats were not affected by the amount of arginine in the diet.     

Elevated body fat in rats by the dietary nitric oxide synthase inhibitor, L-N omega nitroarginine.

The influence of the dietary nitric oxide (NO) synthase inhibitor, L-N omega nitroarginine (L-NNA) on body fat was examined in rats. In experiment 1, all rats were fed with the same amount of diet with or without 0.02% L-NNA for 8 wk. L-NNA intake caused elevations in serum triglyceride and body fat, and reduction in serum nitrate (a metabolite of nitric oxide). The activity of hepatic carnitine palmitoyltransferase was reduced by L-NNA. In experiment 2, rats were fed for 8 wk with the same amount of diets with or without 0.02% L-NNA supplemented or not with 4% L-arginine. The elevation in body fat, and the reductions in serum nitrate and in the activity of hepatic carnitine palmitoyltransferase by L-NNA were all suppressed by supplemental L-arginine. The results suggest that lower NO generation elevated not only serum triglyceride, but also body fat by reduced fatty acid oxidation.     

Hepatic and adipose tissue lipogenic enzyme mRNA levels are suppressed by high fat diets in the rat

Small changes in lipogenic enzyme activity induced by dietary fats of different composition may, over the long term, have significant impact on the development of obesity. We have investigated the effect of high fat diets (45% of calories as fat) on abundance of mRNA encoding fatty acid synthetase (FAS) and glycerophosphate dehydrogenase (GPDH) in male Sprague-Dawley rats. When caloric intake was equal, the relative amount of hepatic FAS mRNA was greater in rats fed a saturated compared to a polyunsaturated fat diet. This difference could not be attributed to diet-induced changes in plasma insulin concentration. However, both fat diets suppressed hepatic FAS mRNA compared to a sucrose diet. Close correlation between FAS specific activity and the relative amount of mRNA suggested that regulation was mainly at a pre-translational level. Adipose tissue FAS mRNA was suppressed by the two fat diets equally while GPDH mRNA was unaffected by dietary composition. Retroperitoneal fat pads were significantly larger in rats fed saturated compared to those fed polyunsaturated fat for 26 weeks. We concluded that dietary saturated fats fail to suppress hepatic de novo lipogenesis as effectively as polyunsaturated fats, which may have implications for the prevention of obesity in humans.     

The effect of TCDD on acyl CoA:retinol acyltransferase activity and vitamin A accumulation in the kidney of male Sprague-Dawley rats

Previous studies have shown that rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) show signs of toxicity that are similar to the responses of animals to a vitamin A-deficient diet. These include hypophagia, loss of body weight, loss of hepatic vitamin A, and accumulation of renal retinoids. Male Sprague-Dawley rats treated with 10, 30, or 100 nmol/kg of TCDD accumulated renal vitamin A, with retinyl palmitate concentrations reaching 8 times those of control animals, similar to that of male rats fed a vitamin A-free diet for 26 days. Acyl CoA:retinol acyltransferase (ACARAT) activities in both TCDD-treated rats and rats fed a vitamin A-free diet for 26 days were similarly elevated, and were strongly and positively correlated with the renal retinyl palmitate concentrations. Retinol concentrations in the kidneys of rats treated with TCDD or fed a vitamin A-free diet were only slightly elevated when compared to control rats. We suggest that accumulation of retinyl esters in the kidneys of rats treated with TCDD or fed a vitamin A-free diet occurs as a result of increased rates of retinol esterification.     

Effect of methotrexate on long-chain fatty acid metabolism in liver of rats fed a standard or a defined, choline-deficient diet

The effect of methotrexate on lipids in serum and liver and key enzymes involved in esterification and oxidation of long-chain fatty acids were investigated in rats fed a standard diet and a defined choline-deficient diet. Hepatic metabolism of long-chain fatty acids were also studied in rats fed the defined diet with or without choline. When methotrexate was administered to the rats fed the standard diet there was a slight increase in hepatic lipids and a moderate reduction in the serum level. The palmitoyl-CoA synthetase activity and the microsomal glycerophosphate acyltransferase activity in the liver of rats were increased by methotrexate. The data are consistent with those where the liver may fail to transfer the newly formed triacylglycerols into the plasma with a resultant increase in liver triacylglycerol content and a decrease in serum lipid levels. Fatty liver of methotrexate-exposed rats can not be attributed simply to a reduction of fatty acid oxidation as the carnitine palmitoyltransferase activity was increased. The methotrexate response in the rats fed the defined choline-deficient diet was different. There was a reduction in both serum and hepatic triacylglycerol and the glycerophosphate acyltransferase and palmitoyl-CoA synthetase activities. The carnitine palmitoyltransferase activity was unchanged. Hepatomegaly and increased hepatic fat content, but decreased serum triacylglycerol, total cholesterol and HDL cholesterol were found to be related to the development of choline deficiency as the pleiotropic responses were almost fully prevented by addition of choline to the choline-deficient diet. Addition of choline to the choline-deficient diet normalized the total palmitoyl-CoA synthetase and carnitine palmitoyltransferase activities. In contrast to methotrexate exposure, choline deficiency increased the mitochondrial glycerophosphate acyltransferase activity. The data are consistent with those of where fatty liver induction of choline deficiency may be related to an enhanced esterification of long-chain fatty acids concomitant with a reduction of their oxidation.     

Anti-oxidant effects of cinnamon (Cinnamomum verum) bark and greater cardamom (Amomum subulatum) seeds in rats fed high fat diet

In order to gain insight into the antioxidant effect of cinnamon (Cinnamomum verum; Lauraceae) and cardamom (Amomum subulatum; Zingiberaceae) hepatic and cardiac antioxidant enzymes, glutathione (GSH) content and lipid conjugated dienes were studied in rats fed high fat diet along with cinnamon or cardamom. The antioxidant enzyme activities were found to be significantly enhanced whereas GSH content was markedly restored in rats fed a fat diet with spices. In addition, these spices partially counteracted increase in lipid conjugated dienes and hydroperoxides, the primary products of lipid peroxidation. Thus, it appears that these spices exert antioxidant protection through their ability to activate the antioxidant enzymes.     

The effect of TCDD on Acyl CoA: Retinol acyltransferase activity and vitamin a accumulation in the kidney of male sprague-dawley rats

Previous studies have shown that rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) show signs of toxicity that are similar to the responses of animals to a vitamin A-deficient diet. These include hypophagia, loss of body weight, loss of hepatic vitamin A, and accumulation of renal retinoids. Male Sprague-Dawley rats treated with 10, 30, or 100 nmol/kg of TCDD accumulated renal vitamin A, with retinyl palmitate concentrations reaching 8 times those of control animals, similar to that of male rats fed a vitamin A-free diet for 26 days. Acyl CoA:retinol acyltransferase (ACARAT) activities in both TCDD-treated rats and rats fed a vitamin A-free diet for 26 days were similarly elevated, and were strongly and positively correlated with the renal retinyl palmitate concentrations. Retinol concentrations in the kidneys of rats treated with TCDD or fed a vitamin A-free diet were only slightly elevated when compared to control rats. We suggest that accumulation of retinyl esters in the kidneys of rats treated with TCDD or fed a vitamin A-free diet occurs as a result of increased rates of retinol esterification.     

Interaction Between Dietary Carbohydrate and Copper Nutriture on Lipid Peroxidation in Rat Tissues

The effects of the interactions between dietary carbohydrates and copper deficiency on superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and their roles in peroxidative pathways were investigated. Weanling rats were fed diets deficient in copper and containing either 62% starch, fructose, or glucose. Decreased activity of SOD was noted in all rats fed the copper-deficient diets regardless of the nature of dietary carbohydrate. However, the decreased activity was more pronouced in rats fed fructose. Feeding the fructose diets decreased the activity of GSH-Px by 25 and 50% in the copper-supplemented and copper-deficient rats, respectively, compared to enzyme activities in rats fed similar diets containing either starch or glucose. The decreased SOD and GSH-Px activities in rats fed the fructose diet deficient in copper were associated with increased tissue per-oxidation and decreased hepatic adenosine triphosphate (ATP). When the fructose in the diet of copper-deficient rats was replaced with either starch or glucose, tissue SOD and GSH-Px activities were increased and these increases in enzyme activity were associated with a tendency toward reduced mitochondrial peroxidation when compared to the corre-sponding values for rats fed fructose throughout the experiment Dietary fructose aggrevated the symptoms associated with copper deficiency, but starch or glucose ameliorated them. The protective effects were more pronounced with starch than with glucose.     

Effect of oxalomalate on lipid metabolism and antioxidant defense system in rats

The metabolic functions of NADP(+)-specific isocitrate dehydrogenase (ID2), which may participate in the production of NADPH and biosynthesis of fatty acids, are not yet clearly understood. Accordingly, the current study investigated the effect of oxalomalate, known as a competitive inhibitor of ID2 in vitro, on lipid metabolism and the cellular defense system in vivo. Male Sprague Dawley rats (3 weeks old) were divided into two groups, fed a pelletized AIN-76 semisynthetic diet for 8 weeks, and injected intraperioneally with either saline or oxalomalate (25 mg/kg BW) dissolved in saline every 2 days. Oxalomalate did not lower the body weight and adipose tissue weight significantly; however, it significantly lower the plasma leptin concentration (p < 0.000), plasma and hepatic triglyceride levels (p < 0.01, p < 0.05), and adipocyte lipoprotein lipase activity (p < 0.01) compared to the control group. Meanwhile, hepatic antioxidant enzyme activities, except for superoxide dismutase activity (p < 0.01), glutathione content, and thiobarbituric acid reactive substances levels were not significantly different between the groups. Therefore, the current data suggests that oxalomalate produces a triglyceride-lowering activity and play a possible inhibitory role in fat accumulation. Furthermore, it was not found to affect the most antioxidative enzyme activities, glutathione content, and thiobarbituric acid reactive substances levels in rats fed normal diet.     

The effect of dietary fat on the activity,content, rates of synthesis,and degradation and translation of messenger RNA coding for malic enzyme in mouse liver

The specific activity (units activity/mg cytosolic protein) of malic enzyme was found to be three-fold higher in the livers of mice fed a semipurified diet containing 50% ($\text{w}\text{w}$) glucose and 15% ($\text{w}\text{w}$) saturated and monounsaturated but no polyunsaturated fat (hydrogenated cottonseed oil) over an 11-day period than in the livers of mice fed a standard laboratory mouse chow (Purina) diet. In contrast, when other lab chow-fed mice were fed an isocaloric diet containing 15% ($\text{w}\text{w}$) polyunsaturated fat (corn oil), no change in the specific activity of malic enzyme occurred over a similar period of time. Rocket immunoelectrophoresis performed on cytosols from both dietary groups demonstrated that the livers of mice consuming the hydrogenated cottonseed oil diet contained approximately three times more malic enzyme protein than did the livers from the corn oil-fed animals. In mice pulse-labeled with l-[4,5-³H]leucine, the rate of hepatic malic enzyme synthesis (relative to that for total protein) was approximately twofold greater in the hydrogenated cottonseed oil-fed mice than in their corn oil-fed counterparts whereas the rate of hepatic malic enzyme degradation was similar for both groups. Immunotitration of liver malic enzyme from hydrogenated cottonseed oil-fed and corn oil-fed mice revealed identical equivalence points, demonstrating that the catalytic efficiency of mouse liver malic enzyme had not been affected by the type of dietary fat administered. When total liver RNA, isolated from the hydrogenated cottonseed oil- and the corn oil-fed animals, was translated in cell-free translation systems (wheat germ extract and reticulocyte lysate) we found that both dietary treatments had resulted in an increase in the activity of malic enzyme messenger RNA. Furthermore, there were no significant differences between the two dietary groups in this regard. These results suggest that hepatic malic enzyme specific activity in high-carbohydrate polyunsaturated fat-fed mice is regulated principally by dietary-induced changes in the rate of enzyme synthesis and not by the activity of messenger RNA coding for the enzyme.     

Effect of clofibrate feeding on some lipogenic enzyme activities induced by high carbohydrate diet

Clofibrate administration by stomach tube or intraperitoneally for 3 successive days to rats fed standard diet or starved for 72 hr caused about 2-fold increase of malic enzyme activity in the liver and adipose tissue. The drug administered by stomach tube (but not intraperitoneally) to the rats fed fat free-high carbohydrate diet significantly blocked the inducing effect of the diet on malic enzyme activity in both tissues. Clofibrate blocked the induction by fat free-high carbohydrate diet of hexose monophosphate shunt dehydrogenases and ATP-citrate lyase in the liver. The amount of fat free-high carbohydrate diet consumed by rats received clofibrate by stomach tube was much less than by untreated animals. It is concluded therefore that the significant decrease of food consumption by rats receiving clofibrate by stomach tube is responsible for the inhibitory effect of the drug on some lipogenic enzymes activity induced by fat free-high carbohydrate diet.     

Very low-carbohydrate versus isocaloric high-carbohydrate diet in dietary obese rats

Objective: The effects of a very low‐carbohydrate (VLC), high‐fat (HF) dietary regimen on metabolic syndrome were compared with those of an isocaloric high‐carbohydrate (HC), low‐fat (LF) regimen in dietary obese rats. Research Methods and Procedures: Male Sprague‐Dawley rats, made obese by 8 weeks ad libitum consumption of an HF diet, developed features of the metabolic syndrome vs. lean control (C) rats, including greater visceral, subcutaneous, and hepatic fat masses, elevated plasma cholesterol levels, impaired glucose tolerance, and fasting and post‐load insulin resistance. Half of the obese rats (VLC) were then fed a popular VLC‐HF diet (Weeks 9 and 10 at 5% and Weeks 11 to 14 at 15% carbohydrate), and one‐half (HC) were pair‐fed an HC‐LF diet (Weeks 9 to 14 at 60% carbohydrate). Results: Energy intakes of pair‐fed VLC and HC rats were less than C rats throughout Weeks 9 to 14. Compared with HC rats, VLC rats exhibited impaired insulin and glycemic responses to an intraperitoneal glucose load at Week 10 and lower plasma triacylglycerol levels but retarded loss of hepatic, retroperitoneal, and total body fat at Week 14. VLC, HC, and C rats no longer differed in body weight, plasma cholesterol, glucose tolerance, or fasting insulin resistance at Week 14. Progressive decreases in fasting insulin resistance in obese groups paralleled concomitant reductions in hepatic, retroperitoneal, and total body fat. Discussion: When energy intake was matched, the VLC‐HF diet provided no advantage in weight loss or in improving those components of the metabolic syndrome induced by dietary obesity and may delay loss of hepatic and visceral fat as compared with an HC‐LF diet.