Biomedical subjects
X Remesar
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Leptin: an annotated addendum.
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Short-term handling of the slimming agent oleoyl-estrone in liposomes (Merlin-2) by the rat.
Female adult rats were injected in the jugular vein with oleoyl-3H-estrone incorporated into liposomes. The label rapidly disappeared from the blood, being taken up by the tissues, mainly liver, spleen and lung, which filtered most of the label. However, many other tissues, such as the heart, brown adipose tissue, adrenals and visceral fat incorporated significant amounts of oleoyl-estrone. The analysis of the form in which the label remained 10 min after the injection showed that it was hydrolysed in a large proportion even in liver and lungs. However, in most tissues (brain, brown and white - periovaric - adipose tissues and ovaries), intact oleoyl-estrone accounted for less than one quarter of all tissue label, and less than 10% in the case of subcutaneous adipose tissue and uterus. This rapid destruction of oleoyl-estrone is in agreement with the active role of this compound in the control of body weight.
Carbohydrate handling in exercising muscle of obese Zucker rats.
OBJECTIVE: To determine the differential substrate utilization of substrates by exercising muscle and in the fatigued state in lean and obese rats. DESIGN: The rats were treadmill-exercised until fatigued, when their oxygen consumption increased by 1.85 x factor. Blood and hind leg tissue (muscle and skin) were sampled at intervals during exercise and recovery. SUBJECTS: Lean and obese adult Zucker female rats. MEASUREMENTS: Three series of rats were used to determine hind-leg glucose, lactate and oxygen arterio-venous balances, blood flow and muscle levels of glucose, hexose-P, glycogen, lactate and skin lactate. The rates of glycosyl unit flow during exercise and recovery were then calculated. RESULTS: In obese rats, exercising muscle showed higher glucose uptake, increased glycogen mobilization and lower lactate production than in the lean. In the obese rats' muscle, there were more glycosyl units available for oxidative metabolism. Excess glycosyl (or 3C) units were used probably for lipid synthesis. Lean rats managed their glycosyl units more efficiently, stretching the available glycogen, thus prolonging the exercise. During recovery, obese rats massively synthesized glycogen and lowered lactate efflux, which left only a few glycosyl units to oxidative metabolism; probably the rest of oxidative energy was derived from lipids. CONCLUSION: In lean rats glucose is the main source of muscle energy during exercise and recovery, whereas obese rats use glucose during exercise, and probably synthesize lipid during exercise. Obese rats rely more on lipids for energy during recovery.
Regulation of ammonia-metabolizing enzymes expression in the liver of obese rats: differences between genetic and nutritional obesities.
OBJECTIVE: To determine the expression of carbamoylphosphate synthetase (CPS) and glutamine synthetase (GS) in two different models of obese rats: genetically obese rats and diet obese rats. SUBJECTS: Lean and genetically obese (fa/fa) Zucker rats were used. DESIGN: Lean animals (30-60 d old) were fed for 30 d with standard chow pellets or with a hypercaloric cafeteria diet. Genetically obese rats were fed with standard chow pellets. MEASUREMENTS: Enzyme activity, protein (Western blot) and mRNA (Northern blot) contents of CPS and GS were measured in liver homogenates. RESULTS: In genetically obese animals CPS mRNA content was higher, and GS mRNA content was lower than in control animals; CPS protein content did not change and CPS activity was lower than in control rats. Diet-obese rats had higher levels of CPS and GS mRNAs than control animals; GS protein content and activity was higher than in the control group and at the same time, CPS activity was very low. CONCLUSIONS: In the genetically obese animals the expression of CPS and GS is mainly regulated at the pre-translational level, whereas in the diet obese rats there is a noticeable post-translational component. A reciprocal regulation between CPS and GS can be established at pre-translational levels, whereas at post-transcriptional levels it cannot. It can be concluded that in diet-obese animals the mechanisms involved in retaining nitrogen (low CPS activity) are modulated at the post-translational level.
Muscle amino acid pattern in obese rats.
OBJECTIVE: To determine how the ability of skeletal muscle to manage amino acids is conditioned by obesity. The test was performed in two different models of obese rats: diet-obese rats and genetically obese rats. SUBJECTS: Lean and genetically obese (fa/fa) male Zucker rats were used. DESIGN: For up to 60 d of life lean animals were fed with standard chow pellet or with a hypercaloric cafeteria diet. Genetically obese rats were fed with standard chow pellet during the same period. MEASUREMENTS: Amino acid concentration in the femoral artery and vein and leg blood flow were measured. Free amino acid concentration, protein and nitrogen content and enzyme activities were determined in whole leg muscle. RESULTS: Amino acid availability was increased in diet-obese animals and remained unchanged in the genetically obese group. The genetically obese groups had a lower protein content and unchanged concentration of amino acids in leg muscle. Furthermore, total nitrogen remained unchanged in these animals and they showed an increased activity in alanine aminotransferase and glutamine synthetase. The leg muscle of the diet-obese rats took up several amino acids (Ala, Arg and Val) or released others (mainly Gln and Gly). Conversely, genetically obese rats took up many amino acids and did not release any. CONCLUSIONS: We conclude that in nutritionally obese rats there is an increased availability of amino acids in skeletal muscle. This augmented availability propitiates the increase in the uptake of many amino acids. In genetically obese rats, the lack of variation in amino acid availability points to a possible hereditary alteration that increases the capacity of different amino acid transport systems. Furthermore, the diminished protein content of fa/fa muscle is not due to a lower availability and intracellular pool of amino acids.
Effect of the slimming agent oleoyl-estrone in liposomes on the body weight of Zucker obese rats.
OBJECTIVE: To determine whether the mechanisms by which estrone acyl-esters carried by lipoproteins induce the loss of body fat can affect Zucker fa/fa rats, since they are hyperphagic and could not eliminate excess energy through thermogenesis, two aspects essential for the slimming effect of oleoyl-estrone in normal rats. DESIGN: The rats were infused for 28 d (osmotic minipumps) with oleoyl-estrone in liposomes (Merlin-2) at a dose of 3.5 mmol/day.kg. SUBJECTS: Lean (L) and obese (O) Zucker rats. MEASUREMENTS: Body weight changes. Oxygen consumption, body composition (water, lipid, protein), nitrogen balance, plasma chemistry. RESULTS: Treatment resulted in loss of body weight: 12.0% (28 g) L, 9.4% (34 g) O, mainly due to fat: 37.5% (10.8 g) L, 11.7% (15.5 g) O and water, preventing further increases in body weight and fat storage. Untreated rats increased their body weight: 10.5% (24 g) L, 32.2% (101 g) O and lipid stores: 20.3% (5.9 g) L, 39.8% (49.0 g) O, making the differences more marked. On day 28, glucose levels were maintained in all groups; in L, triacylglycerols increased and total cholesterol decreased; O showed no changes in plasma composition. In all rats, food intake decreased with treatment, and heat production (oxygen consumption) was unchanged (L) or slightly decreased (O). Energy expenditure per unit of fat-free mass remained unchanged. Protein balance was maintained in all groups; slimming was achieved without loss of body protein. CONCLUSION: Treatment of genetically obese rats with oleoyl-estrone in liposomes (Merlin-2) results in sustained loss of body weight-mainly lipid, sparing protein-for up to 28 d, essentially preventing further increase in body weight and accumulation of lipid and protein. This is achieved through lower food intake and relatively small changes (if any) in energy expenditure.
Amino acid nitrogen handling by hind leg muscle of the rat during exercise.
The arterio-venous differences and balance of amino acids across the hind leg of rats were measured during an intense bout of exercise in a treadmill, as well as in the subsequent recovery period. The size and composition of muscle amino acid pool were also determined using another series of animals. Finally, the amino acid composition of hind leg protein was determined and computed. During intense exercise and recovery, the muscle was a net contributor of amino acids to the bloodstream, the rates being higher during exercise than in recovery. This efflux was not only due to changes in pool size, but implied the hydrolysis of protein, in the range of 20-25 micrograms.min-1.g-1 during exercise. Branched chain amino acids were metabolized during exercise, but mainly during recovery. During exercise, there was also an increase in alanine and glutamine pool buildup and efflux. In conclusion, the data presented show that protein--and amino acid--metabolism in the exercising muscle are not as dormant as usually accepted, because branched chain amino acids are actively oxidized and the efflux of alanine, glutamine and other amino acids is maintained thanks to the net hydrolysis of protein.
Effect of the slimming agent oleoyl-estrone in liposomes on the body weight of rats fed a cafeteria diet.
Weaned lean Zucker rats, 21-days old, were fed a cafeteria diet for 70 days. The cafeteria diet-obese rats were infused for 28 days (using miniosmotic pumps) with oleoyl-estrone in liposomes (Merlin-2) at a dose of 3.5 mmol/day.kg. Treatment resulted in loss of body weight: 11.6% (32 g), mainly due to fat: 20.0% (8.8 g), protein 5.2% (2.0 g) and water, preventing further increases in body weight and fat storage. Untreated rats increased their body weight: 7.6% (20 g), lipid: 10.5% (4.2 g) and protein: 13.2% (4.8 g). Plasma glucose, urea, triacylglycerols and cholesterol practically did not change with treatment. Merlin-2 decreased energy intake (to 83.7%) and energy output (to 87.7%, oxygen consumption). Decreases in nitrogen intake were partly compensated by higher digestive efficiency in treated rats. The size of the nitrogen gap was higher in treated rats than in controls. Essentially, protein balance was maintained and slimming was achieved with a minimal loss of body protein. Treated rats selected less carbohydrate, in particular sugars, in their diet than controls, but consumed practically the same protein and lipid. Treatment of cafeteria diet-fed rats with oleoylestrone in liposomes results in sustained loss of body weight--mainly lipid--for up to 28 days. Nitrogen balance is maintained overall. This is achieved through lower food intake--mainly of sugars--and less marked changes in energy output.
Rats receiving the slimming agent oleoyl-estrone in liposomes (Merlin-2) decrease food intake but maintain thermogenesis.
Oleoyl-estrone given i.v.--incorporated in liposomes to mimic lipoprotein delivery--(Merlin-2) to normal weight rats, induces a dose-dependent weight loss. Analysis of body composition showed that body protein concentration was preserved and fat stores wasted. The respiratory quotient was consistent with the massive oxidation of body fat, since the diet contained practically no lipid. Appetite was affected by Merlin-2, and thus food intake showed a transient decrease. But oxygen consumption (and basal metabolic rates) was kept practically unchanged at the levels of the controls, i.e. higher than needed to oxidize the food ingested during the weight loss period. Brown adipose tissue uncoupling protein levels were proportionally preserved with a 2-week treatment, but it lost a substantial amount of lipid. In conclusion, Merlin-2 is a slimming agent with considerable potential given its powerful fat-wasting action, since it maintains thermogenesis despite lowered energy intake.
Carbohydrate handling in the hind leg muscle of exercising rats.
The arterio-venous concentrations of oxygen, glucose and lactate, as well as blood flow and muscle levels of lactate, glucose, hexose-phosphates and glycogen of rat hind leg muscle were determined under basal conditions and under mild and intense exercise, as well as during post-exercise recovery. During intense exercise and fatigue glycogen is practically exhausted, providing glycosyl residues to the hexose-phosphates pool in addition to increased glucose uptake from the blood. The result is the production of huge amounts of lactate, which accumulates in muscle and the skin, and buildup the arterial concentrations. During recovery lactate is slowly disposed of, and the muscle takes up large amounts of glucose which is stored into glycogen, with fully reinstated glucose oxidation. The data shown suggest that the shift from oxidative to mainly anaerobic utilization of glucose is not as streamlined as is usually assumed, since the results found here hint at the wasteful utilization of glycogen-derived hexose skeletons for other synthetic pathways. Glucose, nevertheless, is of paramount importance as energy staple to sustain untrained intense exercise in the rat.
Amino acid metabolism in the kidneys of genetic and nutritionally obese rats.
The ability of the kidney to take up and/or release amino acids has been determined in two models of obesity in Zucker rats, one genetic and the other nutritional (diet-obese). There was a noticeable increase in gluconeogenic amino acids in the arterial blood of diet-obese animals whereas the genetically obese rats showed small variations in the levels of these amino acids. There were significant decreases in renal Gly and Ser, only in the genetically obese rats. Genetically obese animals showed an increase in Glutamine synthetase activity. The uptake and/or release of amino acids showed important variations between the groups. The diet-obese group exhibited greater variation, since this group took up Glu, Ala, Gy, Phe and Citrulline and released Gln, Ser, Arg and Tyr. Genetically obese rats took up Gln, His and Taurine and released Ser. These different patterns may be related to variations in the whole body metabolic rate, since the diet-obese group was more active than the genetically obese group.
3-Hydroxybutyrate co-infused with noradrenaline decreases resulting plasma levels of noradrenaline in Wistar rats.
Pentobarbital-anaesthetized male Wistar rats were infused with 6microgkg-1min-1 of noradrenaline. The infusion was supplemented with 8.5 mgkg-1min-1 of D-3-hydroxybutyrate (3-OHB) for 15 min in order to determine its effect on the adrenergic response of the rat. Plasma levels of noradrenaline rose to a plateau of approximately 50 nmoll-1 with infusion. In the group infused with noradrenaline alone, noradrenaline levels were maintained for 1h. Supplementation with 3-OHB induced a decrease in plasma noradrenaline level that was inversely correlated with 3-OHB level. Aortic and interscapular brown adipose tissue temperatures increased with noradrenaline infusion, but the rise was arrested by 3-OHB; replacing 3-OHB with glucose had no effect. Infusion of saline, glucose or 3-OHB in the absence of noradrenaline did not induce a rise in temperature in either tissue. Blood 3-OHB concentration increased to 1.2 mmoll-1 during 3-OHB infusion, decreasing rapidly at the end of infusion. Blood glucose levels increased with noradrenaline infusion; the presence of high 3-OHB levels decreased glucose concentration. The effects observed were transient and dependent on 3-OHB concentration; these effects may help explain most of the other effects of noradrenaline described here. The role of 3-OHB as a regulator of adrenergic responses seems to be part of a complex fail-safe mechanism which prevents wasting.
Muscle blood flow during intense exercise in the obese rat.
Tissue blood flow has been measured in Zucker lean and obese rats during treadmill exercise and later recovery, by using a fluorescent-dyed latex microsphere method. The procedure used allowed up to six different timed blood flow measurements in the same animal. Exercise resulted in grossly increased muscle blood flow, compensated by lowered intestinal and liver irrigation. At the onset of fatigue, and during early recovery, liver portal blood flow increased in detriment of muscle. Obese rats showed a similar pattern, but their intestinal and hepatic blood flow was maintained during recovery, in contrast with lean rats. In obese - but not in lean - rats, skin blood flow increased in post-exercise recovery to disposal of excess heat hampered by blubber insulation. Metabolic inability to recover markedly affects post-exercise haemodynamics in Zucker obese rats, thus prolonging the consequences of fatigue.
3-Hydroxybutyrate decreases noradrenaline affinity for rat erythrocyte ghost beta 2-adrenergic receptors.
The effects of physiological levels of 3-hydroxybutyrate on noradrenaline binding to rat erythrocyte membranes were studied. The binding of noradrenaline to membranes was determined by measuring the union of 3H-noradrenaline in the presence of varying concentrations of 3-hydroxybutyrate. Scatchard plots of the results were used to determine that 3-hydroxybutyrate provoked a loss of affinity of the beta 2-adrenergic receptors for adrenaline. Thus high (but physiological) 3-hydroxybutyrate levels can lower the binding of the catecholamine, thus diminishing the extent or intensity of adrenergic-driven responses.
Oleoyl-estrone induces the loss of body fat in rats.
OBJECTIVE: Four experiments were devised to test the possible role of estrone fatty esters as adipose tissue signals carried by the blood within lipoproteins. DESIGN: Oleoyl-estrone was synthesized and incorporated in liposomes; it was administered i.v. (to mimic lipoprotein delivery) for 14-day periods using implantable osmotic minipumps. The study included the finding of oleoyl-estrone in blood lipoproteins, the correlations of the effects of body weight to the dose and the uptake of labelled oleoyl-estrone by tissues, its internalization and disposal. SUBJECTS: Normal-weight Wistar female rates were used. Pooled human blood was used as source of HDL3. MEASUREMENTS: Oleoyl-estrone was identified in rat white adipose tissue and in human blood HDL3 lipoprotein fraction. Changes in body weight, food intake, oxygen consumption, respiratory quotient and nitrogen balance were measured in chronically injected rats. The uptake and hydrolysis of oleoyl-estrone by tissues was also determined following its acute administration. RESULTS: Oleoyl-estrone induced a dose-dependent loss of weight, with decreased food intake. In 14 days, and compared with controls at the end of this period, a dose of 0.78 mumol/day induced the loss of 16.4 +/- 5.5% of body weight; the difference was maximal for doses of 15 mumol/day or higher: 24.7 +/- 3.1%. Under oleoyl-estrone treatment, body protein was preserved (positive nitrogen balances) and fat stores were wasted: lowered respiratory quotient, and deficit in energy balance; a dose of 0.78 mumol/day induced the loss of 9.6 +/- 2.2 g of total body lipids in 14 days. Most of oleoyl-estrone taken up by tissues was hydrolysed; however, in part it reached intact the cell nucleus of incubated adipocytes. Oleoyl-estrone effects were different from those of free estrone. CONCLUSION: A lipophilic pathway for oleoyl-estrone transport by lipoproteins is postulated, allowing chemical communication between tissues. Oleoyl-estrone may be directly involved in the control of body weight.
Brown adipose tissue temperature in lean and obese rats during exercise.
OBJECTIVE: To determine the extent to which brown adipose tissue (BAT) heat output is influenced by treadmill exercise. DESIGN: The aortic blood core and interscapular BAT temperatures were recorded continuously during a short bout of intense exercise (different for each rat stock) in a treadmill and the ensuing 1-h recovery, sampling blood flows at timed intervals. SUBJECTS: Conscious Wistar, Zucker lean and Zucker obese rats. MEASUREMENTS: Aortic and interscapular BAT temperatures and tissue blood flow. RESULTS: Basal mean temperatures were highest for Wistar. Exercise provoked increases in aortic core temperatures in all three groups, slowly cooling off during recovery. Exercise and/or fatigue induced increases (vs aortic core temperature) of IBAT temperature. The effects were less marked in obese rats. CONCLUSION: Increases in BAT temperatures induced by exercise were counteracted by parallel decreases in blood flow, resulting in insignificant losses of heat from intarscapular BAT during exercise and recovery both in lean and obese rats.
Adipose tissue extraction of circulating insulin in anaesthetized Zucker obese rats.
OBJECTIVE: To determine whether adipose tissue removes a significant proportion of circulating insulin in the obese rat in vivo. DESIGN: Blood samples were obtained from the carotid artery and the venous side of hind leg muscle, epididymal fat pads and liver (portal and suprahepatic veins), they were used for estimation of insulin disappearance across the tissue. SUBJECTS: Anaesthetized Zucker lean (Fa/?) and obese (fa/fa) adult male rats. MEASUREMENTS: Blood flow, glycaemia and insulinaemia. RESULTS: In lean rats, the liver accounted for practically all insulin extraction (498 +/- 149 fmol.s-1), removing more than half of the portal insulin in a single pass. In the obese rats, the liver extracted a similar amount in absolute terms (397 +/- 108 fmol.s-1), representing only 16% of portal insulin. In the hind leg muscle of both groups and in the adipose tissue of lean rats, insulin balances were not different from zero; but in obese rats, adipose tissue extracted a similar amount of insulin (405 +/- 127 fmol.s-1) to that removed by the liver. CONCLUSIONS: In the Zucker obese rat, peripheral adipose tissue removes as much insulin from the blood as the liver does, in contrast with lean rats, in which the latter is responsible for practically all insulin extraction.