oleoyl-estrone and Obesity

Oleoyl-estrone (OE) is a powerful slimming agent that is also present in plasma and adipose tissue, where it is synthesized. It acts through the formation of a derivative W. OE effects (and W levels) are proportional to the dose. OE reduces food intake but maintains energy expenditure (thermogenesis). The energy gap is fulfilled with adipose tissue fat, sparing body protein and maintaining glycemia (and glycogen) with lower insulin and leptin levels. OE (in fact W) acts through specific receptors, different from those of estrogen. OE increases cholesterol catabolism, reducing hypercholesterolemia in obese rats. The main metabolic effect on adipose tissue is lowering of lipid synthesis, maintaining unchanged the intracellular lipolytic processes; the imbalance favors the progressive loss of fat, which is largely used by the muscle. OE administration induces additive effects with other antiobesity agents, such as β(3)-adrenergic agonists, forcing a massive loss of lipid. Corticosteroids markedly limit OE action by altering the liver control of lipogenesis. OE also inhibits the action of 17β-hydroxysteroid dehydrogenase, decreasing the synthesis of β-estradiol and testosterone. Discontinuous treatment allows for maximal efficacy both in rats and humans. OE has the advantage that the loss of fat is maintained and does not require additional dietary limitations.

Topics: Animals; Energy Metabolism; Estrone; Humans; Insulin Resistance; Lipoproteins; Obesity; Oleic Acids; Receptors, Cell Surface

Oleoyl-estrone (OE) has been presented as a potential antiobesity therapeutic, but the published series of studies from one laboratory has not yet been independently confirmed, and the exact mechanism of action is unknown. Based on the hypothesis that OE has potential for the treatment of obesity, male and female rats were chronically treated with several doses of OE to evaluate the impact of this compound on energy metabolism. Body weight, body composition, energy balance parameters and the expression of hypothalamic neuropeptides regulating food intake as well as key markers of the reproductive system were examined. OE impressively reduced food consumption and body weight gain in both sexes. Although a major part of the loss in body weight could be explained by decreased fat mass, a substantial loss of lean mass also occurred after OE administration. The loss of weight can be sufficiently explained by the suppression of food consumption, as there were no major changes in energy expenditure, locomotor activity or respiratory quotient. In situ hybridization data showed no significant change in the expression of key neuropeptides and hormone receptors regulating feeding behavior after OE treatment. Cocaine-amphetamine-regulated transcript (CART) mRNA levels were decreased in the arcuate nucleus of OE-treated rats. Hypogonadism and low plasma testosterone levels were found in OE-treated males, whereas females showed substantially increased liver size. The present data suggest that OE decreases food intake and body weight but also appears to cause a significant impact on the hypothalamus-pituitary-reproductive axis.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Arcuate Nucleus of Hypothalamus; Body Fluid Compartments; Energy Intake; Estrone; Female; Hypogonadism; Hypothalamo-Hypophyseal System; In Situ Hybridization; Liver; Male; Nerve Tissue Proteins; Obesity; Oleic Acids; Organ Size; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sex Factors; Testosterone; Weight Gain

In rats, oral oleoyl-estrone (OE) decreases food intake and body lipid content. The aim of this study was to determine whether OE treatment affects the energy metabolism of pregnant rats and eventually, of their pups; i.e. changes in normal growth patterns and the onset of obesity after weaning.. Pregnant Wistar rats were treated with daily intragastric gavages of OE in 0.2 ml sunflower oil from days 11 to 21 of pregnancy (i.e. 10 nmol oleoyl-estrone/g/day). Control animals received only the vehicle. Plasma and hormone metabolites were determined together with variations in cellularity of adipose tissue.. Treatment decreased food intake and lowered weight gain during late pregnancy, mainly because of reduced adipose tissue accumulation in different sites. OE-treated pregnant rats' metabolic pattern after delivery was similar to that of controls. Neonates from OE-treated rats weighed the same as those from controls. They also maintained the same growth rate up to weaning, but pups from OE-treated rats slowed their growth rate afterwards, despite only limited differences in metabolite concentrations.. The OE influences on pup growth can be partially buffered by maternal lipid mobilization during the second half of pregnancy. This maternal metabolic "imprinting" may condition the eventual accumulation of adipose tissue after weaning, and its effects can affect the regulation of body weight up to adulthood.

Topics: Adipose Tissue; Age Factors; Animals; Anti-Obesity Agents; Body Composition; Eating; Energy Metabolism; Estrone; Female; Male; Obesity; Oleic Acids; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Weaning

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

Oleoyl-estrone (OE) decreases appetite, maintains energy expediture, induces lipolysis (sparing protein), and decreases cholesterolemia and insulin resistance. Rimonabant (SR141716) is a cannabinoid-receptor inhibitor that decreases appetite and mobilizes fat. We studied whether their combination improves their slimming effects. Male overweight rats received daily gavages of 5.3 mg/kg OE, 10 mg/kg rimonabant, or both drugs during 10 days. Body weight and composition, energy balance, adipose tissue weight, and serum hormones and metabolites were measured. OE halved food intake and maintained energy expenditure at the expense of body fat. Rimonabant effects on appetite and energy balance were less marked, resulting in lower lipid mobilization. OE and rimonabant followed the OE pattern, with no additive or synergic effects. Glycemia was maintained, but OE decreased insulin, GLP-1, and cholesterol, whilst rimonabant increased cholecystokinin and cholesterol, and decreased NEFA. Both drugs decreased leptin and triacylglycerols; ghrelin was unchanged. The results hint at different mechanisms of action of both drugs: we can assume that OE effects do not involve the cannabinoid pathway. OE does not seem to act, either, after 10 days, through the secretion of ghrelin or the intestinal appetite-controlling peptides tested.

Topics: Animals; Anti-Obesity Agents; Appetite; Blood Glucose; Cholecystokinin; Cholesterol; Drug Synergism; Drug Therapy, Combination; Eating; Energy Metabolism; Estrone; Fatty Acids, Nonesterified; Ghrelin; Glucagon-Like Peptide 1; Insulin; Leptin; Male; Obesity; Oleic Acids; Overweight; Peptide Hormones; Piperidines; Pyrazoles; Rats; Rats, Wistar; Rimonabant; Triglycerides

The combined effects of limited food intake and OE treatment have been analysed in order to determine whether hypocaloric diets enhance the slimming effects of OE on mature overweight male rats. Two levels of dietary limitation at 50 and 25% of a standard intake were established, roughly corresponding to the human LCDs and VLCDs.. Wistar male rats (6 weeks old) were made overweight by a cafeteria diet. After transition to standard diet, they were subjected to food restriction: down to 50 or 25% with respect to the transition period. Half the animals were given daily oral gavages of 10 nmol/g oleoyl-estrone (OE), and the rest received only the vehicle during 10 days.. Changes in weight and body composition: water, lipid, protein or gross energy were determined by comparing the final pool size with that of day 0, calculated from the initial body weight and the composition of untreated rats. Energy and nitrogen balances were estimated. Plasma levels of metabolites and hormones were also measured.. OE induced changes in body composition similar to those elicited by a 50% reduction in food, with massive loss of lipid and energy. OE-treated rats ate less than the controls, but additional effects on body composition on reduced diet were minimal. OE improved metabolic homoeostasis: better maintained glycaemia, lower cholesterol and shallower hormonal changes, but at the expense of slightly increased protein mobilisation.. The data presented suggest that no advantages are accomplished by combining OE treatment and hypocaloric diets compared with OE alone, at least under the experimental conditions tested, since the effects were not additive. Despite OE affecting food intake, mechanisms other than that are deemed responsible for the mobilisation of body fat, since intake alone cannot explain the effects on body weight, nor the metabolic and hormonal changes in OE-treated rats. It is concluded that the combination of food restriction and OE may result in unwanted increased protein mobilisation with no synergy between both slimming treatments.

Topics: Animals; Anti-Obesity Agents; Body Composition; Caloric Restriction; Combined Modality Therapy; Eating; Energy Intake; Energy Metabolism; Estrone; Male; Nitrogen; Obesity; Oleic Acids; Overweight; Rats; Rats, Wistar

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

Topics: Adipocytes; Animals; Anti-Obesity Agents; Cannabinoid Receptor Modulators; Disease Models, Animal; Drug Design; Estrone; Fatty Acids; Humans; Obesity; Oleic Acids; Oxidation-Reduction; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant

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

Oleoyl-estrone (OE) decreases appetite, induces adipose tissue wasting and resets the ponderostat setting, sparing glucose and protein. The beta3-adrenergic agonists increase energy expenditure and lipolysis. We studied the combination of both treatments to enhance fat mobilization. Overweight male rats received oral OE for 10 days; they were compared with controls and rats receiving a beta3-adrenergic agonist, CL316,243 (B3A); another group received both OE and B3A. Serum 3-hydroxybutyrate, NEFA, triacylglycerols and glucose showed only slight changes in all groups vs. controls; OE-treated rats showed lower cholesterol. OE decreased food intake and B3A increased energy expenditure. OE rats lost about 15%, B3A 24%, and those receiving both compounds lost 39% of their initial total body energy. In all cases, most of this energy imbalance was accounted for by the loss of body lipid. The combined treatment of OE and B3A reduced food intake, nevertheless maintaining a high energy expenditure. The combination of a beta3-adrenergic agonist with OE may help compensate the short-lived effects of the agonist and enhance the lipid mobilization action of OE. The eventual combination of both compounds should be explored as a way to obtain faster and more effective ways to treat obesity.

Topics: 3-Hydroxybutyric Acid; Adrenergic beta-Agonists; Analysis of Variance; Animals; Blood Glucose; Dioxoles; Eating; Energy Metabolism; Estrone; Fatty Acids, Nonesterified; Insulin Resistance; Lipid Mobilization; Male; Obesity; Oleic Acids; Rats; Rats, Wistar; Triglycerides

Topics: Drug Industry; Estrone; Humans; Obesity; Oleic Acids; Peptide Fragments; Peptide YY; Satiety Response; United States

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

There is a considerable variability in the responses of Zucker fa/fa rats in metabolic studies, which could not be solely attributed to the leprfa mutation. In order to fathom the extent of this variability, we compared the response to oleoyl-estrone (OE), a powerful lipid-mobilising agent, of two strains of Zucker lean and obese rats: Harlan (H) and Charles River (CR). Rats were given an oral gavage of 10 micromol/day/kg of OE in sunflower oil, and were compared with oil-receiving controls. Body composition, energy and water balances, and plasma parameters were studied after 10 days of treatment. H rats showed a higher water turnover than CR rats; OE treatment reduced water intake, partly compensated by metabolic water, and decreased stool water. H rats accrued more cholesterol than CR animals, which showed higher cholesterolaemia. OE facilitated cholesterol disposal in lean (CR and H) and H obese rats. CR rats had higher body and liver lipids than H animals. No differences in energy balance were found. Insulin decrease following OE treatment was greater in lean CR than in H rats, but this trend was reversed in the obese rats, lacking effective responses to leptin. The red cell glucose compartment was smaller in H than in CR rats; the higher insulin levels in H rats may be partly responsible for that difference. Obese H maintained glycaemia (and liver glycogen) with higher insulin levels than CR animals. The extent to which the leprfa mutation affects the responses of Zucker fa/fa rats could not be singled out unless the metabolic environment of the batch used is known. This variability must be taken into account when developing a metabolic or hormonal study in which this model of obesity is used.

Topics: Animals; Blood Glucose; Body Composition; Body Water; Cholesterol; Drinking; Eating; Energy Metabolism; Estrone; Feces; Insulin; Lipids; Liver; Mutation; Obesity; Oleic Acids; Plant Oils; Rats; Rats, Zucker; Receptors, Cell Surface; Receptors, Leptin; Species Specificity; Sunflower Oil; Weight Loss

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

To study the effect of oral oleoyl-estrone on the plasma lipoprotein profile and tissue lipase activities in order to determine the handling of circulating lipids by adipose tissue, liver and muscle of obese female rats.. Lean (Fa/?) and obese (fa/fa) female Zucker rats treated for 10 days with a daily gavage of 0.2 ml sunflower oil containing 0 (controls) or 10 micromol/kg of oleoyl-estrone. After sacrifice, samples of tissues and plasma were taken.. Plasma lipoprotein classes and composition; lipoprotein lipase and hepatic lipase activities in plasma, liver, skeletal muscle and periovaric and mesenteric white adipose tissue (WAT).. Oleoyl-estrone decreased plasma cholesterol (mainly in HDLs: 76%) of lean rats, but dramatically decreased all lipid classes in obese rats, in which chylomicra and VLDL lost most of their triacylglycerols (95 and 81%, respectively). Hepatic lipase activity decreased markedly with oleoyl-estrone in all groups, both in plasma (79% lean, 100% obese) and liver (62% in both groups). Lipoprotein lipase activity was largely unchanged by oleoyl-estrone in lean rats, but in the obese it decreased in WAT (82% in periovaric, and 49% in mesenteric), and increased in plasma (x4) and in skeletal muscle (x5); liver levels showed no change.. The shift observed in obese rats from a decrease in liver and WAT lipoprotein lipase and hepatic lipase activities to an increase in muscle lipoprotein lipase is coincident with the hypolipemic effect of oleoyl-estrone, especially in obese rats, and indicates that muscle is a key site for the disposal of endogenous fat mobilized due to oleoyl-estrone treatment.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Cholesterol; Cholesterol, HDL; Estrone; Female; Lipase; Lipoprotein Lipase; Lipoproteins; Liver; Muscle, Skeletal; Obesity; Oleic Acids; Rats; Rats, Zucker

Food deprivation induces the mobilization of fat reserves and, consequently, the transport of lipids in plasma. Zucker obese rats are grossly hyperlipidemic and do not use lipids as an efficient energy substrate. They also have lower circulating levels of acyl-estrone than expected because of their large fat stores.. To measure the effect of 24 h food deprivation on hyperlipidemia and acyl-estrone distribution in plasma in Zucker obese rats.. The plasma lipoprotein distribution and composition of Zucker lean (Fa/?) and obese (fa/fa) rats was determined after 24 hours of food deprivation. Lipid classes: phospholipid, free and esterified cholesterol and triacylglycerols, and protein and total (mainly acyl-) estrone were also measured in total plasma and lipoprotein fractions.. Food-deprived rats showed lower triacylglycerol levels than fed rats, but obese rats maintained high lipid levels, mainly in the VLDL fraction. The ratio of total plasma free-to-esterified cholesterol was lower in fed lean rats (0.29) than in the obese (0.61); the situation improved slightly after 24-h starvation, since the corresponding ratios were 0.30 and 0.41. Acyl estrone levels changed little with 24-h food deprivation. The chylomicra + VLDL total estrone compartment was essentially unchanged in lean and obese fed and starved groups, but the HDL pool decreased with food deprivation in the obese.. Short-term starvation helped to enhance the differences between lean and obese Zucker rats in the handling of lipoprotein lipids, the latter showing a marked impairment in their ability to dispose of circulating lipids. The different pace of plasma lipid utilization may compound the problems of cholesterol transfer, partly explaining the dyslipemia that characterizes this animal model of obesity. The differences in acyl-estrone distribution also indicate that fat mass is preserved more effectively in obese rats even after food deprivation.

Topics: Adipose Tissue; Animals; Blood Proteins; Chylomicrons; Estrone; Female; Food Deprivation; Hyperlipidemias; Lipids; Lipoproteins; Obesity; Oleic Acids; Rats; Rats, Zucker

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

Oleoyl-estrone elicits powerful slimming effects on lean and obese rats, sparing protein, lowering appetite and maintaining energy expenditure. Leptin synthesis is markedly reduced by oleoyl-estrone. However, this effect is not observed in the obese Zucker fa/fa rats; these rats do not fully respond to leptin but they lose fat under oleoyl-estrone treatment.. To determine the role of leptin in the conversion of estrone to fatty-acyl estrone in white adipose tissue both in vivo in Zucker lean and obese rats, and in vitro.. Two series of experiments were performed: a) Growth and differentiation of 3T3L1 preadipocytes into adipocytes followed by incubation with tritium-labeled estrone in the medium in the presence/absence of 1 nM leptin, and estimation of the incorporation of label into estrone and estrone ester fractions of cell extracts. b) Zucker lean (Fa/?) [ZL] and obese (fa/fa) [ZO] rats were injected i.v. with carrier-free oleoyl-estrone in chylomicra-sized liposomes, then euthanized after 10 min. Free and esterified estrone were measured in blood, liver, muscle, skin, white adipose tissue (WAT), and brown adipose tissue (BAT).. In the first study, in a 72-h incubation, adipocytes took up 20-27% of the medium estrone. In the leptin(-) controls, 47% of the label in the cell fraction was in the form of estrone esters and 45% as free estrone; in the leptin(+) cells, 71% of the label was in the estrone ester fraction and 24% was free estrone. In the second study, a large part of the injected tritium-label remained in the ZO blood, with only a small part remaining in ZL. In ZL 39% of the label was found in the tissues in the form of free estrone, and in ZO only 22%; in both cases about half of it was in WAT. Plasma free estrone levels were 0.3 +/- 0.1 nM in ZL and 0.5 +/- 0.3 nM in ZO, and esterified estrone was 242 +/- 99 nM for ZL and 201 +/- 29 nM for ZO. Plasma leptin levels were 1.73 +/- 0.16 ng/ml in ZL and 61.0 +/- 1.4 ng/ml in ZO.. The presence of an infact leptin pathway is critical for the uptake and synthesis of estrone esters as well as for the plasma acyl-estrone turnover. The presented results show a direct relationship between oleoyl-estrone and leptin in the WAT. A fully functional leptin pathway is needed for the synthesis of acyl-estrone and the removal of free estrone from the bloodstream, as well as for the disposal of excess circulating oleoyl-estrone. This has a direct bearing on human and animal obesity, since estrone induces increases in fat deposition.

Topics: 3T3 Cells; Adipose Tissue; Adipose Tissue, Brown; Animals; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Estrone; Female; Leptin; Liver; Mice; Muscles; Obesity; Oleic Acids; Proteins; Radioimmunoassay; Rats; Rats, Zucker; Reference Values; Scintillation Counting; Skin

Thirteen-week-old female Zucker lean (Fa/Fa) and obese (fa/fa) rats were injected through a cannula inserted in the left jugular vein with 1 mL/kg of 3H-labeled oleoyl-estrone in liposomes (Merlin-2) (i.e., 670 fmol, 84 kBq). The rats were killed 10 minutes later and dissected. The presence of intact or hydrolyzed oleoyl-estrone was later determined in all samples. The pattern of distribution of estrone was quite different from that of oleoyl-estrone both in rats that were lean and in those that were obese. Estrone was better retained by white adipose tissue than oleoyl-estrone. Liver, spleen, and lungs accumulated more oleoyl-estrone and split part of it, from 4.7% (lung, obese) to 27% (liver, lean). The overall high retention of estrone by the rat tissues results in its very low circulating levels. The fast splitting of liposome-carried oleoyl-estrone by most tissues (up to more than 67% by intestine and skin of lean rats) may help explain the rise in blood free estrone. The differences between lean and obese Zucker rats are mainly quantitative in the case of estrone, the main differences being found in blood and adipose tissues. However, when we compare the data for oleoyl-estrone, the differences cannot be dismissed simply as due to differences in body size or the extent of fat deposits. A large portion of the label remained in the blood of the rats that were obese but not in those that were lean, the tissues of which took up more label. Brown adipose tissue shows a fair affinity for oleoyl-estrone in the rats that were lean but practically does not retain label in the rats that were obese, suggesting that oleoyl-estrone may have a direct effect on brown adipose tissue. The decreased uptake of oleoyl-estrone in rats that were obese shows that the mechanism regulating the turnover or disposal of this signal is altered in this type of genetic obesity.

Topics: Adipose Tissue; Animals; Estrone; Female; Liposomes; Liver; Lung; Muscles; Obesity; Oleic Acids; Rats; Rats, Zucker; Spleen; Tissue Distribution

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

Adult female Zucker lean and obese rats were treated for 14 days with 3.5 nm/kg oleoyl-estrone (OE) in liposomes (Merlin-2) through continuous i.v. injection with osmotic minipumps. Rat wt. and food intake were measured daily. On days 0, 3, 6, 10, and 14, groups of rats were killed and their hypothalamic nuclei [lateral preoptic (LPO), median preoptic (MPO), paraventricular (PVN), ventromedial (VMH), and arcuate (ARC)] were dissected, homogenized, and used for the measurement of corticosterone-releasing hormone (CRH) by radioimmunoassay. The OE treatment decreased food intake by 67.4% in lean and 62.6% in obese rats (means for 14 days). Body wt. decreased steadily in lean and obese rats, the gap between controls and treated rats becoming 11.5% of initial body wt. in the lean and 12.4% in the obese. The levels of CRH in the ARC nucleus were at least 10-fold higher than in the other nuclei. No changes in CRH were observed in any of the nuclei of obese rats, with levels up to day 6 similar to those of lean rats. In the lean rats, the LPO and ARC nuclei showed peaks on day 10, while the MPO showed no changes and the PVN and VMH nuclei showed a progressive increase, to a maximum at the end of the study (day 14). This contrasted with the peak of plasma adrenocorticotropic hormone (ACTH) and corticosterone (day 6 in lean and day 14 in obese rats). There was a definite lack of correlation between the plasma levels of these two hormones and the levels of CRH in the hypothalamic nuclei, and between the latter and the decreases in appetite in the rats. The loss of appetite induced by OE is not necessarily mediated by CRH, because the obese rats show an intense decrease in voluntary food intake but their hypothalamic nuclei CRH levels do not change at all. Hypothalamic nuclei CRH does not, necessarily, mediate the rise in glucocorticoids induced by OE treatment, because this is observed in lean and obese rats, lean rats increases being mismatched with those of hypothalamic CRH. The OE induced changes in hypothalamic CRH require a fully functional leptinergic pathway, because it is not observed in Zucker fa/fa rats lacking a working leptin receptor. This--indirectly--shows that leptin is needed for its synthesis or modulation.

Topics: Adrenocorticotropic Hormone; Animals; Anti-Obesity Agents; Appetite; Corticosterone; Corticotropin-Releasing Hormone; Eating; Energy Metabolism; Estrone; Female; Hypothalamus; Liposomes; Obesity; Oleic Acids; Rats; Rats, Zucker

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