Interdependent effects of thyroid hormones and cAMP on lipolysis and lipogenesis in the fat cell.
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In order to estimate the possible changes of the functional state of beta-adrenergic receptors during ontogenesis, the lipid mobilizing effects of isoprenaline (ISO), adrenaline (ADR) and noradrenaline (NA) were studied in trimmed subcutaneous adipose tissue of rats at different stages of postnatal development (5, 14, 21 and 35 days after birth. The release of free acids (FFA) into the incubation medium was measured after addition of increasing concentrations of catecholamines and the dose-response curves were evaluated. In all the studied age groups, ISO produced the highest maximum effect and had the greatest potency. The calculated pD2 values indicate the same potency order ISO much greater than NA = ADR in all age groups and they also demonstrate that there exist no appreciable differences in the affinity single catecholamines at different stages of postnatal development. In comparison with all the other groups, the intrinsic activity of the studied adrenomimetics was relatively low in 14-day-old rats.
We report on clinical and metabolic studies of a newly delineated lipomatosis, characterised by an abnormal mediastinal and abdominal accumulation of fat, without obesity. The clinical features, which occurred in all the patients studied, are: Exertional dyspnoea due to a space-occupying mediastinal accumulation of fat, without evidence of cardiac or pulmonary disease. A pseudo-ascitic abdominal enlargement, due to intra- and retroperitoneal accumulation of fatty tissue. Insulin-independent diabetes mellitus. Type IV hyperlipidaemia and elevated levels of plasma uric acid were observed in four patients. Intra-abdominal lipomatous tissue, obtained during laparoscopy from four patients, demonstrated a reduced lipolytic response to beta-adrenergic stimulation. Thus, fat deposition in the abdominal and mediastinal areas could be causally related to defective lipid mobilization in lipomatocytes. Lipoprotein lipase activity in abdominal adipose tissue were normal in two patients (10.0 and 10.6 nmol/g/min) and markedly elevated in another two patients (37.3 and 49.9 nmol/g/min), as compared with controls (12.7 +/- 2.1 nmol/g/min). When expressed on per cell basis, LPL activity in lipomatous tissue was significantly higher than in control tissue (3.21 +/- 1.1 nmol/10(5) cell/min vs 0.92 +/- 0.16 nmol/10(5) cell/min). Lipoprotein fractionation did not demonstrate consistent modification of the serum lipoprotein pattern. HDL and HDL2 cholesterol values were reduced, even in patients with elevated LPL activity in adipose tissue.
We investigated the effect of intravenous infusions of aminophylline on plasma glucose and nonesterified fatty acid (NEFA) levels in 14 newborns with apnea (mean birthweight: 2.514 +/- 866 g; mean gestational age: 34.8 +/- 3.94 weeks). Theophylline apparent volume of distribution was 0.55 liters per Kilogram and the half-life was major than 12 hours. It was found that theophylline caused pronounced and prolonged lipid mobilization, as measured by the plasma NEFA. The ability of theophylline to induce a rapid rise in blood glucose was confirmed. Elevation in plasma NEFA might be an important factor in facilitating the competition with bilirubin for binding sites of albumin and the development of arrythmias in newborns with acute myocardial injury.
In order to estimate the relationship of the adipokinetic effect of morphine (MO) to adrenergic-mediated lipolysis the interaction between MO and isoprenaline (ISO) was studied in epididymal adipose tissue of rats and perirenal adipose tissue of rabbits. Two preparations of adipose tissue (AT)-trimmed tissue and fat cells (FC)-were used. Increment of non-esterified fatty acids (NEFA) release into the medium during 90 min of incubation was the measure of lipolysis. In rats, especially in FC, MO stimulated NEFA release up to 900% of basic values and also in rabbits the lipid-mobilizing action of MO was found as high as 320% of the non-stimulated level. The net increase due to MO expressed as % of maximum lipolysis induced by ISO was fluctuating between 30-50% except rat FC, where MO reached almost the level of ISO maximum effect. The calculated pD2 values of MO were in FC of both species 5.8, in trimmed AT 5.1 (rats) and 5.3 (rabbits). Different concentrations of MO (1-100 mumol/l) did not significantly alter the concentration-response adipokinetic curve of ISO. Naloxone in concentrations of 1 and 10 mumol/l did not exert any antagonistic action in MO-induced lipolysis. The MO effect is most probably not mediated via adrenergic receptors; the possibility of opiate receptor involvement has not been excluded. Pronounced species differences between rats and rabbits in sensitivity to the lipolytic morphine effect were observed.
Lipoprotein lipase activity in lipomatous tissue, post-heparin lipoprotein lipase activity in plasma, and the composition and concentration of serum lipoproteins were studied in 15 patients with Multiple Symmetric Lipomatosis (MSL). Extremely elevated lipoprotein lipase activity in adipose tissue was found in MSL patients. Total and hepatic post-heparin plasma lipolytic activity was normal, while a moderate but statistically significant increase of extrahepatic lipolytic activity was present. An abnormal composition of serum lipoproteins, characterized by a significant increase in high density lipoproteins, namely HDL2 subfraction, and apoprotein A-I, was demonstrated. A concomitant decrease in and abnormal composition of low density lipoproteins were found. This lipoprotein pattern is consistent with a newly recognized type of hyperalphalipoproteinemia. Significant correlations were found between serum HDL2 cholesterol values and lipoprotein lipase activity in adipose tissue (as well as between serum VLDL-triglyceride and HDL2 cholesterol values). These observations confirm the role of adipose tissue lipoprotein lipase in triglyceride-rich lipoprotein catabolism. The elevated levels of lipoprotein lipase activity in adipose tissue, in addition to a previously demonstrated decrease in adrenergic-stimulated lipid mobilization, could account for both the abnormal fat accumulation in lipomatous fat cell and for hyperalphalipoproteinemia in MSL patients. The occurrence of MSL in two brothers suggests an inherited enzymatic defect, indicating MSL as a "triglyceride storage disease in adipose tissue".
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The effects of strenuous exercise on serum electrolytes, blood metabolites, and serum enzymes were studied in a group of 13 horses participating in a 50-mile endurance ride. Blood samples were collected before, during, and at the end of the ride, as well as 1 hour and 16 hours after the completion of the ride. There were significant changes in these values when preride values were compared with those of samples taken at different sample-collection periods. Significant (P less than 0.001) decreases were observed in serum concentrations of chloride, potassium, and calcium. A significant increase in the serum concentration of phosphorous also was observed. The mean concentrations of chloride and calcium remained significantly reduced in the 16-hour postride sample. A small, but significant (P less than 0.05), increase in sodium and decrease in glucose concentrations were observed at the midride sample. Although midride samples did not reflect a significant change in blood pyruvate concentration, a significant (P less than 0.05) increase was observed at the end of the ride. Changes in the hematocrit and the total protein concentration were statistically significant at levels of P less than 0.001 and P less than 0.01, respectively. The horses showed highly significant increases in concentrations of free fatty acids, serum enzymes (P less than 0.001), and lactate (P less than 0.005) during the ride. The elevated values of creatine kinase and lactic dehydrogenase decreased, while the aspartate aminotransferase values remained increased long after completion of the ride. The lactate and free fatty acids, which rose significantly during the ride, decreased to approximately preride values by 16 hours after the ride was completed. We conclude that the changes in serum electrolytes, enzymes, and blood metabolites reflect the sweating, muscle damage, and increased dependency on anaerobic glycolysis and lipid mobilization that these horses experienced during the competitive endurance ride.
It was shown that the multifold increase of intermediate products of lipids peroxidation, their hydroperoxides, and terminate products of this process, Shiff's bases, occurred in rats with experimental myocardial infarction both in the ischemic and in nonischemic zones. Simultaneously the activity of antioxidant enzymic systems reduced in the myocardium; the superoxydismutase and catalase activities decreased insignificantly and the glutatione peroxidase activity was 2-fold decreased. The preliminary adaptation of the animals to the periodic action of hypoxia itself did not influence the antioxidant systems of the organism but it significantly decreased the accumulation of the lipids peroxidation products and the size of ischemic necrosis. It is suggested that the protective effect of the adaptation of hypoxia during the heart ischemic damage is realized not by the increase of the antioxidant systems activity but by the change in the membrane lipid composition.
The author carried out a dynamic study on the metabolic changes in liver under the influence of nicotinic acid, administered singly by intramuscular injection in a dose of 2mM/kg of body weight. She examined at the 1th, 3th, 6th and 24th hour the changes in the levels of nicotine-amide coenzymes (NAD, NAD-H and NADP), adenine nucleotides (ATP, ADP and AMP), the metabolic lactate and pyruvate and the enzymes LDH, MDH, GOT and GPT. The obtained data were compared with those of the control groups, treated with saline and killed at the same intervals as the experimental animals. Furthermore she made also a comparison with an intact group, presented as O group, whose values served as basal. The obtained data showed that after application of the nicotinic acid (NA) complex metabolic changes occurred in liver, due to its basic effects-stimulation of biosynthesis of nicotinamide coenzymes and inhibition of lipolysis in the fatty tissue. Most probably the effect on the biosynthesis of NAD was primary, which showed later substantial regulatory influence both on lipolysis in the fatty acid and on the metabolization of mobilizing lipids on behalf of the liver. Parallel occurring metabolic processes in the aorta and in the vascular wall in general, stimulation of the biological oxidation and bioenergetics formed the whole antilipolytic and antiarteriogenic action of nicotinic acid.
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In an experiment comparing pregnant then lactating mares with dry non-pregnant mares, the changes in plasma components were studied as indicators of the metabolic utilization of energy (glucose, non-esterified fatty acids, beta-hydroxybutyrate), nitrogen (urea, proteins) or minerals (calcium, phosphorus, magnesium). The mares were fed daily 2 kg concentrate and hay ad libitum. Beta-hydroxybutyrate, magnesium and to a lesser extent glucose were the only constituents whose levels were affected within the period starting one month before and ending one month after foaling. The increase in food intake between late pregnancy and early lactation may be explained by an increase in nutrient requirements, since plasmatic levels of non-esterified fatty acids and urea, known to be indicators of body lipids mobilization and nitrogen status respectively, remained constant.
Obesity is the common expression of several diverse interacting genetic, familial and environmental factors. In addition to having hypertrophic fat cells because of inordinate triglyceride accumulation, many patients with childhood-onset obesity and those who are massively obese regardless of age at onset have an excessive number of adipocytes. Several endocrinologic and metabolic abnormalities are associated with obesity. Triglyceride formation in and lipid mobilization from hypertrophic adipocytes are exaggerated. The increased availability of free fatty acids to the liver contributes to the excessive synthesis of triglycerides and very-low-density lipoproteins; thus, hypertriglyceridemia is frequently associated with obesity. Hepatic synthesis and biliary excretion of cholesterol are also increased. Most of the excess cholesterol is stored in fat cells. The plasma concentrations of high-density lipoproteins are decreased. Hyperinsulinemia, which is characteristically found in the obese, leads to a decreased number of insulin receptors in target cells. The relative insulin insensitivity of the obese frequently results in glucose intolerance. The endocrinologic and metabolic abnormalities are correctable by an appropriate program of meal planning and physical activity.
1-O-Hexadecyl-2-O-pyrenedecanyl-sn-glycero-3-phosphocholine, a non-hydrolyzable fluorescent diether analog of phosphatidylcholine (PC), was synthesized as a probe for studying phospholipid transfer to different lipoprotein classes with potential phospholipase activities. After incubation of total human plasma with the new probe at 37 degrees C for 4.5 h, a characteristic partition between the main lipoprotein fractions was observed. The fluorescent lipid was not degraded under these conditions and, therefore, served as a measure for choline glycerophospholipid distribution between plasma lipoproteins. In low density lipoprotein (LDL) and high density lipoprotein-3 (HDL3) the fluorescent PC analog showed only monomer fluorescence, whereas in Lp[a] and HDL2 monomer and excimer fluorescence were observed, indicating that the fluorescent phosphatidylcholine analog was incorporated into the respective lipoproteins to a different extent. According to the increased pyrene excimer fluorescence in Lp[a] compared with LDL the labeled phosphatidylcholine must be enriched and/or clustered in Lp[a]. Data from phospholipid and total fluorescence analyses are compatible with the assumption of higher label concentration in Lp[a]. On the other hand, transfer rates for serum protein-catalyzed lipid transport into isolated Lp[a] were slower as compared to LDL. It is suggested that slower lipid transfer to Lp[a] under these conditions is due to the decreased lipid mobility in the Lp[a] surface, whereas the higher extent of label partition into Lp[a] as observed in total plasma might be due to the higher affinity of apolipoproteins for phosphatidylcholine in Lp[a] (Sommer, A., et al. 1992. J. Biol. Chem. 267: 24217-24222). The use of a fluorescent dialkyl- instead of diacyl-glycerophosphocholine for transfer studies was mandatory, as we found that lipoproteins contained phospholipase A2 activity toward long-chain phosphatidylcholine. The lipoprotein-associated phospholipase A2 was three times more active in Lp[a] than in LDL. The degradation products formed by the phospholipase, fatty acids, and lyso-PC may add to the high atherogenic potential of Lp[a].
The authors studied disturbances of lipid clearance in cases of aseptic osteonecrosis of the femoral head by means of an induced intravenous hyperlipemia test. With reference to investigations in 19 patients, the authors first draw attention to the frequency of ethylism and of fatty degeneration of the liver (13 patients). A significant decrease was noted in the coefficient of lipid clearance in the 19 patients. This was particularly marked when fatty degeneration of the liver was present. The etiological role of these anomalies should be considered, as fatty degeneration and hyperlipaemia may also be found in other pathological conditions responsible for primary osteonecrosis of the femoral head (corticotherapy).
Diabetes mellitus is usually recognized as a major risk factor for coronary heart disease (CHD) morbidity and mortality. As chronic hyperglycaemia defines diabetes mellitus, it is logical to think that hyperglycaemia itself is related to these complications. But, in diabetic patients, there appears to be no relation between CHD and the specific characteristics of diabetes, namely the duration of the disease and the level of blood glucose. Moreover, in the UGDP trial, the group of patients with the best-controlled glycaemia failed to demonstrate a reduction in CHD death, in comparison with the group with poor blood-glucose control. These results are reinforced by the data from 15 prospective studies, which failed to demonstrate a homogeneous and significant increase in CHD risk with asymptomatic hyperglycaemia. Coronary heart disease mortality depends on a constellation of risk factors which are interrelated to some extent; one of the risk factors, namely blood glucose, is not an independent risk factor, nor is diabetes mellitus. In patients with abnormal glucose tolerance, the factors contributing to CHD risk are hypertriglyceridaemia and also a central fat distribution. This central fat distribution could explain the low CHD risk in nondiabetic women, which contrasts with the high risk in diabetic women, who are characterized by central adiposity, as are diabetic men. Björntorp hypothesized that intra-abdominal fat, which has an exceedingly sensitive lipid mobilization capacity, could play a key role in the development of the cluster of metabolic abnormalities that are present in the plurimetabolic syndrome. Hyperglycaemia, one of the anomalies of the syndrome, could be an 'innocent bystander' rather than a 'partner in crime', in the manifestations of CHD.
Results derived from animal experimentation depend to a considerable degree on the health and welfare of the animal from which the results are obtained. This, in turn, reflects the quality of housing, care, and nutrition provided the animal. Most diets designed for a particular species provide a reasonable balance of nutrients in quantities sufficient for normal growth and maintenance and reproduction of that species. Under usual conditions of animal feed manufacture, however, concentrations of essential ingredients may vary appreciably in different batches of a formulation made with different lots of natural ingredients, even though the guaranteed analysis shown on the label remains correct. A feed may also contain intentional or unintentional additives and other biologically active components. Variations in the concentrations of essential dietary components, as well as the presence of extraneous materials, can significantly influence the performance of an experimental animal consuming the diet and can thus lead to a biased interpretation of esperimental results. Investigators must consider factors which can result in efficient or inefficient utilization of energy, the variation in prepared diets whether from natural or purified products, and how these can modify the animal and change the response to a given experimental regimen. Proteins, fat, carbohydrates, vitamins, and minerals can all have pharmacological as well as physiological effects on a biological system. The control of vitamin D metabolism and calcium, parathormone, calcitonin among others are important factors subject to dietary modification. A conditioned marginal or frank deficiency of folic acid can result from oral contraceptives and administration of anticonvulsants; if studies are done in animals using these types of chemicals, dietary folate will be highly significant. Newer information about the role of ascorbic acid in activation of lipase and lipid mobilization is of direct concern to those using research animals requiring a source of dietary ascorbic acid. Trace elements, some amino acids, natural enzyme inducers, and toxic contaminants, all of which can affect the response of experimental animals, are highly important to the quality of animal research in pharmacologic investigations.
The effect of progesterone on lipolysis in blood and in adipose tissue of female rats has been investigated. The hormone was administered to the studied animals subcutaneously during 20 days. The lipid mobilizing activity was determined in blood serum according to the four experimental protocols: test serum--test tissue, test serum--control tissue, control serum--test tissue, and control serum--control tissue. Blood serum concentrations of triglycerides, free fatty acids and glucose, as well as lipolytic activity against exogenous substrate, were determined in addition. Progesterone administration was found to enhance the activity of factors potentiating lipolysis in adipose tissue of female rats after 20 days administration of the hormone. There was an increase in free fatty acids, triglycerides and glucose concentrations. Progesterone was found not to change the activity of factors influencing lipolysis in the blood of female rats during the period of administration of the hormone.