Biomedical subjects

S K Fried

Publications and source records attributed to S K Fried.

49 records · Page 3Linked to original sources

PubMed1989

Cachectin/tumor necrosis factor decreases human adipose tissue lipoprotein lipase mRNA levels, synthesis, and activity.

The effects of the cytokine cachectin/tumor necrosis factor (TNF) on human adipose tissue lipoprotein lipase (LPL) were studied. TNF is produced by activated macrophages and is thought to play a role in mediating hypertriglyceridemia and wasting of adipose tissue triglyceride stores (cachexia) that often accompany infection and malignancy. TNF effects were studied in human adipose tissue fragments maintained in organ culture in the presence of insulin and dexamethasone to induce high LPL activity. Addition of TNF to the culture medium for 20 h caused a dose-dependent inhibition of LPL activity to an average of 37% of controls at 50 U/ml TNF. This inhibition of LPL activity was explained by specific decreases in levels of LPL mRNA (to 40% of controls) and rates of LPL synthesis determined by biosynthetic labeling and immunoprecipitation (to 32% of controls). The decline in LPL synthesis was specific, as it occurred despite a small increase in overall protein synthesis in the presence of TNF. Comparable decreases in LPL activity were observed when TNF was added to adipose tissue cultured solely in the presence of insulin. Thus, similar to results in rodent models, TNF is a potent inhibitor of LPL gene expression in human adipose tissue. TNF may therefore play a role in the disorders of triglyceride catabolism and the pathogenesis of cachexia that occur with stimulation of the immune system in humans.

Adipose Tissue↗

PubMed1987

Adipose tissue of morbidly obese patients: clinical implications of distribution, morphology, and metabolism.

As a consequence of their increased total adipose tissue mass, morbidly obese patients have many more fat cells than individuals of normal weight and the cells are enlarged compared to normal. Contrary to earlier beliefs, fat cell numbers can increase throughout adult life. Once formed, fat cells do not undergo involution. Thus, it seems that an individual who has reached the morbidly obese state maintains an increased amount of body fat that limits his/her ability to achieve and maintain commonly accepted levels of "ideal" body weight. Recently the distribution of adipose tissue has been shown to be an important predictor of obesity-associated morbidity and mortality in large population studies. A "male" or central distribution of fat is a significant risk factor for the development of diabetes, hyperlipidemia, hypertension, and coronary heart disease. Sex- and site-specific variations in the distribution of adipose tissue cell size and metabolic activity have been demonstrated that may be of etiologic importance for the development of serious comorbid conditions in obesity.

Adipose Tissue↗

PubMed1987

Insulin binding and glucose transport in adipocytes of acarbose-treated Zucker lean and obese rats.

The intestinal glucosidase inhibitor acarbose was administered as a dietary admix (30 mg/100 g chow diet) to male Zucker obese and lean rats. After 15 weeks, epidiymal fat pads were removed and adipocytes isolated by collagenase digestion. Equilibrium binding of A-14 tyrosine 125I-insulin, and transport of U-14C-glucose was determined was adipocytes incubated for 50 min at 37 degrees C in 0-16000 pM insulin. Insulin binding/cell was enhanced two-fold in lean (P less than 0.01) and obese (n.s.) drug groups. In drug-treated leans, increased sensitivity of glucose transport to submaximally stimulating concentrations of insulin was observed (P less than 0.02). For both genotypes, acarbose mildly decreased insulin levels and body weight gain, although adipocyte size was unaffected. Results indicate that enhanced insulin binding accompanies metabolic improvements induced by acarbose in lean Zucker rats.

Acarbose↗

PubMed1987

Sex differences in regional distribution of fat cell size and lipoprotein lipase activity in morbidly obese patients.

Adipose tissue distribution is an important predictor of obesity-associated morbidity and mortality. A central ('male') fat distribution is associated with increases in intra-abdominal adipose tissue which might be of metabolic importance. Although many recent studies have pointed out significant regional differences in the size and metabolism of subcutaneous fat cells intra-abdominal depots have not been systematically examined. We compared fat cell sizes (FCS) and lipoprotein lipase activity (LPLA) of two internal (omental, mesenteric) and four subcutaneous (SQ) sites (femoral, gluteal, abdominal, epigastric) in morbidly obese patients (26 premenopausal women and 14 men). Men had larger internal FCS than women while women had larger SQ FCS in the gluteal and femoral depots. Mesenteric FCS were largest of all sites in men. In women, omental fat cells were the smallest of all sites sampled but omental fat cells were as large as SQ sites in men. A more central distribution of fat in women (high waist/hip ratio) was associated with large mesenteric fat cells. Calculation of total fat cell number based on SQ FCS only, revealed sex differences that were eliminated by also using intra-abdominal FCS in the calculation. Averaged across all six sites, women had higher LPLA than men. Higher LPL activities were found in the lower-body subcutaneous sites with enlarged fat cells in women. However, the relative enlargement of intra-abdominal FCS in men was not associated with increased LPLA. In conclusion, sex- and site-specific variations in the distribution of FCS and LPLA in internal and SQ fat depots emphasize the importance of analyzing these depots in studies of fat cell number and adipose tissue metabolism.

Adipose Tissue↗

PubMed1986

Lipoprotein lipase secretion from isolated rat fat cells of different size.

Lipoprotein lipase(LPL) release from isolated small fat cells from young rats and large fat cells from older, fatter rats was compared during in vitro incubation at 30 degrees C. Although large fat cells had nearly three times higher cellular LPL activity, they secreted similar amounts of LPL activity into the incubation medium under both basal conditions (Krebs Ringer bicarbonate buffer containing 4% albumin and 6mM glucose) and after stimulation of LPL release by 5% human serum, or serum plus 1 U/ml heparin. These data suggest that previous observations of an altered tissue distribution of LPL in adipose tissue containing large fat cells can be at least in part explained by an alteration at the level of LPL secretion.

Adipose Tissue↗

PubMed1984

Effects of fasting and restricted refeeding on utilization of ingested energy in rats.

Ingested metabolizable energy was partitioned into 3 components--storage, cost of storage, and maintenance--to study energy utilization during 20 days of refeeding following a 3-day fast in adult male Wistar rats. During the refeeding period, one experimental group was refed ad libitum, whereas two others were restricted to approximately 75 and 50%, respectively, of prefast food intake. Energy utilization in the experimental groups was compared with that in nonfasted controls. Energy conservation occurred in all experimental groups during refeeding, and the primary form of that conservation was a decrease in the energy required for maintenance. The decreased requirement for maintenance allowed a greater proportion of ingested energy to be used for restoration of carcass energy. The degree of energy conservation was, in general, proportional to the degree of food restriction during refeeding.

Adipose Tissue↗

PubMed1983

Effects of a high-fat diet on energy intake and expenditure in rats.

The effects of a high-fat diet supplying a constant energy/protein ratio, with and without overeating, on energy intake and expenditure was studied in mature male rats. A control group (LF) received ad libitum access to a low-fat diet. Body weight gain, efficiency of food utilization, and dietary-induced thermogenesis were increased relative to controls in a group with ad libitum access to the high-fat diet (HF-A), but not in a group which was pair fed the diet (HF-P) in amounts (kcal) equal to that of LF animals. However, the individual variability within the HF-A group was high for each measure. An arbitrary separation of that group into 2 subgroups (based on high vs low weight gain) produced one subgroup with increased efficiency, greater weight gain and no change in dietary-induced thermogenesis (HF-AH), and another with no difference in efficiency or in weight gain from the LF group but which had higher dietary-induced thermogenesis (HF-AL). Food intake was slightly, but not significantly, greater for the HF-AH subgroup than for the HF-AL subgroup. We conclude that rats can increase thermogenesis in response to overeating but that the increase is highly variable. The thermogenic response appears to be related to the overeating rather than to the fat content of the diet.

Adipose Tissue↗

PubMed1983

Lactate release from isolated rat adipocytes: influence of cell size, glucose concentration, insulin and epinephrine.

Release of lactate was studied during in vitro incubations with isolated fat cells. Lactate release increased (approximately 3-fold) with increasing medium glucose concentration (from 3 to 12 mM) in both large and small fat cells. Large fat cells from older, fatter rats, however, released 3-4 times more lactate per cell than small fat cells from young rats when incubated with 3, 6 or 12 mM glucose. Insulin and epinephrine produced a marked stimulation of lactate release in small fat cells, but these hormones had no effect in large fat cells. Lactate accounted for only 10-15% of the glucose metabolized by small fat cells under all incubation conditions but was nearly 40% of glucose utilized by large fat cells at glucose concentrations greater than 6 mM. In conclusion, lactate is a major metabolite of glucose in adipocytes, particularly in the large fat cells. Adipose tissue may therefore be a major site of lactate production, particularly in states of altered glucose metabolism (i.e., hyperglycemia) and obesity.

Adipose Tissue↗

PubMed1983

Prolonged effects of fasting-refeeding on rat adipose tissue lipoprotein lipase activity: influence of caloric restriction during refeeding.

We studied lipoprotein activity in white adipose tissue of male rats during a 3-day fast and up to 21 days of refeeding. Changes in LPL were considered in relation to concomitant changes in fat cell size. During fasting fat cell size decreased and LPL activity declined markedly (80%). With ad libitum refeeding LPL activity returned to control values by 3 or 5 days of refeeding, increased above control values (60-100%) by 10 days of refeeding and returned to control values by 20 days of refeeding. The normalization and overshoot of LPL activity preceded and accompanied increases in fat cell size, which occurred between days 5 and 10 of refeeding; LPL activity returned to control values Only after fat cell size also returned to control values. Mild food restriction (approximately 25%) during refeeding allowed LPL activity to return to control values but reduced the magnitude and duration of the overshoot. Severe food restriction (approximately 50%) during refeeding delayed the return of LPL activity to control values until day 20 of refeeding. These data support a role for LPL in restoration of adipocyte lipid stores during refeeding. Food restriction during refeeding influences LPL and may modulate the rate of lipid accumulation by adipocytes during refeeding.

Adipose Tissue↗

PubMed1983

Novel regulation of lipoprotein lipase activity in rat brown adipose tissue: effects of fasting and caloric restriction during refeeding.

We studied the effects of a 3-day fast and 20 days of refeeding on lipoprotein lipase activity (LPL) in the interscapular brown adipose tissue (BAT) of sexually mature male rats. Rats were refed either ad libitum or restricted quantities (75 or 50% of normal ad libitum food intake). BAT-LPL, expressed on a per depot basis, decreased with fasting and returned to control values by day 3 of refeeding ad libitum. In contrast, refeeding restricted quantities for 5 to 20 days limited regain of body weight and increased BAT-LPL significantly above the values observed in rats refed ad libitum. These adaptations in BAT-LPL activity differ markedly from those observed in rat white adipose tissue or heart muscle and may serve to increase the supply of fatty acids from circulating lipoproteins for BAT metabolic needs and maintenance of thermogenesis during undernutrition.

Adipose Tissue, Brown↗

PubMed1982

Variations of glucose metabolism by fat cells from three adipose depots of the rat.

Fat cells isolated from the epididymal (E) and dorsal subcutaneous (S) depots from 150g male Wistar rats were similar in size, but differed markedly in glucose metabolism. Retroperitoneal (RP) fat cells were slightly larger but were metabolically similar to epididymal fat cells. Basal incorporation of [1-14C] glucose into fatty acids was lower in S than E and RP, CO2 production and glyceride-glycerol synthesis were similar in all three; and lactate production was increased in RP and S compared to E. S adipocytes exhibited a blunted respond to both submaximally and maximally-stimulating concentrations of insulin compared to RP and E adipocytes in glucose incorporation into fatty acids, CO2 and lactate production, but not glyceride-glycerol. Maximally insulin-stimulated fatty acid synthesis by S fat cells was 19% and 29% of the values in E and RP fat cells respectively. Basal and maximally insulin-stimulated glucose transport (2-deoxy [14C] glucose uptake) was depressed by 30%-40% in S cells compared to E and RP. Thus, the decreased basal glucose utilization of S could be attributed primarily to a decreased glucose transport capacity. The markedly lower insulin-stimulated glucose metabolism in S fat cells, however, may be explained by alterations of the capacities for both transport and intracellular metabolism. Subcutaneous fat cells were also somewhat less sensitive to submaximal doses of insulin and this was reflected in rightward shift in the dose-response curves for 2-deoxyglucose uptake and fatty acid synthesis. The decreases in insulin stimulated glucose oxidation and fatty acid synthesis were paralleled by decreases in the major lipogenic enzymes. Although the reason for these variations in the capacity for glucose metabolism among depots is unknown, they are important in assessing the metabolic function of the whole adipose organ.

Adipose Tissue↗

PubMed1981

Role of fatty acid synthesis in the control of insulin-stimulated glucose utilization by rat adipocytes.

A decreased capacity for fatty acid synthesis is associated with a decreased insulin effect on glucose metabolism in large fat cells and fat cells from rats fed a high-fat diet. We have investigated the relationship between these processes by specifically inhibiting fatty acid synthesis with (-)-hydroxycitrate (2.5 mM), an inhibitor of citrate cleavage enzyme, and cerulenin (0.05 mM), an inhibitor of fatty acid synthetase. (-)-Hydroxycitrate and cerulenin decreased maximally insulin-stimulated fatty acid synthesis from [6-(14)C]glucose to 10% and 25% of controls, respectively, while only (-)-hydroxycitrate decreased basal values. Oxidation of [1-(14)C]glucose in the presence of insulin was markedly depressed by each inhibitor. Thus, the percent increase over basal value was decreased from 540% in controls to 151% and 154% by (-)-hydroxycitrate and cerulenin, respectively. In contrast, oxidation of [6-(14)C]glucose was slightly enhanced by both inhibitors. Thus, oxidation of glucose via the pentose shunt was reduced, while Krebs cycle oxidation was unaffected. Basal and insulin-stimulated incorporation of [1-(14)C]glucose and [6-(14)C]glucose into glyceride-glycerol and basal lactate production was unchanged by the inhibition of fatty acid synthesis. Insulin-stimulated lactate production was halved by the inhibition of fatty acid synthesis. Total glucose utilization, as assessed by measuring the disappearance of glucose from the medium, was not detectably changed by inhibiting fatty acid synthesis under basal conditions, but insulin-stimulated values were decreased to 52% and 64% of control by (-)-hydroxycitrate and cerulenin, respectively. This occurred despite the fact that neither agent affected the initial rate of 2-deoxyglucose uptake, or glucose-6-phosphate dehydrogenase or 6-phosphogluconate dehydrogenase activities. These data therefore provide direct evidence that a limitation of the fatty acid synthetic pathway decreases the ability of insulin to stimulate both pentose shunt glucose oxidation and overall glucose utilization, but not Krebs cycle oxidation or glyceride-glycerol synthesis. The enzymatic capacity of the fat cell for fatty acid synthesis is therefore an important determinant of insulin-stimulated glucose utilization.-Fried, S. K., M. Lavau, and F. X. Pi-Sunyer. Role of fatty acid synthesis in the control of insulin-stimulated glucose utilization by rat adipocytes.

Adipose Tissue↗

PubMed1979

Mechanism of insulin resistance in adipocytes of rats fed a high-fat diet.

Insulin's ability to stimulate glucose metabolism is severely diminished in the adipose tissue of rats fed a high-fat diet as compared to that of rats fed a low-fat diet. To elucidate the mechanism for this effect we have measured the binding of insulin, the hormone effect on 2-deoxyglucose uptake and the major pathways of [1-(14)C]glucose metabolism, and the activity of lipogenesis-related enzymes in adipocytes of rats fed a low- or high-fat diet for 7 days. Rats fed high- or low-fat diets bound equal amounts of insulin per adipocyte at all insulin concentrations tested. Basal and maximally insulin-stimulated 2-deoxyglucose uptake per fat cell were reduced in high-fat-fed rats. However, the insulin stimulation over basal was the same in both groups (230%). Submaximal doses of insulin produced equivalent increments of 2-deoxyglucose uptake in both groups, as would be predicted by the binding studies. The effect of both submaximal and maximal insulin concentration on the labeling of CO(2) and fatty acids was markedly decreased by high-fat feeding. The insulin response of the glyceride-glycerol pathway was less severely, though significantly, reduced. Acetyl CoA carboxylase and malic enzyme in adipocytes of high-fat-fed rats were reduced to 13% of the activity in the low-fat-fed rats. Glucose-6-phosphate and 6-phosphogluconate dehydrogenases were decreased to 20% and 34% of their activities in low-fat-fed rats, respectively. These reductions paralleled the changes in insulin-stimulated glucose oxidation and fatty acid synthesis. The data therefore strongly suggest that the blunted response of glucose metabolism to insulin in adipocytes of high-fat-fed rats is a result of a decreased intracellular capacity to utilize glucose for lipogenesis.

Adipose Tissue↗