oleoyl-estrone and Body-Weight

Oleoyl-estrone (OE) induces a marked loss of body fat in rats by maintaining energy expenditure, body protein and blood glucose despite decreasing food intake. OE increases glucocorticoids, but they arrest OE lipid-mobilization. We studied here whether OE induces a direct effect on adrenal glands function as part of this feedback regulation. Dietary overweight male rats were given oral 10nmol/g OE gavages for ten days. A group (PF) of pair-fed to OE rats, and controls received vehicle-only gavages. OE rats lost slightly more body than PF, but had larger adrenal glands. Tissue corticosterone levels, and gene expressions for glucocorticoid-synthesizing enzymes were increased in OE versus controls and PF; thus, we assumed that adrenal growth affected essentially its cortex since OE also lowered the expression of the medullar catecholamine synthesis enzyme genes. Serum corticosterone was higher in PF than in OE and controls, but liver expression of corticosteroid-disposing steroid 5alpha-reductase was 3x larger in OE than PF and controls. Circulating glucocorticoids changed little under OE, in spite of higher adrenal gland and liver content, hinting at modulation of glucocorticoid turnover as instrumental in their purported increased activity. In conclusion, we have observed that OE considerable enhanced the expression of the genes controlling the synthesis of glucocorticoids from cholesterol in the rat and increasing the adrenal glands' corticosterone, size and cellularity, but also the liver disposal of corticosteroids, suggesting that OE increases corticosterone synthesis and degradation (i.e. serum turnover), a process not driven by limited energy availability but directly related to the administration of OE.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Adrenal Cortex Hormones; Adrenal Glands; Animals; Body Weight; Cholesterol Side-Chain Cleavage Enzyme; Corticosterone; Estrone; Gene Expression Regulation, Enzymologic; Glucocorticoids; Liver; Male; Molecular Weight; Oleic Acids; Organ Size; Overweight; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Steroid 11-beta-Hydroxylase; Steroid 21-Hydroxylase

To determine whether treatment of rat dams with oleoyl-estrone (OE) has an effect on the offspring's long-term response to diet restriction during lactation.. Control, OE-treated, and diet-restricted dams were treated up to day 15 of lactation. Changes in food intake and body weight were recorded for dams and their pups. After weaning, pups received a 4-week standard diet followed by a 4-week period of high-fat diet. Lipid, protein, and energy content of pups plus energy intake and efficiency. Serum metabolites (glucose, urea, and cholesterol) and serum hormones (adiponectin, leptin, insulin, and sexual hormones).. Neither pups from dams in the OE-treated nor in the diet-restricted group showed significant changes in weight, though these two groups ingested 79% of food ingested by controls. At weaning, the pups from OE-treated rats were smaller than those of the control or diet-restricted groups. These pups maintained the differences in size and lipid content during the 4-week standard-diet period, whereas pups from diet-restricted dams showed a sharp decrease in their lipid content. During the 4 weeks of high-fat diet, the male offspring from OE-treated dams increased the difference in lipid content in relation to the pups from control dams whereas in females the differences decreased. Female offspring from diet-restricted dams showed the most marked changes in metabolite and hormone levels in relation to controls.. Treatment of lactating dams with OE programs the metabolic response of their offspring to resist the challenge of a high-fat diet that would lead to obesity in adulthood.

Topics: Aging; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Caloric Restriction; Dietary Fats; Eating; Estrone; Female; Lactation; Lipid Metabolism; Male; Maternal Nutritional Physiological Phenomena; Milk; Obesity; Oleic Acids; Pregnancy; Rats; Rats, Wistar; Time Factors

Low-dose oral oleoyl-estrone (OE) (i.e. in dairy products) is hydrolysed to estrone, which promotes growth and fat deposition. However, pharmacological doses of OE are absorbed largely intact and elicit fat losses. Thus, in order to find out how the intestine handles OE, esterase activity (at pH 5, 7 or 8) was measured in rat stomach, duodenum, jejunum, ileum, cecum, large intestine, and liver using OE as substrate. There were no sex-related differences. Pure pancreatic cholesterol-ester esterase hydrolysed OE even in the absence of taurocholate. The differences in the pH-related activity distribution pattern and selective inhibition and taurocholate dependence show that, in addition to the luminal (i.e. pancreatic) cholesterol-ester esterase, other esterases hydrolyse OE; these combined activities may be sufficient to rapidly dispose of pharmacological doses of OE. Female rats received a tritium-labeled OE gavage; the luminal and tissue label content were measured up to 24 h. The high retention of label in the stomach suggest that this may be a significant site of absorption. The rapid decrease of label in intestinal lumen (and rat tissues) shortly after the administration, hint at rapid absorption and disposal. In conclusion, the high OE-esterase activity and early absorption of OE are indicative of upper gastro-intestinal tract absorption skipping most of the medium-tract esterases.

Topics: Animals; Body Weight; Cholesterol Esters; Estrone; Female; Intestinal Absorption; Intestinal Mucosa; Intestines; Male; Oleic Acids; Rats; Rats, Wistar; Sex Characteristics; Sterol Esterase; Swine; Time Factors; Tissue Distribution

To determine the effects of oleoyl-estrone treatment on the lactating dams and on the growth pattern of developing rats, female Wistar rats were randomly divided into two groups after delivery. One group received a daily gavage of 0.2 mL sunflower oil containing 10 micromol oleoyl-estrone/kg (treated group) and the other received a daily intragastric gavage of 0.2 mL sunflower oil (control group). Treatment was carried out during the first 15 days of lactation. Dams were killed on days 1, 15 or 20 after delivery and pups were sacrificed on days 1, 15, 20 or 30. Treated dams showed a transient decrease in food intake, significant lower lipid content than control dams, with a parallel maintenance of protein content and no appreciative changes in plasmatic parameters. However, a significant increase in brown adipose tissue mass was detected in treated group. Pups from treated dams showed a decrease in their growth rate that was reflected in the lower adipose tissue mass in different locations, except in the case of brown adipose tissue and, that continued after cessation of treatment. Thus, treatment affects dams in a selective way that does not coincide with a simple food restriction model.

Topics: Adipose Tissue, White; Animals; Animals, Newborn; Anti-Obesity Agents; Body Composition; Body Weight; Eating; Estrone; Feeding Behavior; Female; Growth and Development; Growth Disorders; Lactation; Male; Oleic Acids; Rats; Rats, Wistar

Short-term OE (oleoyl-estrone) treatment causes significant decreases in rat weight mainly due to adipose tissue loss. The aim of this work was to determine if OE treatment affects the expression of genes that regulate lipid metabolism in white adipose tissue.. Gene expression in adipose tissue from female treated rats (48 hours) was analysed by hybridization to cDNA arrays and levels of specific mRNAs were determined by real-time PCR. Treatment with OE decreased the expression of 232 genes and up-regulated 75 other genes in mesenteric white adipose tissue. The use of real-time PCR validate that, in mesenteric white adipose tissue, mRNA levels for Lipoprotein Lipase (LPL) were decreased by 52%, those of Fatty Acid Synthase (FAS) by 95%, those of Hormone Sensible Lipase (HSL) by 32%, those of Acetyl CoA Carboxylase (ACC) by 92%, those of Carnitine Palmitoyltransferase 1b (CPT1b) by 45%, and those of Fatty Acid Transport Protein 1 (FATP1) and Adipocyte Fatty Acid Binding Protein (FABP4) by 52% and 49%, respectively. Conversely, Tumour Necrosis Factor (TNFalpha) values showed overexpression (198%).. Short-term treatment with OE affects adipose tissue capacity to extract fatty acids from lipoproteins and to deal with fatty acid transport and metabolism.

Topics: Adipose Tissue; Animals; Biological Transport; Body Weight; Carnitine O-Palmitoyltransferase; Estrone; Fatty Acids; Female; Gene Expression Regulation; Lipid Metabolism; Oleic Acids; Rats

To determine whether or not the long-term intermittent treatment with oleoyl-estrone (OE) in rats induces a cumulative weight loss, adult male rats were treated with OE over three alternating 10-day periods, with a 30-day "recovery" period occurring between each period. At the end of the third treatment period, the rats were allowed to recover and were then mated with females. Each treatment period produced a decrease of ca. 7% in body weight with no rebound during the recovery periods, whereas weight changed at the same pace in controls. The greatest difference in body weight was observed during the last days of treatment. OE-treated rats retained their initial protein pools throughout the treatment. Furthermore, treated and control males remained fertile and were able to procreate. Thus, we can conclude that intermittent OE treatment induces a cumulative weight loss in adult male rats.

Topics: Adipose Tissue; Administration, Oral; Animals; Anti-Obesity Agents; Body Composition; Body Weight; Dietary Fats; Dose-Response Relationship, Drug; Drug Carriers; Energy Intake; Energy Metabolism; Estrone; Male; Obesity; Oleic Acids; Rats; Rats, Zucker; Time Factors; Weight Loss

Oral treatment with oleoyl-estrone induces the loss of body fat and improvement of insulin resistance. Since cholesterol levels are deeply affected by oleoyl-estrone, we investigated here whether short-term treatment affected cholesterol turnover and overall metabolite changes.. Wistar female rats received a single oral dose of 10 mumol/kg oleoyl-estrone in 0.2 ml of sunflower oil. Groups of animals were killed at timed intervals and blood samples were taken. In a second experiment series, rats had implanted carotid and jugular cannulas and were given a single gavage of oleoyl-estrone. These rats were used for the measurement of the cholesterol turnover rate.. Body weight change and food intake: Glucose, total and HDL-cholesterol, triacylglycerols, 3-hydroxybutyrate, nonesterified fatty acids, insulin, HOMA score in the rats of the first series. Cholesterol: Cholesterol pool changes and cholesterol turnover rates in the rats of the second series.. OE induced early effects, decreasing food intake, cholesterol and HDL-cholesterol levels, and increasing insulin sensitivity (HOMA score). OE also increased cholesteryl-ester turnover, and decreased circulating total cholesterol, especially esterified cholesterol pools.. The role of early changes in insulin sensitivity induced by oral OE cannot explain per se the deep changes in cholesterol handling, essentially a consequence of accelerated lipoprotein turnover. However, the increase in cholesteryl-ester turnover observed with OE treatment may be, at least in part, a consequence of the decrease in insulin resistance. The compounded effect of increased insulin sensitivity and accelerated lipoprotein turnover may help explain the early and marked hypocholesterolaemic effects of OE.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Cholesterol; Cholesterol, HDL; Drug Administration Schedule; Eating; Estrone; Female; Insulin; Lipids; Oleic Acids; Rats; Rats, Wistar

We studied the combination of oleoyl-estrone with either dexfenfluramine, sibutramine or phentermine in overweight male rats treated for 10 days in order to determine whether they shared a mechanism of action. Oleoyl-estrone, dexfenfluramine and sibutramine decreased body weight and energy (essentially lipids); losses were higher when combined with oleoyl-estrone. Glycemia was maintained except under phentermine; oleoyl-estrone induced decreases in triacylglycerols, cholesterol, insulin and HOMA (homeostasis model assessment). Combination of oleoyl-estrone and sibutramine resulted in the loss of up to 29% body energy in 10 days. Energy expenditure was maintained. The effects of oleoyl-estrone and dexfenfluramine or sibutramine on appetite were substantially additive. All oleoyl-estrone-treated rats showed increased insulin sensitivity. In conclusion, combined treatment of overweight rats with oleoyl-estrone and sibutramine or dexfenfluramine results in a dramatic loss of weight and fat, whilst maintaining circulating energy homoeostasis.

Topics: Animals; Anti-Obesity Agents; Body Weight; Cyclobutanes; Dexfenfluramine; Drug Interactions; Drug Therapy, Combination; Energy Metabolism; Estrone; Insulin; Lipids; Male; Obesity; Oleic Acids; Phentermine; Rats; Rats, Wistar

Spontaneously hypertriacylglycerolemic obese and diabetic inbred IIM Beta rats were treated with oleoylestrone for 10 days. Pair-feeding was performed to determine some oleoyl-estrone effects dependent on the caloric restriction it promotes. Twenty-five 200 day-old Beta males receiving a daily gavage of 0.2 ml sunflower oil were divided into the following groups: 1) daily dose of 10 nmol/g oleoyl-estrone; 2) pair-fed; 3) control. The variables measured were: whole body protein, water and lipid; retroperitoneal and epididymal fat depot weights; plasma urea, glucose, insulin, triacylglycerols and cholesterol. Biomass and food intake were assessed daily. Oleoyl-estrone and pair-fed groups expressed similar variations in body composition and significant body weight losses due to reduction in food intake. Oleoyl-estrone and pair-fed treatments significantly reduced retroperitoneal fat depot weights, but not epididymal ones. In oleoyl-estrone and pair-fed groups hyperglycemia decreased and insulinemia lowered significantly. Plasma normal total cholesterolemia and hypertriacylglycerolemia values typical of Beta rats decreased strongly compared to controls, though attaining significantly different values between oleoyl-estrone and pair-fed groups. Plasma total cholesterol appeared as more sensitive to caloric restriction than triacylglycerols through a specific oleoyl-estrone-mediated effect.

Topics: Animals; Anti-Obesity Agents; Body Weight; Caloric Restriction; Cholesterol; Diabetes Mellitus, Type 2; Eating; Estrone; Male; Obesity; Oleic Acids; Rats; Rats, Inbred Strains; Triglycerides; Weight Loss

Oleoyl-estrone is a powerful, slimming adipose tissue-derived signal that has biological effects widely opposed to those of its estrone moiety. The present experiment was designed to determine whether oleoyl-estrone effects on body energy are mediated by the estrogen receptor, blocked with the antagonist tamoxifen. Male Wistar rats were given daily oral doses of 10 micromol/kg d of oleoyl-estrone in oil containing 0 or 0.40 mg/kg d of tamoxifen. The data were compared with controls receiving only oil or 50 nmol/kg d of free estrone. After 10 days, the rats were killed, and their body composition and plasma metabolites and hormones were analyzed. Rats receiving estrone increased their body energy and lipid content compared with controls. Both groups of oleoyl-estrone-treated rats lost body weight, energy, and lipid; the losses in the rats receiving tamoxifen alone were less marked than in those receiving oleoyl-estrone. No significant changes in plasma glucose or triacylglycerols were observed. The patterns of change of estrone sulphate, estradiol, and oleoyl-estrone were consistent with a noticeable hydrolysis of oleoyl-estrone. The lack of differences in the fat mass in oleoyl-estrone-treated rats irrespective of the presence of tamoxifen suggested that the estrogenic pathway was not responsible for the slimming effects observed. Thus, it can be concluded that oleoyl-estrone effects are not mediated through its conversion to estrone or estradiol acting through the estrogen receptor. Tamoxifen partly mimicked the slimming effects of oleoyl-estrone; this could be speculatively explained by tamoxifen acting through the oleoyl-estrone signalling pathway.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Composition; Body Weight; Energy Intake; Energy Metabolism; Estradiol; Estrogen Antagonists; Estrone; Lipid Mobilization; Male; Oleic Acids; Rats; Rats, Wistar; Receptors, Estrogen; Tamoxifen; Triglycerides

To measure acyl-estrone levels in the plasma of Zucker obese rats. If these are lower than expected on the basis of their body-fat content, as observed in morbidly obese humans, this might provide a possible link relating obesity and low body estrone levels. We also examined the effect of pharmacological treatment with oral oleoyl-estrone on the accumulation of estrone.. Undisturbed Wistar, Goto-Kakizaki and Zucker (lean Fa/?and obese fa/fa) rats were used to determine the relation between circulating acyl-estrone and body lipids, as well as the total body estrone/lipid ratios. One group of Wistar rats was used to measure the effect of oral gavages of oleoyl-estrone (from 0 to 20 micromol/kg/day) for 10 days on the body content of estrone.. Body weight change and food intake. Total estrone intake, estrone accrual and excretion (by difference) in rats receiving oleoyl-estrone. Total body lipid and estrone. Circulating acyl-estrone levels.. In lean rats (Wistar, Zucker and Goto-Kakizaki) there was a direct relation between body lipid content and circulating acyl-estrone; this relation was not found in Zucker obese rats. The estrone/lipid mass ratio was in a similar range in lean rats, but obese animals showed much lower values. Wistar rats receiving pharmacological doses of oleoyl-estrone did not accumulate significant amounts of estrone, but excreted almost all the estrone ingested.. The pharmacological administration of acyl-estrone to rats does not result in the accrual of estrone within a wide range of doses, which confirms the safety of this compound. In rats there is a similar relation between the percentage of body lipids and circulating acyl-estrone to that found in humans. Likewise, obese rats showed lower levels of acyl-estrone than expected. The total content of estrone in the bodies of obese rats was also lower than expected from their high lipid content, which suggests that obese rats are deficient in acyl-estrone.

Topics: Adipose Tissue; Animals; Body Weight; Eating; Estrone; Female; Male; Obesity; Oleic Acids; Rats; Rats, Wistar; Rats, Zucker

We studied the effects of a 10-day oral 10 micromol/kg oleoyl-estrone (OE) treatment on streptozotocin-diabetic Wistar, Goto-Kakizaki and control Wistar rats. Streptozotocin rats lost more than half the energy ingested as urine glucose. Oleoyl-estrone induced the loss of body weight (mainly body fat) in all groups. Energy expenditure was similar in the three groups of rats studied. Water turnover was deranged in streptozotocin rats, which spent 14% of energy available heating the water drunk. Body lipids were highest in Goto-Kakizaki; lipid levels in streptozotocin rats were very low. Oleoyl-estrone decreased body lipid content in Wistar and Goto-Kakizaki; oleoyl-estrone decreased triacylglycerols (44% in Wistar and Goto-Kakizaki and 22% in streptozotocin rats) and phospholipids but did not affect body cholesterol. Oleoyl-estrone decreased insulin and leptin, did not affect blood glucose but decreased plasma glucose in all groups. There were no changes in plasma triacylglycerols or fatty acids, but HDL, LDL and cholesterol decreased in all groups. The same effects of OE on insulin, plasma (but not blood) glucose and leptin were observed in both models, but the presence of insulin seems to be needed for OE to normalise glycaemia and to facilitate the uptake and utilisation of glucose by tissues. This different handling of glucose and triacylglycerol energy accounts for the disparate effects of OE on energy balance. The main conclusion of this study is that OE function as a lipid-mobilising hormone is dependent on the mass of reserves available, which in turn is closely related to insulin status. Lack of insulin thus results in limited OE effects, and insulin resistance does not prevent or limit the effects of OE on energy homeostasis or the mobilisation of fat.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Blood Glucose; Body Water; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Drinking; Energy Metabolism; Estrone; Glucose; Insulin; Leptin; Lipid Metabolism; Lipids; Oleic Acids; Rats; Rats, Inbred Strains; Rats, Wistar; Streptozocin; Urea

Oleoyl-estrone administration induces the rapid loss of fat preserving body protein.. We intended to check whether the fat-shedding effect of oleoyl-estrone arrests growth in young rats, limiting the buildup of protein and fat.. Oleoyl-estrone diluted in a powdered hyperlipidic diet (33 mumol/kg) was given for 30 days to 30-day old Zucker lean (Fa/?) rats. Their body weight and food consumption were followed daily; on day 30 of treatment (60-day old rats), whole body composition (lipid, protein) was determined, and plasma energy parameters and leptin were measured.. Oleoyl-estrone-treated rats grew more slowly than controls fed the hyperlipidic diet alone, and on day 60 their lipid content was about half that of controls. Protein content per kg was identical in both groups, but treated rats tended to accumulate less nitrogen and energy because of their smaller size. No changes in plasma glucose, urea, triacylglycerols or total cholesterol were observed, but oleoyl-estrone-treated rats showed lower circulating leptin than controls.. Despite limiting the accumulation of lipids, oleoyl-estrone slowed, but did not arrest growth of young rats, nor elicit a loss of fat or protein.

Topics: Animals; Anti-Obesity Agents; Body Composition; Body Weight; Energy Intake; Energy Metabolism; Estrone; Female; Growth; Leptin; Nitrogen; Oleic Acids; Rats; Rats, Zucker

To establish whether single daily oral doses of oleoyl-estrone result in dose-dependent slimming effects on normal weight rats, and to determine the changes in energy parameters induced by this treatment.. The effects of a daily oral gavage of oleoyl-estrone (0, 0.2, 0.5, 1, 2, 5, 10, and 20 micromol/kg per day) in 0.2 ml of sunflower oil given over a 10-day period were studied in groups, each of which contained six adult female Wistar rats initially weighing 190 to 230 g. A group of intact control rats receiving no gavage was included for comparison. Body weight and food intake were measured daily. Rats were killed on day 10 of treatment, and body composition (protein nitrogen, lipids, and water), liver lipids, and plasma parameters (glucose, triacylglycerols, total cholesterol, free fatty acids, 3-hydroxybutyrate, urea, aspartate, alanine transaminases, insulin, leptin, and free and acyl-estrone) were measured.. The administration of oleoyl-estrone resulted in a dose-dependent loss of body fat, because of a partly maintained energy expenditure combined with decreased food intake. The differences in the energy budget were met by internal fat pools. The changes recorded did not affect the levels of the main plasma energy homeostasis indicators: unaltered glucose, triacylglycerols, free fatty acids, 3hydroxybutyrate, and urea. Protein was accrued even under conditions of severe lipid store drainage. There were no changes in transaminases. No lipid accumulation was recorded in the liver. Plasma insulin and leptin levels decreased with increased oleoyl-estrone doses, whereas the levels of free and esterified estrone increased with treatment, although not in proportion to the dose received.. Oral treatment with oleoyl-estrone resulted in the specific dose-related loss of fat reserves with little change to other metabolic parameters. These results agree with the postulated role of oleoyl-estrone as a ponderostat signal.

Topics: Adipose Tissue; Administration, Oral; Animals; Anti-Obesity Agents; Body Composition; Body Weight; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Estrone; Female; Homeostasis; Lipid Metabolism; Oleic Acids; Rats; Rats, Wistar

This study was carried out to determine the effect of sex and oral administration of oleoyl-oestrone on body weight of 12-week-old female and male Zucker obese (fa/fa) rats initially weighing 350-380 g and 405-420 g, respectively. The rats were maintained in standard conditions and given a daily oral gavage of 0.2 ml oleoyl-oestrone dissolved in sunflower oil at a dose of 10 micromol/kg/day for 10 days, and their body weight and food intake was monitored. They were then killed, and their carcass composition (water, lipid, protein and total energy), liver lipids and glycogen and plasma chemistry, insulin, free and total oestrone were measured. Oral administration of oleoyl-oestrone via gavage resulted in significant losses of fat, energy and-ultimately-weight. Treatment with oleoyl-oestrone decreased food intake; the energy expenditure was kept close to that of controls at the expense of internal fat stores. Nevertheless, body protein and plasma metabolite homeostasis were preserved. The slimming effects were more marked in males than in females. Treatment increased circulating acyl-oestrone and reduced to normal levels the high insulin observed in controls. Treatment of genetically obese rats with a daily oral gavage of oleoyl-oestrone resulted in the loss of fat reserves with little modification of other metabolic parameters, except for lower plasma glucose and insulin levels. The results suggest that oleoyl-oestrone, in addition to its slimming effects may be effective as an antidiabetic agent in type 2 diabetes.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Body Weight; Drug Carriers; Eating; Estrone; Female; Intubation, Gastrointestinal; Male; Oleic Acids; Rats; Rats, Zucker; Sex Characteristics

Homozygous obese db/db (BKS-Lepr(db) and ob/ob (B6-Lep(ob)) mice were treated for 14 days with a continuous infusion of a fat emulsion (controls) or loaded with oleoyl-estrone at doses of 12.5 and 50 nmol/g x d using surgically inserted osmotic minipumps. Treatment with oleoyl-estrone resulted in a marked decrease in body weight in both strains, compared with the unchecked growth of controls. In db/db mice, plasma urea and insulin, as well as liver lipid decreased with treatment. In ob/ob mice, the effect on insulin was more marked, in parallel with higher plasma lipids pointing to increased fat mobilisation. The results suggest that oleoyl-estrone effects on body fat reserves and insulin resistance are not mediated by leptin, since ob/ob mice lack this hormone and in the db/db it is present but cannot induce effects because of defective leptin receptors; in both cases oleoyl-estrone treatment lowers body weight.

Topics: Animals; Anti-Obesity Agents; Body Weight; Estrone; Female; Insulin; Lipids; Mice; Mice, Obese; Oleic Acids

To test whether oleoyl-estrone affects body weight when given orally, which may help curtail the secondary growth-boosting effects of derived estrone.. The rats were fed for 15 days with a powdered hyperlipidic diet (16.97 MJ/kg metabolizable energy) in which 46.6% was lipid-derived and 16.1% protein-derived energy (HL group), containing 1.23+/-0.39micromol/kg of fatty-acyl esters of estrone. This diet was supplemented with additional oleoyl-estrone to produce diets with 2.5 micromol/kg (diet OE2.5), 4.4 micromol/kg (diet OE4.4), and 33.3 micromol/kg content in fatty-acyl estrone (diet OE33).. Twelve-week old female Zucker lean (Fa/?) rats initially weighing 200-235g.. Food intake and body weight changes; urine and droppings production and nitrogen content. Body composition (water, lipid, protein) and total energy. Energy and nitrogen balances. Plasma chemistry including free amino acids.. Oral administration of oleoyl-estrone in a hyperlipidic diet resulted in significant losses of fat, energy and, ultimately, weight, which were dependent on the dose of oleoyl-estrone ingested. Treatment induced the maintenance of energy expenditure combined with lower food intake, creating an energy gap that was filled with internal fat stores whilst preserving body protein. The decrease in food intake was not a consequence of food aversion but of diminished appetite. Energy expenditure was practically constant for all groups except for the OE33, which showed values about 25% lower than the controls. In most of the groups studied, there was a net protein deposition in spite of severe lipid and energy drainage. Amino acid levels agreed with this N-sparing shift. In spite of lowered energy intake, the N balance was positive or near zero in all groups, with a sizeable N-gap in controls and in lower-dose groups that disappeared in the OE33 group.. Treatment of rats with a hyperlipidic diet containing added oleoyl-estrone resulted in the dose-related loss of fat reserves with scant modification of other metabolic parameters and preservation of body protein. The results agree with the postulated role of oleoyl-estrone as a ponderostat signal and open the way for its development as anti-obesity drug.

Topics: Adipose Tissue; Administration, Oral; Amino Acids; Animals; Anti-Obesity Agents; Body Composition; Body Weight; Diet; Dietary Fats; Dose-Response Relationship, Drug; Energy Intake; Energy Metabolism; Estrone; Female; Nitrogen; Obesity; Oleic Acids; Proteins; Rats; Rats, Zucker; Time Factors

To determine whether the slimming effects of treatment with oleoyl-estrone (OE) in liposomes of normal and obese rats are permanent, or disappear as soon as the treatment with the drug ceased. This study was devised to gain further knowledge on the postulated role of OE as a ponderostat signal, evaluating whether (in addition) it can lower the ponderostat setting of the rat.. The rats were infused for 14d (using osmotic minipumps) with oleoyl-estrone in liposomes at a dose of 3.5 micromol/kg x d, and were studied up to one month after the treatment ceased.. Young adult lean controls (CL) or treated (TL) and obese controls (CO) or treated (TO) Zucker rats.. Energy balance, blood glucose, liver glycogen, plasma insulin, leptin corticosterone, ACTH and estrone (free and total) concentrations, and expression of the OB gene in white adipose tissue (WAT).. The loss of body weight caused by OE was recovered quickly in the TO, which gained weight at the same rate as the CO. TL rats, however remained at the low weight attained for one month after the treatment ceased. However, no differences were observed in calculated energy expenditure (EE) between the TL and TC rats once treatment had stopped. In TL and TO rats, liver glycogen concentrations decreased to normal shortly after treatment ceased, and leptin expression and concentrations remained normal and unchanged after the end of OE treatment. In TO rats, plasma glucose, insulin and leptin were lower than in the CO. Total estrone concentrations decreased rapidly in TL rats and more slowly in the TO, and free estrone followed a similar pattern.. Continuous infusion of liposomes loaded with OE resulted in a decreased energy intake (EI), maintenance of EE and the utilization of body fat reserves in lean and obese rats alike. This process ended in obese rats as soon as the infusion ceased, so that even when the levels of free and total estrone in plasma remained high, there was a marked (and relatively fast) shift toward the basal situation, which translated into an increase in EI, maintenance of estimated EE and a marked buildup of energy stores. In lean rats, the effects of OE on leptin concentrations and OB gene expression persisted after infusion ended.

Topics: Adrenocorticotropic Hormone; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Energy Intake; Energy Metabolism; Estrone; Female; Glycogen; Insulin; Leptin; Liposomes; Liver; Obesity; Oleic Acids; Proteins; Rats; Rats, Zucker; Urea

Female adult 9-week old Wistar rats were implanted with osmotic minipumps releasing for 14 days a liposome suspension (controls) loaded with oleoyl-estrone or other compounds of the Merlin series: estrone, estradiol, oleoyl-estradiol, oleoyl-DHEA, stearoyl-estrone, palmitoyl-estrone, oleoyl-diethylstilbestrol (DES), estrone oleoyl-ether and oleoyl-3-methoxy-estrone. All compounds were given at the same dose of 3.5 micromol/day x kg for 14 days. The effects on body weight and food intake were recorded. In the case of estrone esters, the body composition and nitrogen balance were also determined. The chronic administration of oleoyl-estrone in liposomes to rats lowers food intake, maintaining energy consumption, thus inducing the active utilization of internal stores and, consequently, the loss of body weight. This loss is mainly due to a decrease in fat, with lower proportional losses of water and a limited consumption of body protein. Free estrone had no effects on body weight, but estradiol did induce a decrease in body weight, similar to that of oleoyl-estradiol. Oleoyl-DHEA had no significant effect on body weight nor in food intake. Oleoyl-DES mimicked fairly well the effects of oleoyl-estrone, both affecting food intake and body weight. There was a relative lack of effects of estrone oleoyl-ether and of oleoyl-3-methoxy-estrone. The effects of oleoyl-estrone were in part mimicked by stearoyl- and palmitoyl-estrone, but their activity on a molar basis was lower, which suggests that the fatty acid moiety significantly influences the activity of the estrone ester as a slimming agent. The differences observed in the appetite suppression and overall slimming power of the stearoyl and palmitoyl-estrone clearly indicate that the sites of action of the physiological agonist oleoyl-estrone are at least two; the shape of the molecule, thus, may elicit a different degree of response of the systems controlled by oleoyl-estrone levels. From this interaction a series of global effects are elicited, such as appetite suppression and the loss of body (fat) weight, the latter in part (but not only) due to decreased food intake. The results shown here also suggest that the overall configuration of fatty acyl-estrone is more constrictive for its function as slimming agent than for its role as appetite suppressant, which hints to different target organs or sites of action endowed with receptors showing different degrees of fulfilling the structural constrictions of the a

Topics: Animals; Body Weight; Eating; Estrone; Female; Oleic Acids; Rats; Rats, Wistar; Structure-Activity Relationship

A group of female Zucker lean and obese rats was treated with 3.5 micromol/day kg of oleoyl-estrone in liposomes (OE) injected i.v. continuously for 14 days with inserted osmotic minipumps. Samples of liver were extracted on days 0, 3, 6, 10 and 14 and the expression of corticosterone-binding globulin (CBG) was determined by Northern blot. On the same dates, the total binding capacity of plasma, liver, periovaric white adipose tissue (WAT) and subcutaneous WAT was also determined using tritium-labelled corticosterone. Treatment with OE resulted in diminished CBG gene expression in the liver, this being more marked in the obese rats. Basal (time 0) corticosterone binding was higher in the plasma, liver and WAT of lean rats. Treatment with OE resulted in a gradual and general loss of binding capacity in the plasma and all tissues studied, for lean and obese rats alike. Since CBG decreases may result in enhanced glucocorticoid availability (and effects), the global decrease in corticosterone binding observed can be interpreted as a counteractive response to the energy imbalance elicited by OE.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Blotting, Northern; Body Weight; Corticosterone; Estrone; Female; Injections, Intravenous; Liposomes; Liver; Obesity; Oleic Acids; Ovary; Protein Binding; Rats; Rats, Zucker; RNA, Messenger; Transcortin

Female Zucker lean and obese rats were treated for 14 days with 3.5 micromol/kg oleoyl-estrone (OE) in liposomes (Merlin-2). After 0, 3, 6, 10, and 14 days of treatment, the rats were killed and hypothalamic nuclei (lateral preoptic, median preoptic, paraventricular, ventromedial and arcuate) were used for neuropeptide Y (NPY) radioimmunoassay. In 14 days, OE decreased food intake by 26% in lean and 38% in obese rats and energy expenditure by 6% in lean and 47% in obese rats; the body weight gap between controls and treated rats becoming -17.8% of initial b.wt. in the lean and -13.6% in the obese rats. Obese rats showed higher NPY levels in all the nuclei than the lean rats. Despite a negative energy balance and decreased food intake, there were practically no changes in NPY with OE treatment. The results indicate that oleoyl-estrone does not act through NPY in its control of either food intake or thermogenesis in lean and genetically obese rats.

Topics: Animals; Anti-Obesity Agents; Body Weight; Eating; Energy Metabolism; Estrone; Female; Hypothalamus; Neuropeptide Y; Obesity; Oleic Acids; Rats; Rats, Zucker

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.. 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.. Lean (L) and obese (O) Zucker rats.. Body weight changes. Oxygen consumption, body composition (water, lipid, protein), nitrogen balance, plasma chemistry.. 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.. 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.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Body Composition; Body Weight; Cholesterol; Cohort Studies; Disease Models, Animal; Drug Carriers; Eating; Energy Metabolism; Esters; Estrone; Female; Infusion Pumps, Implantable; Liposomes; Nitrogen; Obesity; Oleic Acids; Rats; Rats, Zucker; Triglycerides; Urea

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.

Topics: Animals; Anti-Obesity Agents; Body Weight; Diet; Drug Carriers; Energy Intake; Energy Metabolism; Estrone; Female; Liposomes; Oleic Acids; Rats; Rats, Zucker

Four experiments were devised to test the possible role of estrone fatty esters as adipose tissue signals carried by the blood within lipoproteins.. 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.. Normal-weight Wistar female rates were used. Pooled human blood was used as source of HDL3.. 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.. 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.. 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.

Topics: Adipocytes; Adipose Tissue; Animals; Body Composition; Body Weight; Cells, Cultured; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Eating; Esters; Estrone; Female; Infusion Pumps, Implantable; Lipid Metabolism; Lipids; Liposomes; Nitrogen; Oleic Acid; Oleic Acids; Oxygen Consumption; Rats; Rats, Wistar; Time Factors; Weight Loss