Characterization of a model of dietary-induced hypertriglyceridemia in young, nonobese rats.

Healthy, nonobese, young rats developed hypertriglyceridemia (mean triglyceride levels of 250 mg/dl) following consumption of a sucrose-lard diet. The hypertriglyceridemia was apparent three days after start of the diet and persisted throughout the 4-week experimental period. Body weight, liver weight, and serum glucose levels were similar in animals eating either the sucrose-lard diet or standard rat chow. On the other hand, serum free fatty acid levels were slightly increased and serum insulin levels were substantially increased in animals eating the sucrose-lard diet. Determination of very low density lipoprotein turnover revealed that total triglyceride secretion in rats eating the sucrose-lard diet was significantly (P < 0.01) increased over that of rats eating standard chow. Direct measurement of hepatic and intestinal very low density lipoprotein secretion indicated that the observed rise in total triglyceride secretion was secondary to increased secretion of very low density lipoproteins by the liver. Finally, lipoprotein lipase activity of adipose tissue from rats eating the sucrose-lard diet was equal to, or greater than (depending upon sampling time), the activity of the enzyme from adipose tissue of rats eating the control diet. These data indicate that young, nonobese, rats develop hypertriglyceridemia when they ingest a sucrose-lard diet, and that the rise in plasma triglyceride levels results from an increase in hepatic very low density lipoprotein secretion. The dietary-induced hypertriglyceridemia is associated with elevated serum insulin levels, and, as such, may provide a useful animal model to use in studies aimed at defining the pathogenesis of endogenous hypertriglyceridemia in man.-Reaven, G. M., T. R. Risser, Y-D. I. Chen, and E. P. Reaven. Characterization of a model of dietary-induced hypertriglyceridemia in young, nonobese rats.     

Studies on the mechanism of hypertriglyceridemia in the genetically obese Zucker rat

The possibility that impaired removal of lipoprotein triglyceride from the circulation may be a participating factor in the hypertriglyceridemia of the obese Zucker rat was examined. We found no significant differences in the heparin-released lipoprotein lipase (LPL) activities of the adipose tissue, skeletal muscle, and heart (expressed per gram of tissue) from the lean and obese Zucker rats. Furthermore, the kinetic properties of adipose tissue and heart LPL from the lean and obese rats were similar, indicating that the catalytic efficiency of the enzyme was unaltered in the obese animals. The postheparin plasma LPL activities of lean and obese rats were also similar. However, the postheparin plasma hepatic triglyceride lipase (H-TGL) activity in the obese rats was elevated. The higher activity of H-TGL could not alleviate the hypertriglyceridemia in these animals. Since hypertriglyceridemia in the obese rats could also be due to the hepatic production of triglyceride-rich lipoproteins which are resistant to lipolysis, we therefore isolated very low density lipoproteins (VLDL) from lean and obese rat liver perfusates and examined their degradation by highly purified human milk LPL. Although certain differences were observed in hepatic VLDL triglyceride fatty acid composition, the kinetic patterns of LPL-catalyzed triglyceride disappearance from lean and obese rat liver perfusate VLDL were similar. The isolated liver perfusate VLDL contained sufficient apolipoprotein C-II for maximum lipolysis. These results indicate that impaired lipolysis is not a contributing factor in the genesis of hypertriglyceridemia in the genetically obese Zucker rat. The hyperlipemic state may be attributed to hypersecretion of hepatic VLDL and consequent saturation of the lipolytic removal of triglyceride-rich lipoproteins from the circulation.     

"Liking" and "wanting" of sweet and oily food stimuli as affected by high-fat diet-induced obesity, weight loss, leptin, and genetic predisposition

Cross-sectional studies in both humans and animals have demonstrated associations between obesity and altered reward functions at the behavioral and neural level, but it is unclear whether these alterations are cause or consequence of the obese state. Reward behaviors were quantified in male, outbred Sprague-Dawley (SD) and selected line obesity-prone (OP) and obesity-resistant (OR) rats after induction of obesity by high-fat diet feeding and after subsequent loss of excess body weight by chronic calorie restriction. As measured by the brief access lick and taste-reactivity paradigms, both obese SD and OP rats "liked" low concentrations of sucrose and corn oil less, but "liked" the highest concentrations more, compared with lean rats, and this effect was fully reversed by weight loss in SD rats. Acute food deprivation was unable to change decreased responsiveness to low concentrations but eliminated increased responsiveness to high concentrations in obese SD rats, and leptin administration in weight-reduced SD rats shifted concentration-response curves toward that seen in the obese state in the brief access lick test. "Wanting" and reinforcement learning as assessed in the incentive runway and progressive ratio lever-pressing paradigms was paradoxically decreased in both obese (compared with lean SD rats) and OP (compared with OR rats). Thus, reversible, obesity-associated, reduced "liking" and "wanting" of low-calorie foods in SD rats suggest a role for secondary effects of the obese state on reward functions, while similar differences between select lines of OP and OR rats before induction of obesity indicate a genetic component.     

Management of dietary essential metals (iron,copper, zinc,chromium and manganese) by Wistar and Zucker obese rats fed a self-selected high-energy diet

The balances and content of essential elements (iron, copper, zinc, chromium and manganese) in the body of Wistar, Zucker lean and Zucker obese rats fed a reference or cafeteria diet from day 30 to 60 after birth have been studied. Intestinal iron absorption compensated for low iron content of the cafeteria diet and the extra needs of growth and fat deposition. It can be assumed that the altered energy regulation processes that afflict the genetically obese rat are not directly related to altered iron metabolism. Obese Zucker rats had lower copper tissue concentrations than lean rats, but when fed a cafeteria diet the differences between Zucker rats strains disappear. This cannot be traced to large differences in diet copper concentration. A low diet availability of zinc—such as that of cafeteria-fed fa/fa rats—is easily compensated for by increasing absorption. So, as a consequence, we can conclude that genetic obesity did not impair zinc absorption. There was no deficit of zinc in any of the groups studied; the rats have enough capacity to extract zinc within a wide range of dietary concentrations. The absorption of dietary chromium was inversely proportional to its concentration. The ability to extract chromium from the diet and the very low urinary losses are a consequence of its scarcity in most dietary items. Despite wide variations in the manganese of the diets, the absorption rates were practically unchanged except for obese rats fed the cafeteria diet. It seems that this low absorptive capacity is enough to supply the rat with the manganese it needs, since a sizeable—but subjected to 8-fold-span variations-proportion is lost in the urine. This alone points towards a considerable excess of manganese in both diets studied. Obesity does not have a significant effect on the abilities to absorb and retain minerals, since these processes were more related to dietary availability. Management of essential metals by obese rats depends whether this condition is genetic or induced by diet. Most of the differences observed can be related to differences in diet concentration, to the excess fat content or different metabolic attitude to use substrates of obese animals. The data presented show that the cafeteria diet used adequately serves the mineral needs of the rat, since the rat adapts its absorbing and retaining strategies to match the dietary availability of these minerals.     

Short-term very low calorie diet reduces oxidative stress in obese type 2 diabetic patients

Oxidative stress is higher in obese diabetic than in non-diabetic subjects. This pilot study evaluates oxidative stress during short-term administration of a very low calorie diet in obese persons. Nine obese Type 2 diabetic patients (age 55+/-5 years, BMI 35.9+/-1.9 kg/m2) and nine obese non-diabetic control subjects (age 52+/-6 years, BMI 37.3+/-2.1 kg/m2) were treated by a very low calorie diet (600 kcal daily) during 8 days stay in the hospital. Serum cholesterol, triglycerides, non-esterified fatty acids (NEFA), beta-hydroxybutyrate (B-HB), ascorbic acid (AA), alpha-tocopherol (AT), plasma malondialdehyde (MDA) and superoxide dismutase (SOD) activity in erythrocytes were measured before and on day 3 and 8 of very low calorie diet administration. A decrease of serum cholesterol and triglyceride concentrations on day 8 was associated with a significant increase of NEFA (0.30+/-0.13 vs. 0.47+/-0.11 micromol/l, p<0.001) and B-HB (0.36+/-.13 vs. 2.23+/-1.00 mmol/l, p<0.001) in controls but only of B-HB (1.11+/-0.72 vs. 3.02+/-1.95 mmol/l, p<0.001) in diabetic patients. A significant decrease of plasma MDA and serum AT together with an increase of SOD activity and AA concentration (p<0.01) was observed in control persons, whereas an increase of SOD activity (p<0.01) was only found in diabetic patients after one week of the very low calorie diet. There was a significant correlation between NEFA or B-HB and SOD activity (p<0.01). We conclude that one week of a very low calorie diet administration decreases oxidative stress in obese non-diabetic but only partly in diabetic persons. Diabetes mellitus causes a greater resistance to the effects of a low calorie diet on oxidative stress.     

Intestinal very-low-density lipoprotein secretion in the genetically obese Zucker rat

The objectives of this study were to measure intestinal very-low-density lipoprotein (VLDL) production in obese Zucker rats and to assess an eventual effect of a high-fat diet. VLDL secretion was specifically inhibited by orotic acid, and intestinal VLDL output was measured following the Triton WR-1339 method. After a control diet, total VLDL secretion (without orotic acid) was 4.8 +/- 0.3 and 1.4 +/- 0.1 mg triacylglycerol/ml in obese and lean rats, respectively, decreasing by 30% in obese rats after fat-feeding. Intestinal VLDL production was similar in obese and lean rats fed the control diet (0.32 +/- 0.05 and 0.27 +/- 0.05 mg triacylglycerol/ml, respectively), increasing 2.5-fold after fat-feeding in both genotypes. Thus, intestine contributed 21 and 60% of total VLDL in lean but only 7 and 24% in obese rats with the control and high-fat diets, respectively. These results show that the intestine of obese Zucker rats does not contribute to their hypertriglyceridemia, suggesting that it originates solely from liver. Moreover, their intestinal VLDL production was stimulated by fat-feeding to the same extent as in lean animals.     

The Zucker-fatty rat: a review.

The Zucker (fatty) rat is one of a group of animals that inherit obesity as an autosomal Mendelian recessive trait. These rats are obese, hyperphagic, and hyperinsulinemic, but blood glucose remains at normal levels. Although these rats eat more than normal rats, their response to the addition of adulterants to the food or after exposure to the cold is more like that of normal rats than rats with hypothalamic obesity. The hypertriglyceridemia which characterized these animals is due to the increased hepatic production of a very low density lipoproteins. Adipocytes are increased in size and in number with the subcutaneous fat depot showing the largest increase in the number of fat cells. Lipogenesis from glucose is brisk in the young animals but declines with age. Enzymatic patterns of glycolysis and gluconeogenesis appear to reflect the altered internal milieu rather than specific defects. Endocrine changes in the fatty rat include hyperinsulinemia, reduced levels of glucagon, hypothyroidis, and impaired reproductive function. A model is presented in which the features of the genetically obese (Zucker) fatty rat are compared with those of animals with hypothalamic obesity.     

Effects of phenotype, sex, and diet on plasma lipids in LA/N-cp rats

The LA/N-corpulent (cp) rat is a recently developed congenic strain which exhibits obesity. The effects of phenotype and sex on serum and lipoprotein lipid content were examined in LA/N-cp rats fed either a control or an atherogenic diet high in saturated fat and protein. Obese rats were pair-fed to equivalent lean animals. Results from this study indicate that sex, phenotype, and diet exert significant effects on plasma and lipoprotein cholesterol content. Plasma cholesterol levels were higher in obese compared with lean rats, females than in males, and rats consuming the atherogenic diet compared with the control diet. Plasma and lipoprotein triglyceride levels were significantly increased only in obese compared with lean animals. The increased plasma cholesterol and triglyceride was observed primarily in the chylomicron and very low density lipoprotein fractions. Increased levels of plasma cholesterol were not a result of increased dietary cholesterol absorption or increased liver cholesterol biosynthesis. These data suggest that LA/N-cp rats can serve as a unique rodent model for the study of the interrelationships between hyperlipidemia, obesity, and coronary heart disease.     

Programmed metabolic syndrome: prenatal undernutrition and postweaning overnutrition

Maternal nutrient restriction results in intrauterine growth restriction (IUGR) newborns that develop obesity despite normal postweaning diet. The epidemic of metabolic syndrome is attributed to programmed "thrifty phenotype" and exposure to Western diets. We hypothesized that programmed IUGR newborns would demonstrate greater susceptibility to obesity and metabolic abnormalities in response to high-fat diet. From day 10 to term gestation and lactation, control pregnant rats received ad libitum (AdLib) food, whereas study rats were 50% food restricted (FR). Cross-fostering techniques resulted in three offspring groups: control (AdLib/AdLib), FR during pregnancy (FR/AdLib), and FR during lactation (AdLib/FR). At 3 weeks, offspring were weaned to laboratory chow or high-fat calorie diet (9% vs. 17% calorie as fat). Body composition, appetite hormones, and glucose and lipid profiles were determined in 9-mo-old male and female offspring. High-fat diet had no effect on body weight of AdLib/AdLib, but significantly increased weights of FR/AdLib and AdLib/FR offspring. High-fat diet significantly increased body fat, reduced lean body mass, and accentuated plasma leptin but not ghrelin levels in both sexes in all groups. In males, high-fat diet caused a significant increase in glucose levels in all three groups with increased insulin levels in AdLib/AdLib and AdLib/FR, but not in FR/AdLib. In females, high-fat diet had no effect on glucose but significantly increased basal insulin among all three groups. High-fat diet caused hypertriglyceridemia in all three groups although only food-restricted females exhibited hypercholesterolemia. Sex and offspring phenotype-associated effects of high-fat diet indicate differing pathophysiologic mechanisms that require specific therapeutic approaches.     

Effects of a Fat Substitute,Sucrose Polyester,on Food Intake,Body Composition,and Serum Factors in Lean and Obese Zucker Rats

Sucrose polyester, a fat substitute, has shown promise in reducing blood cholesterol and body weight of obese individuals. Effects of this compound in the Zucker rat, a genetic model of obesity, are unknown. Thus, we examined food intake, body weight, body composition, and several metabolic parameters in sera of lean and obese female Zucker rats. Eight-week-old lean and obese animals were given a choice between a control diet (15% corn oil) and fat substitute diet (5% corn oil and 10% sucrose polyester) for 2 days. Next, one-half of the lean and obese groups received control diet; the remaining lean and obese rats received fat substitute diet for 18 days. Cumulative food intake was depressed in fat substitute groups relative to control-fed animals; however, this effect was more predominant in obese animals. Obese rats consuming fat substitute diet (O-FS) gained less weight as compared to obese control-fed animals (O-C). Lean rats given fat substitute (L-FS) did not have significantly different body weights as compared to the L-C group. Fat substitute groups, combined, had lower body fat and higher body water as compared to controls. The O-FS group had lower serum glucose and insulin and higher fatty acid levels compared to the O-C group. There were no differences in serum cholesterol, HDL, or triglyceride levels due to fat substitute diet. These data suggest that the obese Zucker rat is unable to defend its body weight when dietary fat is replaced with sucrose polyester.     

Influence of restricted food intake on brown adipose tissue function in genetically obese mice (genotype, ob/ob)

Measurements were made of cytochrome c oxidase activity and the GDP-binding capacity of mitochondria in brown adipose tissue of genetically obese mice and wild-type siblings, to estimate the thermogenic capacity of the tissue. The binding capacity was decreased in ad libitum fed obese animals compared with wild-type animals. Limited feeding of obese animals to restrict their body weight caused a large increase in the binding capacity of the tissue, which was greater than that in wild-type animals fed either ad limitum or on a limited diet. The decreased binding capacity of brown adipose tissue mitochondria in obese mice appears to be a consequence of ad libitum feeding and therefore not a cause of the obesity. Limit feeding of obese animals also corrected their characteristic hypothermia at low ambient temperature. The large increase in the thermogenic capacity of brown adipose tissue in obese animals, induced by limited feeding, may account for the vital improvement of their thermoregulation. However, close similarities were found between obesity hypothermia and hypothermia induced in wild-type animals by restraint. It is suggested that changes in posture caused by obesity, resulting in increased loss of body heat, may be important in the development of obesity hypothermia. Obese animals fed less than wild-type grained more weight than wild-type animals, indicating that the high thermogenic capacity of their brown adipose tissue did not function to regulate their calorie intake.     

Contribution of EDRF and EDHF to restoration of endothelial function following dietary restrictions in hypercholesterolemic rats

The mechanisms underlying the impairment of endothelium-mediated vasorelaxation induced by dietary hypercholesterolemia and the mechanisms of restoration of endothelial function following reintroduction of low cholesterol diet were evaluated. Feeding rats with high cholesterol diet induced hypercholesterolemia and high blood pressure. This was associated with reduced vasorelaxation in response to acetylcholine, isoproterenol, and adenosine. At the same time, exaggerated contractile responses to serotonin and phenylephrine were observed. Reintroduction of a normal diet to cholesterol fed rats resulted in significant normalization of blood pressure, serum lipid profile, relaxation and contractile responses. The contributions of endothelial derived relaxing factors (EDRF), endothelial derived contractile factors (EDCFs)/prostanoids, and endothelial derived hyperpoalrising factor (EDHF) to the vasorelaxation in each group of animals were assessed. EDCFs constricting activity was increased in both cholesterol fed groups as compared to the control group. EDRF and EDHF were found to be the primary factors involved in the regulation of endothelium-mediated responsiveness. In control animals, EDRF was responsible for 70-90% of relaxation, depending on the agonist used. In cholesterol fed animals, EDRF was significantly reduced while EDHF was maintained or enhanced showing that EDHF had a significant role in maintaining the endothelial responses. Importantly, the restoration of vasorelaxation following reintroduction of normal diet was mediated not only by improvement of EDRF-dependent relaxation, but also to a significant extent by a further increase in EDHF-mediated relaxation. Taken together, the data showed that EDRF was attenuated during hypercholesterolemia and dietary interventions with low fat content restored these responses. However, EDHF-mediated responses were not reduced by hypercholesterolemia and subsequently improved their function after application of low cholesterol diet. The results implicate EDHF-mediated relaxation is also an important mechanism for restoration of endothelial function upon application of dietary restrictions for reduction of serum cholesterol level.     

Influence of intrauterine undernutrition on the development of hypercholesterolemia in an animal model

A low birth weight is a new risk factor for the development of premature atherosclerosis. The effect of intrauterine undernutrition on hypercholesterolemia in later life was studied in an experimental model using the Prague Hereditary Hypercholesterolemic (PHHC) rat. Compared to animals in the control group (Wistar rats), animals with an increased sensitivity to high-cholesterol diet (PHHC rats) display hypercholesterolemia. Only in PHHC animals, individuals undernourished in their intrauterine life (hypotrophic group, HG) had a significantly higher total cholesterol, compared with individuals without food restriction in pregnancy (eutrophic group, EG). Restricted food intake in pregnancy led to smaller nests and a decreased number of pups in each litter. We found no significant diferences in birth weight between HG and EG. In spite of similar birth weights in PHHC and Wistar rats, intrauterine undernutrition caused an increase in cholesterolemia in the HG group of the PHHC rats. The effect of intrauterine undernutrition on the development of hypercholesterolemia will most likely play a role in individuals with geneticaly determined increased susceptibility to a high-cholesterol diet. The use of this model of intrauterine undernutrition for the study of hypercholesterolemia has proved to be feasible.     

Obesity, insulin resistance and diabetes in the sand rat exposed to a hypercaloric diet; possible protective effect for IL1-β

It is well established that, upon changing their natural desert low caloric (succulent halophilic plants) to a regular laboratory high caloric diet, sand rats undergo various phenotypic changes depending on their genetic background and including obesity and various degrees of insulin resistance. Our aim was to investigate the acute effects of Interleukin-1β (IL-1β) and Interferon-γ (IFN-γ) on glucose-induced insulin secretion in normal lean sand rats maintained on their natural diet and in obese insulin resistant normoglycemic or type 2 diabetic animals after a 9-month high caloric diet. Animals were fed either a low or a high caloric diet; after 9 months, pancreatic islets were isolated and incubated in the presence of increasing cytokine concentrations. At the end of the high-energy diet, animals were all over-weight, and probably due to a different genetic background, they displayed either insulin resistance, hyperinsulinemia and normoglycemia or a marked type-2 diabetic state. Pancreatic islets from obese insulin resistant normoglycemic animals were much more sensitive and responsive to IL-1β when compared to lean controls. The cytokine was inefficient in diabetic islets. In conclusion, the markedly increased insulinotropic effect of IL-1β in obese diabetes-resistant sand rat could participate and be involved in pancreatic β-cell hyperactivity that compensates for insulin resistance and thereby prevent the development of type 2 diabetes in these animals.     

Sex Differences in High‐fat Diet‐induced Obesity,Metabolic Alterations and Learning,and Synaptic Plasticity Deficits in Mice

Obesity is a potential risk factor for cognitive deficits in the elder humans. Using a high‐fat diet (HFD)–induced obese mouse model, we investigated the impacts of HFD on obesity, metabolic and stress hormones, learning performance, and hippocampal synaptic plasticity. Both male and female C57BL/6J mice fed with HFD (3 weeks to 9–12 months) gained significantly more weights than the sex‐specific control groups. Compared with the obese female mice, the obese males had similar energy intake but developed more weight gains. The obese male mice developed hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hyperleptinemia, but not hypertriglyceridemia. The obese females had less hyperinsulinemia and hypercholesterolemia than the obese males, and no hyperglycemia and hypertriglyceridemia. In the contextual fear conditioning and step‐down passive avoidance tasks, the obese male, but not female, mice showed poorer learning performance than their normal counterparts. These learning deficits were not due to sensorimotor impairment as verified by the open‐field and hot‐plate tests. Although, basal synaptic transmission characteristics (input–output transfer and paired‐pulse facilitation (PPF) ratio) were not significantly different between normal and HFD groups, the magnitudes of synaptic plasticity (long‐term potentiation (LTP) and long‐term depression (LTD)) were lower at the Schaffer collateral‐CA1 synapses of the hippocampal slices isolated from the obese male, but not female, mice, as compared with their sex‐specific controls. Our results suggest that male mice are more vulnerable than the females to the impacts of HFD on weight gains, metabolic alterations and deficits of learning, and hippocampal synaptic plasticity.     

The effect of dietary copper on rat plasma apolipoprotein B,E plasma levels,and apolipoprotein gene expression in liver and intestine

The plasma levels of apo B and apo E, and the level of hepatic and intestinal mRNA coding for these apolipoproteins were investigated in weanling male rats pair-fed for 6 wk with a control or copperdeficient diet. Plasma cholesterol, triglycerides, and phospholipids were significantly increased, and plasma apo B and apo E levels were also markedly increased in copper-deficient rats as compared to control rats. Copper deficiency significantly increased triglyceride levels and decreased cholesterol levels in the liver. No major differences in the levels of hepatic and intestinal apo B and apo E mRNA occurred between control and copper-deficient rats. These data imply that hypertriglyceridemia dn hypercholesterolemia owing to the copper deficiency are not accompanied by modifications in the gene expression at the mRNA level in the liver and intestine of the apolipoproteins studied.     

Long-Term Weight Cycling in Female Wistar Rats: Effects on Metabolism

LU, HUIQING, ANNE BUISON, VIRGINIA UHLEY AND K-L CATHERINE JEN. Long-term weight cycling in female Wistar rats: effects on metabolism. Obes Res. Weight cycling (WC) induced by ad-lib and restricted high fat (HF) feeding has been shown to reduce final body weight but not body fat percent in female Wistar rats. We examined the metabolic consequences of this type of WC. Five groups of female Wistar rats were fed a HF diet and the sixth group was fed a low fat diet to serve as a control group. Of the five HF groups, four groups were weight cycled by ad-lib and restricted feeding of the HF diet One of these groups weight cycled three times (HFCYC group) while the remaining three groups weight cycled once only, corresponding to the first, second and the third cycle of the HFCYC group. HF feeding induced hyperinsulinemia, hypertriglyceridemia, insulin resistance and elevated adipose tissue lipoprotein lipase (AT-LPL) activity levels as compared to rats fed the low fat (LF) control diet. WC further increased blood insulin concentrations and insulin resistance in rats with three cycles of WC. However, blood pressure was not affected by HF feeding or WC. The magnitude of increase of AT-LPL was reduced in weight cycled, HF fed obese rats after 15 weeks refeeding. We concluded that even though WC did not enhance weight gain nor impair weight loss, it did facilitate the development of insulin resistance and may predispose animals to diabetes.     

Intestinal lipoprotein synthesis. Comparison of nascent Golgi lipoproteins from chow-fed and hypercholesterolemic rats

Hypercholesterolemia, induced by a cholesterol-enriched diet, is associated with distinctive modifications in the serum lipoproteins of a variety of species. Present in the serum of these animals are several classes of lipoproteins enriched in cholesteryl esters and apolipoprotein E. To investigate the role of intestinal lipoprotein synthesis in diet-induced hypercholesterolemia, we characterized nascent lipoproteins retrieved from Golgi apparatus-rich fractions of intestinal epithelial cells from chow-fed control and hypercholesterolemic rats. To eliminate chylomicrons from the preparations, rats were fasted overnight prior to the experiments. Golgi very low density lipoproteins (d less than 1.006 g/ml) from control rats were triglyceride-rich lipoproteins that migrated slightly slower than pre-beta migrating serum very low density lipoproteins. These particles contained apoproteins B-240, A-IV, and A-I. Golgi very low density lipoproteins from hypercholesterolemic rats were likewise triglyceride-rich lipoproteins migrating electrophoretically like control Golgi very low density lipoproteins and they contained apoproteins B-240, A-IV, and A-I. However, these latter particles contained less triglyceride and more cholesterol compared to control Golgi very low density lipoproteins. In addition, by radioisotope incorporation studies, Golgi very low density lipoproteins from hypercholesterolemic rats contained relatively more apoprotein A-IV (21.6 vs. 11.0%) and less apoprotein B-240 (17.0 vs. 27.0%) than found in control Golgi very low density lipoproteins. Approximately 60% of the total apoprotein radioactivity was found in apoprotein A-I in both preparations. We conclude that intestinal lipoprotein synthesis is modified by diet-induced hypercholesterolemia. The significance of these modifications with respect to the marked hypercholesterolemia observed in these animals remains to be determined.     

Defects in resting metabolic rates and mitochondrial respiration in Kwashiorkor and dietary obese rats

Summary Resting metabolic rates have been measured and compared with hepatic mitochondrial respiration in Kwashiorkor and diet-induced obese weaned rats. In Kwashiorkor, resting metabolic rate was 21% lower than the value of controls, while that of the obese rats was 14% higher than in control animals. The resting metabolic rate for Kwashiorkor animals was 50% of the predicted basal metabolic rate (BMR), whereas that of the obese rats was 23% higher than the predicted BMR. The mitochondrial oxygen consumption patterns, using malate plus glutamate or succinate as respiratory substrates, revealed that the resting respiration (state 4) was 23.9% higher in Kwashiorkor and 29.1% higher in obese animals, while the active (state 3) respiration was 34.8% lower in Kwashiorkor and 43.3% lower in obese rats compared to controls. The respiratory control ratios (RCR) were 51.1% and 43.8% in Kwashiorkor and obese rats, respectively, relative to the values in control rats. It is concluded from these studies that Kwashiorkor disease and diet-induced obesity appear to interfere with oxygen utilization at the level of state 3 mitochondrial respiration, which is markedly decreased when compared to the values for control animals.Abbreviations BMR basal metabolic rate - CPD commercially produced diet - KWD low protein, high carbohydrate diet - OBD high fat diet - PEM protein-energy malnutrition - RCR respiratory control ratios Present address: Department of Biochemistry, University of Nairobi, P.O. Box 30197, Nairobi, Kenya