Effect of age on serum lipids and lipoproteins of male and female JCR:LA-corpulent rats

The JCR:LA-cp rat is a strain incorporating the corpulent (cp) gene. When homozygous for the cp gene, the rats are hyperphagous, hyperinsulinemic, hyperlipidemic and obese. The corpulent male rats develop atherosclerotic and myocardial lesions from an early age, while corpulent female and lean rats do not develop lesions. The hyperlipidemia is due to elevated levels of VLDL resulting in moderately raised cholesterol levels and markedly elevated triacylglycerol levels. The VLDL concentrations are similar in corpulent male and female rats at an early age with both having much higher levels than lean rats. As the animals age, the VLDL hyperlipidemia in the corpulent male increases at 3 months and then decreases slowly and rises again at 12 months of age. The corpulent female rats show higher triacylglycerol and phospholipid concentrations than the males at 3 months age and reach values over 1000 mg/100 ml by 9 months of age, then decrease at 12 months of age. The cholesterol concentrations of the corpulent females are greater than those of the males from 9 months of age. Thus, in the period of life up to middle age, the cardiovascular disease incidence does not correlate with the degree of hyperlipidemia. The disease progression does correlate with the severity of insulin resistance and glucose intolerance, which is more severe in the corpulent male than female rats. The results suggest that the hyperlipidemia must be a necessary condition for development of atherosclerotic disease in this strain of rats, but it is not a sufficient condition.     

Prevention of myocardial disease in JCR:LA-corpulent rats by running

The JCR:LA-corpulent rat is a congenic strain that, if homozygous for the cp gene, is obese with a very low-density lipoprotein hyperlipidemia and is insulin resistant. The male corpulent rats develop atherosclerotic lesions of the major arteries and myocardial lesions. Corpulent and lean male rats were induced through mild food restriction to run intensively (approximately 6,000 m/day) from 6 wk to 6 mo of age. Food restriction, especially when coupled with running, lowered all classes of lipids in the whole serum of corpulent rats. The principal changes in lipid concentrations were in the very low-density lipoprotein fraction. Food restriction caused a significant drop in fasting insulin levels of corpulent rats and decreased beta-cell hyperplasia. Both effects were more marked in the running animals. There was a significant decrease in myocardial lesion frequency in the food-restricted corpulent rats and an absence of lesions in the running rats. The results indicate that intensive physical activity can largely correct the lipid abnormalities and insulin resistance of this atherosclerosis-prone strain, and these changes are associated with inhibition of the disease process. However, moderate food restriction has similar effects, and the greater effects seen with intensive running may simply reflect an effectively more severe metabolic restriction in the presence of the exercise.     

Decreased sensitivity to insulin in white adipose tissue from adrenalectomised rats

The ability of insulin to increase both [14C]-glucose incorporation into fatty acids and pyruvate dehydrogenase activity in incubated rat epididymal adipose tissues was considerably lessened after adrenalectomy. Insulin antagonism of adrenaline-stimulated lipolysis in isolated fat cells was abolished after adrenalectomy. Percentage stimulation of lipolysis above basal by adrenaline was not appreciably altered by adrenalectomy.     

Differential secretion of satiety hormones with progression of obesity in JCR:LA-corpulent rats

Objective: To characterize the gastrointestinal tract at the onset and in well‐established obesity. Methods and Procedures: Lean (+/?) and obese (cp/cp) male JCR:LA‐cp rats lacking a functional leptin receptor were killed at 3.5 weeks and 9 months of age and plasma concentrations of satiety hormones determined. The small intestine, colon, and stomach were measured, weighed, and mRNA levels of satiety genes quantified. Results: At the onset of obesity, obese rats had greater intestine, colon, and liver mass when adjusted for body weight compared to lean rats. Conversely, adult rats with established obesity had lower intestine and colon mass and length after adjustment for body weight. Early changes in gene expression included decreased ghrelin mRNA levels in stomach and increased peptide YY (PYY) mRNA levels in duodenum of young obese rats. After massive accumulation of adipose tissue had occurred, adult obese rats had increased proglucagon and ghrelin mRNA expression in the proximal intestine. In the distal small intestine, obese rats had lower proglucagon, ghrelin, and PYY mRNA levels. Finally, at the onset and in well‐established obesity, obese rats had higher plasma insulin, amylin, glucagon like peptide‐1 (GLP‐1), and PYY, a finding, with the exception of insulin, unique to this model. Plasma total ghrelin levels were significantly lower at the onset of obesity and established obesity compared to the lean rats. Discussion: Several defects are manifested in the obese gut early on in the disease before the accumulation of large excesses of body fat and represent potential targets for early intervention in obesity.     

Decreased rate of fatty acid synthesis in brown adipose tissue of hypothalamic obese rats

Intranuclear coinjection of the late SV40 KpnI/BclI DNA fragment and the early promotor/enhancer HpaII/BglI DNA segment into permissive monkey and non-permissive mouse cells allows late SV40 gene expression without T-antigen synthesis and DNA replication. These conditions were chosen to analyse the effect of DNA methylation on V-antigen synthesis detached from the process of DNA replication. We found that in vitro methylation of a single cytosine nucleotide proximal to the major late mRNA cap site by the HpaII methylase does not block capsid protein synthesis. This result is in contrast to reported data obtained in Xenopus laevis oocyte injection experiments [(1982) Proc. Natl. Acad. Sci. USA 79, 5142-5146].     

Effect of gemfibrozil on triacylglycerol synthesis and secretion by liver and lipoprotein lipase activity in adipose tissue of rats

The role of gemfibrozil, a hypotriglyceridemic drug, in synthesis, secretion and catabolism of triacylglycerols (TG) in rats was assessed. Chow diet-fed Sprague-Dawley rats were given various doses of gemfibrozil (10, 30 and 100 mg/kg body weight) for 2 weeks. Rats receiving the drug at the lowest dose significantly lowered the concentration of serum TG and apolipoprotein (apo) B in comparison with control rats. Synthesis of fatty acids from [14C]acetate and esterification of [14C]oleate to TG by the liver were not suppressed by the drug. Secretion rates of TG and apo B, measured by the Triton method, were suppressed at the highest dose. Lipoprotein lipase activity of the acetone powder prepared from adipose tissue was not influenced by the drug. These results indicate that the primary cause of hypotriglyceridemic action of gemfibrozil is not due to suppressing synthesis and secretion of TG by the liver or enhancing lipoprotein lipase activity in adipose tissues.     

Decreased serum creatinine concentration is associated with short telomeres of adipose tissue cells

Decreased serum creatinine concentration has been recently described to constitute a new risk factor of type 2 diabetes. Increased free radicals have been consistently associated with decreased serum creatinine and with cellular senescence. Telomere length is considered as a biological marker for senescence. We aimed to study the association of telomere length with serum creatinine. Telomere length of subcutaneous adipose tissue cells was measured in a sample of obese and nonobese subjects (n = 49). Telomere length of subcutaneous adipose tissue cells was positively associated with serum creatinine (r = 0.40, P = 0.004), i.e., the lower the telomere length, the lower the serum creatinine, but not with glomerular filtration rate (GFR). In addition, telomere length was negatively associated with BMI (r = -0.45, P = 0.001) and systolic blood pressure (r = -0.41, P = 0.003). In a multiple linear regression analysis, BMI (P = 0.005), systolic blood pressure (P = 0.01) and telomere length (P = 0.03) independently contributed to 37% of serum creatinine variance after controlling for sex and age. In conclusion, the association of serum creatinine with a marker of cellular senescence suggests an underlying mechanism influencing both decreased serum creatinine and increased risk of type 2 diabetes.     

Changes in serum lipids in rats treated with PGF2 alpha

Serum lipid concentrations were determined in rats treated with PGF2 alpha, PGE1, and controls. Administration of PGF2 alpha in rats influenced only the HDL lipid composition. HDL-cholesterol decreased while HDL-triglycerides increased. No significant difference was observed in the levels of serum total cholesterol, triglycerides, and phospholipids between animals treated with PGF2 alpha and controls. Reduced concentrations of serum lipid levels and especially of HDL-cholesterol, HDL-triglycerides, and HDL-phospholipids were found in the rats treated with PGE1. These results suggest that PGF2 alpha and PGE1 could modify serum lipid levels influencing lipoprotein metabolism.     

Hypersecretion of VLDL, but not HDL, by hepatocytes from the JCR:LA-corpulent rat

The JCR:LA-corpulent male rat, when homozygous for the cp gene (cp/cp) is hyperlipidemic and prone to atherosclerosis. Both male and female cp/cp rats have markedly elevated serum levels of triacylglycerols and phospholipids [Dolphin, P.J. et al. 1987. Biochim. Biophys. Acta. 919: 140-148]. In the present study, monolayer cultures of hepatocytes were prepared from male and female, corpulent and lean, rats. There was a marked hypersecretion of all very low density lipoprotein (VLDL) lipid and apoprotein components from corpulent-derived cells. The increased secretion most likely accounts for the increased levels of VLDL lipids and apoproteins previously observed in serum. In contrast, there was no difference between the corpulent and lean hepatocytes in their secretion of high density lipoprotein (HDL) lipids and apoproteins. The difference in triacylglycerol secretion between the lean and corpulent cells was sustained even when the cells were cultured for 24, 48, and 72 h prior to the experiment, by which time the hormonal differences between the corpulent and lean animals would have been largely eliminated. The magnitude of the difference in triacyglycerol secretion did not diminish with increasing time in culture. The biochemical basis responsible for the hypersecretion of VLDL has not yet been established. However, preliminary results suggest that there is an inherent difference in glycerolipid metabolism in the two types of hepatocytes.     

Glycerolipid biosynthesis in rat adipose tissue. Influence of adipose-cell size and site of adipose tissue on triacylglycerol formation in lean and obese rats.

The rates of lipid formation were compared in different fat-depots from lean and obese rats by using [14C]glycerol 3-phosphate, [14C]glucose or [14C]acetate as substrates. In lean animals, subcutaneous adipose tissue showed significantly lower rates of lipid synthesis than did perirenal and gonadal fat-tissue. In obese animals, the rates of lipid synthesis were significantly higher and did not vary from one fat-depot to another. Differences in the rates of lipid formation between lean and obese rats disappeared during dietary restriction of obese animals. The isolated adipocyte preparation did not reflect the true metabolic activity of the adipose organ, since this preparation was mainly derived from smaller adipocytes that were metabolically less active than larger adipocytes. The present study suggests that it is better to use whole tissue preparations to measure lipogenesis and esterification reactions, because these measurements represent the contribution of both larger and smaller adipocytes towards lipid formation.     

Diabetogenic diet-induced insulin resistance associates with lipid droplet proteins and adipose tissue secretome,but not with sexual dimorphic adipose tissue fat accumulation in Wistar rats

The role of sexual dimorphic adipose tissue fat accumulation in the development of insulin resistance is well known. However, whether vitamin A status and/or its metabolic pathway display any sex- or depot (visceral/subcutaneous)-specific pattern and have a role in sexual dimorphic adipose tissue development and insulin resistance are not completely understood. Therefore, to assess this, 5 weeks old Wistar male and female rats of eight from each sex were provided either control or diabetogenic (high fat, high sucrose) diet for 26 weeks. At the end, consumption of diabetogenic diet increased the visceral fat depots (p < 0.001) in the males and subcutaneous depot (p < 0.05) in the female rats, compared to their sex-matched controls. On the other hand, it caused adipocyte hypertrophy (p < 0.05) of visceral depot (retroperitoneal) in the females and subcutaneous depot of the male rats. Although vitamin A levels displayed sex- and depot-specific increase due to the consumption of diabetogenic diet, the expression of most of its metabolic pathway genes in adipose depots remained unaltered. However, the mRNA levels of some of lipid droplet proteins (perilipins) and adipose tissue secretory proteins (interleukins, lipocalin-2) did display sexual dimorphism. Nonetheless, the long-term feeding of diabetogenic diet impaired the insulin sensitivity, thus affected glucose clearance rate and muscle glucose-uptake in both the sexes of rats. In conclusion, the chronic consumption of diabetogenic diet caused insulin resistance in the male and female rats, but did not corroborate with sexual dimorphic adipose tissue fat accumulation or its vitamin A status.