Different levels of food restriction have opposite effects on adipocyte cellularity and lipoprotein-lipase activity in obese rats.

The effects of several levels of chronic energy restriction on epididymal and perirenal adipose tissue cellularity and lipoprotein lipase activity, serum glucose and insulin and hepatic enzyme activities were studied in lean Fa/- and genetically obese fafa rats. The restricted rats were compared to rats fed ad libitum 24/24h or 8/24h. Restricting time of feeding was associated with increases in fat cell number in the lean, increases in perirenal adipose tissue fat cell size and serum insulin in the obese and increases in lipoprotein lipase activity in both phenotypes. Mild food restriction (-25%) had similar effects in the obese: perirenal adipose tissue fat cell size and serum insulin levels were even higher but fat cell hyperplasia was reduced. Restriction by 50% normalized lipoprotein lipase activity and markedly reduced fat cell size in the lean; in the obese, lipoprotein lipase activity and insulin levels were similar to or lower than those of the corresponding ad libitum 24/24h group but fat cell hypertrophy was not particularly affected. Restriction by 75% in the obese prevented adipocyte hyperplasia. Furthermore, lipoprotein lipase activity in adipose tissue was normalized, serum insulin and lipids being within normal limits. However, these animals had large adipocytes and were still fat.

Evidence of a defect in energy expenditure in 7-day-old Zucker rat (fa/fa).

The aim of the investigation was to see whether a defect in energy expenditure could be found in the Zucker rat at the onset of obesity. Obese (fa/fa) and lean (Fa/fa) 7-day-old pups were studied at three ambient temperatures. At 33 degrees C fa/fa pups showed a reduction in oxygen consumption, respiratory CO2 production, in vivo oxidation of injected [1-14C]palmitic acid, as well as in core temperature. When the pups were kept at 28 degrees C, the difference between genotypes was considerably accentuated, thus indicating a subnormal thermogenic response of the fa/fa pups to a mildly cold environment. At 20 degrees C, however, the metabolic rates dropped to the same low level, and the core temperature equilibrated with ambient temperature in both genotypes. The results demonstrate that the 1-wk-old fa/fa pup has a defect in thermoregulatory thermogenesis. The magnitude of the deficit in energy expenditure was more than adequate to account for the 50% greater fat content of 7-day-old fa/fa pups.

D-Glucosamine-induced increase of the glycerol-containing lipids in growing cultures of human malignant epithelial cells.

D-Glucosamine was found to inhibit the growth of human malignant epithelial cells SW-839, HT-29, RT-4, and SK-OV-3 in culture in a process that was associated with significant increments in glycerol-containing lipids. Each cell line had a different sensitivity to the drug, but all four cell lines shared the same features in their response, i.e., dose-dependent (at concentrations of 1, 5, and 10 mM), noncytotoxic reductions in growth (minimum 30%, maximum 70%), and simultaneous 1.5-fold to sevenfold increases in lipid contents. Cells regained their normal growth and lipid patterns when glucosamine was removed. Glucosamine did not modify the lipid contents of cells in the late phase of culture when growth was minimal.

The presence of epidermal growth factor receptors in cultured human adipocyte precursors.

The characteristics of 125I-epidermal growth factor urogastrone (125I-EGF) binding to human omental adipocyte precursors over a period of early differentiation in culture, is reported. The results show the presence of cell surface EGF receptor sites (38,000 per cell) that bind 125I-EGF with a high affinity (Ka = 2.7 X 10(9) l/mol). Their presence is not appreciably altered during a 28-day growth period in culture. The existence of such receptors suggests the possibility that growth factors might intervene in the regulatory processes involved in adipose tissue development.

Onset and development of hypertriglyceridemia in the Zucker rat (fa/fa).

Triglyceridemia was studied in genetically obese Zucker rats (fa/fa) and their lean littermates aged 1-8 wk. Hypertriglyceridemia was manifest in the obese from 2 wk onwards. Hepatic triacylglycerol secretion rate (TGSR) measured after administration of Triton WR-1339, was similar in obese and lean pups aged 2 wk. At 4 wk TGSR was twice as high in the obese as in the lean. Lipoprotein lipase (LPL) activity was abnormal in the tissues of obese animals, being either increased in white adipose tissue from 1 wk onwards or decreased in brown adipose tissue and cardiac and skeletal muscle from 2 wk onwards. The simultaneous appearance in the 2-wk-old obese of a decrease in LPL activity of the latter tissues, and hypertriglyceridemia strongly suggests a cause-effect relationship particularly since TGRS is normal. After weaning, LPL capacity of white adipose tissue in the obese, although considerably increased, was apparently not high enough to compensate for both an increased TGSR and a decreased LPL activity in other tissues.

Phenotypic variability in unweaned 3-week-old Zucker rats.

At 3 weeks of age, Zucker rats could not be classified as normal or obese according to body or liver weight. On the other hand, determination of subcutaneous adipose tissue weight per 100 grams of body weight permitted both phenotypes to be distinguished, provided that the growth variations particular to each litter were taken into account. Rats whose future obesity is predictable using this method, have significantly elevated serum levels of triacylglycerols, total cholesterol and phospholipids. However, further analysis of these values indicated that in fact there were two subgroups of both obese and non-obese rats, i.e., those which had elevated serum lipid levels and those which did not.

Lipoprotein lipase at onset of obesity induced in rats by a high-fat diet.

Obesity is detectable in adult male Wistar rats three weeks after initiation of a high-fat diet. Although there was an immediate increase in muscle lipoprotein lipase (LPL) activity, and a progressive adaptative response in adipose tissue leading to inhibition of de-novo lipogenesis, loss of insulin sensitivity and decreased functional LPL activity, the ensuing reorientation of lipid metabolism failed to prevent obesity. It is concluded that there is no fixed relationship between enlargement of adipose tissue and LPL activity in this tissue, at onset of obesity.

Importance of muscle lipoprotein lipase in rats during suckling.

In order to evaluate the relative importance of groups of tissues containing lipoprotein lipase (LPL) in the removal of serum triacylglycerols during development, LPL activity was determined in cardiac and skeletal muscle, brown (BAT) and white adipose tissue (WAT), lung and kidney of rats aged 0-60 days, either fed or fasted for 6 h. On fasting, LPL activity did not change in lung and kidney, decreased in WAT except at 14 days and to a lesser extent in BAT, whereas muscle LPL decreased at 0, 3, and 7 days and increased from 14 days onward. The fasting-induced changes in serum triacylglycerol concentrations in suckling pups could be attributed to corresponding changes in muscle LPL. In the adult, the main contributor to total LPL activity was WAT in fed rats and muscle in fasted rats, as expected. In suckling pups, however, muscle LPL contributed 63-85% of the total and WAT less than 25%, whatever the nutritional state. The results strongly suggest that clearing of circulating chylomicrons during suckling largely depends on muscle LPL.

[Lipid metabolism in the newborn genetically obese (fa/fa) rat]. / Métabolisme lipidique chez le rat nouveau-né génétiquement obèse (fa/fa).

Compared to its lean litter mate (Fa/--) the Zucker rat (fa/fa) develops obesity without hyperphagia in the first week of lite. It is characterized by adipocyte hypertrophy and higher lipid content in adipose tissue. In vitro utilization as well as in vitro oxidation by diaphragm of palmitic acid was decreased in 1 week old Zucker rat.

Onset of genetic obesity in the absence of hyperphagia during the first week of life in the Zucker rat (fa/fa).

The aim of this study was to discover which of three major abnormalities of the genetically obese Zucker rat (fa/fa), namely hyperphagia, excess adiposity, and hyperlipidemia, is the first to appear prior to manifest obesity, i.e., before weaning. Suckling fa/fa rats, bred from heterozygous parents, were detected by sizing fat cells obtained from an inguinal fat pad biopsy. Cell hypertrophy was observed in fa/fa rats, compared to Fa/-littermates of the same sex, as soon as 5-7 days after birth. Prediction of fa/fa genotype at this age by this method was assessed using a series of 80 pups and proved to be totally successful. The identity of the "predicted" obese pups was confirmed morphologically at 6 weeks of age. Food (milk) intake was estimated from water turnover rates determined on 86 pups aged 2-8 days using tritiated water. The results show that 7-day-old fa/fa rats had heavier inguinal fat pads with larger adipocytes and higher lipoprotein lipase activity than their lean controls. There was no genotype effect on water intake adjusted to body weight during the first week of life. Moreover weight of stomach contents and triglyceridemia were similar in all animals at 7 days. These results show that excess adiposity develops in the fa/fa rat during the first week of life, before hypertriglyceridemia and hyperphagia, and raises the question of whether this adiposity results from a defect in energy expenditure or an abnormality of fat cell storage capacity, or both.

Diurnal changes in plasma and liver lipids and lipoprotein lipase activity in heart and adipose tissue in rats fed a high and low fat diet.

In order to evaluate a) the respective roles of adipose and muscle lipoprotein lipase (LPL) in the clearing of alimentary lipemia and b) the role of the resulting nonesterified fatty acids (NEFA) in controlling hepatic ketogenesis and liver triglyceride content, a number of parameters related to lipid metabolism were studied over the 24 hour period (the dark period being from 1930 to 0730 hours), in rats ad libitum fed either a low-fat (LF) or a high-fat (HF) diet containing respectively 1.1% and 41.5% lard. During spontaneous feeding (from 1500-1800 hours onwards), LPL activity in LF rats increased in adipose tissue and decreased in heart; in rats fed the HF diet for 3 weeks, the postprandial rise in adipose LPL was smaller and there was no decrease in heart LPL before 2100 hours. In HF rats, unlike the LF, feeding resulted in a large increase in circulating NEFA and total ketone concentrations, an increase in liver beta-hydroxybutyrate dehydrogenase activity, and a decrease in hepatic triglyceride content. The findings clearly indicate that in HF rats, muscle LPL controls the postprandial rise in plasma NEFA concentrations, which in turn appear to determine the extent of ketonemia and liver triglyceride changes. The possible control of these metabolic events by insulin is discussed.

Lipoprotein lipase activity at onset of development of white adipose tissue in newborn rats.

The low triacylglycerol concentration in inguinal tissue of newborn rats did not change during the first 6h after birth, despite the relatively high lipoprotein lipase activity in the tissue. Subsequently triacylglycerol concentration and enzyme activity rose in parallel. The results show that lipoprotein lipase activity was present in the tissue before fat accumulation.

Metabolism of the mouse made obese by a high-fat diet.

Lean mice were made obese by feeding, ad libitum, a high-lard diet. They showed an increased fat cell size and number which were maintained when this diet was replaced by the control high-carbohydrate diet for 10 weeks. Obese fed mice showed normal glucose and insulin serum levels, but insulinaemia was elevated after an overnight fast. The insulinaemic response after intraperitoneal injection of glucose was insignificant. Thus hyperinsulinism is not a prerequisite for the development of obesity. High-fat diet influenced, in vitro, glucose metabolism of adipose tissue, liver and muscle: basal lipogenesis was markedly reduced in adipose tissue and liver, and glucose oxidation was decreased in muscle. Insulin sensitivity was reduced by increased fat cell size. De novo formation of fatty acids in liver and adipose tissue did not contribute to the development of obesity. The increased lipoprotein lipase activity of the large fat cells suggested that obesity resulted from a direct storage of dietary fatty acids esterified by glycerol formed from circulating glucose.

Adipose-tissue lipoprotein lipase activity and cellularity in the genetically obese Zucker rat (fa-fa).

The lipoprotein lipase activity per adipocyte was increased in the genetically obese rat (fa/fa). However, there was no difference between obese and lean animals when the enzyme activities were related to adipocyte surface area. The possible implications of the findings are discussed.