Biomedical subjects

X Remesar

Publications and source records attributed to X Remesar.

At least 19 recordsLinked to original sources

PubMed1999

Leptin enhances the synthesis of oleoyl-estrone from estrone in white adipose tissue.

BACKGROUND: 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. AIM OF THE STUDY: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

3T3 Cells↗

PubMed1999

Short-term treatment with estrone oleate in liposomes (Merlin-2) does not affect the expression of the ob gene in Zucker obese rats.

Young female Zucker fa/fa rats of 370-430 g were implanted with osmotic minipumps releasing 3.5 micromol/day-kg of estrone oleate in liposomes (Merlin-2) into the bloodstream for up to 14 days. Merlin-2 induced a sustained loss of appetite, and a decrease in body weight of 3.5%, which contrasts with the 8.2% increase in controls during the period studied. Plasma insulin, glucose and urea decreased, and liver glycogen increased with Merlin-2 treatment. Plasma ACTH and corticosterone increased to a maximum at the end of the experiment. The expression of the ob gene in adipose tissue was unchanged, and plasma leptin levels were also unchanged by treatment. Estrone levels increased more than 1500-fold, and estrone oleate rose 100-fold during treatment. The fact that estrone oleate had no effect on the leptin levels or expression in obese rats, in contrast with the marked inhibition observed in the lean suggests that the functionality of the leptin receptor is essential for estrone oleate inhibition of the ob gene. This also suggests that leptin may control ob gene expression in white adipose tissue and that estrone oleate may activate this process. The slimming effect of estrone oleate is, thus, not directly dependent on leptin, since both normoleptinemic and hyperleptinemic animals lose fat following treatment nor are the effects on appetite and energy expenditure mediated by leptin. However, leptin levels and the expression of the ob gene are directly linked with estrone oleate function. A possible involvement of leptin in estrone oleate action is postulated. The results support the participation of estrone oleate in the control of body weight and hint at the complexity of its regulation by leptin and glucocorticoids.

Animals↗

PubMed1999

Ammonium uptake and urea production in hepatocytes from lean and obese Zucker rats.

The metabolic differences in vitro between genetic and dietary obese rats in the uptake of ammonium and amino acids by the liver and their use for ureogenesis have been assayed using hepatocytes isolated from Lean, Obese Zucker (Genetic obese) rats and Dietary obese rats. The hepatocytes of genetic obese animals took up more ammonium and produced higher amounts of urea from ammonium and alanine than those of lean and dietary obese groups (2 and 5 times more respectively). In the lean and dietary obese groups urea synthesis accounted for almost all the nitrogen taken up as ammonium. Thus, dietary and genetic obesity show a widely different handling of nitrogen, and the genetic obese rats need to break down protein to maintain their hepatocyte function.

Alanine↗

PubMed1999

Oleoyl-estrone treatment affects the ponderostat setting differently in lean and obese Zucker rats.

OBJECTIVE: 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. DESIGN: 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. SUBJECTS: Young adult lean controls (CL) or treated (TL) and obese controls (CO) or treated (TO) Zucker rats. MEASUREMENTS: 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). RESULTS: 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. CONCLUSION: 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.

Adrenocorticotropic Hormone↗

PubMed1999

Plasma oestrone-fatty acid ester levels are correlated with body fat mass in humans.

OBJECTIVE: The metabolites of steroidal hormones, including sulphate, glucuronide, and fatty acid (FA) ester derivatives, have received little attention, although these steroid derivatives are essential components in the global assessment of steroid metabolism. The study of FA-derivatives could, in obesity, contribute some insights into factors modulating steroid metabolism and their plasma levels. In a recent study we found that, in rats, an oestrone-fatty acid ester (E1-FA) was produced by white adipose tissue and released into lipoproteins in the blood-stream. We have examined whether E1-FA levels correlate with body fat and insulin sensitivity in humans. SUBJECTS: A sample of 20 men and 22 women with varying levels of total body fat (mean body mass index (BMI) 29.2 +/- 4.7, range 22.2-35.8 in men; mean BMI 27.6 +/- 6.3, range 16.8-37.9 in women). All participants were healthy. MEASUREMENTS: We measured oestrone fatty acid esters (E1-FA), body fatness, and body fat distribution variables, as well as insulin sensitivity through a frequently sampled intravenous glucose tolerance test. Plasma E1-FA and serum leptin levels were measured by radioimmunoassay. RESULTS: E1-FA levels strongly correlated with BMI (r = 0.69, P = 0.001 in men; r = 0.75, P < 0.0001, in women) percent body fat (PBF, r = 0.52. P = 0.018 in men; and r = 0.69, P < 0.0001, in women) and with the sum of 4 fat skinfolds (sigma skinfolds). E1-FA level was significantly and positively associated with fasting insulin (r = 0.62, P = 0.003 in men, and r = 0.48, P = 0.023 in women) but not with fasting glucose levels. E1-FA correlated with insulin sensitivity (SI, r = -0.72 in men; and -0.76, in women, both P < 0.0001). In men, E1-FA levels also correlated with systolic blood pressure (r = 0.59, P = 0.01), total triglycerides (r = 0.63, P = 0.003), VLDL-triglycerides (r = 0.62, P = 0.004) and VLDL-cholesterol (r = 0.48, P = 0.03), but not with diastolic blood pressure, serum total or LDL-cholesterol, or total and HDL2 and HDL3 subfractions of HDL cholesterol. After controlling for fat mass, only the correlation between VLDL-triglycerides and E1-FA levels remained significant. In women, E1-FA levels correlated with total triglycerides (r = 0.66, P = 0.001), VLDL-triglycerides (r = 0.65, P = 0.001), VLDL-cholesterol (r = 0.63, P = 0.002), LDL-cholesterol (r = 0.57, P = 0.005) and total and HDL2 and HDL3 subfractions of HDL cholesterol (r = -0.58, -0.48, -0.61, P = 0.004, 0.02 and 0.002, respectively), but not with systolic or diastolic blood pressure or total cholesterol. However, covariance analysis revealed that controlling for the concomitant variation in body fat mass eliminated all these associations. Fasting plasma E1-FA concentration correlated with serum leptin (r = 0.60, P = 0.005 in men; r = 0.75, P = 0.0001, in women). However, these correlations no longer persisted after controlling for fat mass (r = 0.33 and 0.36, P = NS). Stepwise regression analysis models were tested, with E1-FA as the dependent variable, and sigma skinfolds and SI as independent covariables. Both the sigma skinfolds (P = 0.03) and SI (P = 0.01) entered the equation at a statistically significant level in men. Therefore, insulin sensitivity was related to E1-FA independently of fat in men. In women only sigma skinfolds (P = 0.04) entered the regression model at a statistically significantly level. Fifty-seven percent of the variance in plasma E1-FA levels in men, and 50% in women, was accounted for using a regression model that combined these variables. CONCLUSIONS: Oestrone-fatty acid esters circulate in human blood in proportion to body fat, independently of gender. Plasma oestrone-fatty acid ester levels are associated with insulin sensitivity in men, independently of body fat. These findings may widen our perspective on the regulation of insulin action and control of body weight.

Adipose Tissue↗

PubMed1999

Distribution of oleoyl-estrone in rat plasma lipoproteins.

Pooled adult normal rat plasma was used for the separation of lipoprotein fractions: VLDL, LDL and HDL, from which a total lipids extract was obtained. The presence of fragments with the MW of estrone and oleoyl-estrone in the lipoprotein fractions was analyzed by HPLC-MS. The results show that oleoyl-estrone is the major estrone component in lipoproteins; this molecular species was present in all three lipoprotein lipid extracts. The lipoprotein fractions were used for the analysis of protein and lipid classes: triacylglycerols, total and esterified cholesterol and phospholipids as well as acyl-estrone. About half of the total acyl-estrone was in the HDL fraction and only about 10% in the VLDL fraction. HDLs contained about one molecule in 50 particles, LDLs one molecule per particle and VLDLs 15 molecules per particle, i.e. given their size, the larger lipoproteins contained more oleoyl-estrone than the HDLs. The distribution of this hormone suggests that oleoyl-estrone is lost with other lipids as the lipoproteins shrink. The results presented show that oleoyl-estrone is a molecule found naturally in rat lipoproteins in low concentrations - the lowest in HDLs - that are consistent with its postulated role in the control of body weight.

Animals↗

PubMed1998

Differential short-term distribution of estrone and oleoyl-estrone administered in liposomes to lean and obese Zucker rats.

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.

Adipose Tissue↗

PubMed1998

Hind leg heat balance in obese Zucker rats during exercise.

To analyse the effect of obesity on exercise-derived heat dissipation, lean and obese Zucker rats were exercised on an inclined treadmill until they would no longer run with gentle prodding. We measured their oxygen consumption, water vapour loss, the concentrations of adenosine tri- and diphosphate, creatine phosphate, and lactate in quick-frozen leg muscles, and the temperature of muscle, skin and blood in the aorta. We determined blood flow to leg muscle, fat and skin by measuring the entrapment of fluorescent microspheres. From the measurements we calculated heat flow rates between hind leg muscle, blood, fat and skin and the environment. The obese rats weighed twice as much as the lean (340-400 g and 175-200 g respectively) and ran half as fast (113 +/- 7 m versus 257 +/- 17 m). The differences between the two groups for basal oxygen consumption (lean: 6.7 +/- 0.9 micromol/min, obese: 5.0 +/- 1.9 micromol/min) and exercising oxygen consumption (lean: 37.8 +/- 5.6 micromol/min, obese: 22.2 +/- 3.8 micromol/min) were not significant. Both groups stopped running after the same time at their maximal speed (lean: 4.5 +/- 0.3 min, obese: 4.2 +/- 0.2 min). During exercise, lean rats had higher increases in core temperature (lean: 0.7 degrees C, obese: 0.4 degrees C) and muscle temperatures (lean: 1.3 degrees C, obese: 0.7 degrees C) than the obese rats. The calculated heat flows indicated a predominant conductive transfer of heat from muscle through the skin in lean rats but a higher proportion of heat transfer to the blood in obese rats. It is concluded that muscle heat accumulation did not cause fatigue in either case.

Animals↗

PubMed1998

During intense exercise, obese women rely more than lean women on aerobic energy.

A series of untrained, healthy, obese women (body mass index 32.5 +/- 0.9 kg.m-2) were subjected to a protocol of intense exercise on a cycloergometer and compared with lean controls (body mass index 20. 9 +/- 0.5 kg.m-2). Physiological parameters, blood lactate, bicarbonate, plasma metabolites, oxygen consumption and CO2 production were measured. Impedance-derived extracellular water and plasma changes in lactate and bicarbonate were used to determine changes in bicarbonate pools and lactate-displaced CO2. From these and respiratory gases, the respiratory quotient was calculated and thence overall fuel consumption. Anaerobic energy during exercise accounted for about 1.8% of all energy consumed in the lean but only 0.7% in the obese. Obese women fatigued at lower workloads and energy expenditure levels than did the lean, and their lactate buildup was similar when compared on the basis of fat-free mass. The data support the postulation of fatigue being triggered by a combination of factors: stretched cardiovascular work would be the main factor for obese women, in part limiting lactate production. For lean women, the triggering factor for fatigue could be the loss of buffering capacity; but it is the combination of stretching cardiovascular capacity, exhaustion of glycogen and available glucose and increase in lactate/loss of bicarbonate buffer that determines the onset of fatigue.

Adult↗

PubMed1998

Structural determinants of oleoyl-estrone slimming effects.

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 agonist molecule.

Animals↗

PubMed1998

Formaldehyde derived from dietary aspartame binds to tissue components in vivo.

Adult male rats were given an oral dose of 10 mg/kg aspartame 14C-labelled in the methanol carbon. At timed intervals of up to 6 hours, the radioactivity in plasma and several organs was investigated. Most of the radioactivity found (>98% in plasma, >75% in liver) was bound to protein. Label present in liver, plasma and kidney was in the range of 1-2% of total radioactivity administered per g or mL, changing little with time. Other organs (brown and white adipose tissues, muscle, brain, cornea and retina) contained levels of label in the range of 1/12 to 1/10th of that of liver. In all, the rat retained, 6 hours after administration about 5% of the label, half of it in the liver. The specific radioactivity of tissue protein, RNA and DNA was quite uniform. The protein label was concentrated in amino acids, different from methionine, and largely coincident with the result of protein exposure to labelled formaldehyde. DNA radioactivity was essentially in a single different adduct base, different from the normal bases present in DNA. The nature of the tissue label accumulated was, thus, a direct consequence of formaldehyde binding to tissue structures. The administration of labelled aspartame to a group of cirrhotic rats resulted in comparable label retention by tissue components, which suggests that liver function (or its defect) has little effect on formaldehyde formation from aspartame and binding to biological components. The chronic treatment of a series of rats with 200 mg/kg of non-labelled aspartame during 10 days resulted in the accumulation of even more label when given the radioactive bolus, suggesting that the amount of formaldehyde adducts coming from aspartame in tissue proteins and nucleic acids may be cumulative. It is concluded that aspartame consumption may constitute a hazard because of its contribution to the formation of formaldehyde adducts.

Administration, Oral↗

PubMed1998

Oleoyl-estrone does not alter hypothalamic neuropeptide Y in Zucker lean and obese rats.

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.

Animals↗

PubMed1998

Zucker obese rats are insensitive to the CRH-increasing effect of oleoyl-estrone.

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.

Adrenocorticotropic Hormone↗

PubMed1998

Effect of oleoyl-estrone administration on corticosterone binding to tissues of lean and obese Zucker rats.

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.

Adipose Tissue↗

PubMed1998

3-Hydroxybutyrate inhibits noradrenaline-induced thermogenesis in lean but not in obese Zucker rats.

OBJECTIVE: To determine the effect of 3-hydroxybutyrate (3OHB) on the thermogenic response to noradrenaline (NA) in lean and genetically obese Zucker fa/fa rats. DESIGN: Rats were infused with 18.7 nmol x kg(-1) x min(-1) of NA, supplemented, for 15 min, with 66.7 micromol x kg(-1) x min(-1) of R-3-hydroxybutyrate (3OHB). SUBJECTS: Pentobarbital-anaesthetized lean and obese Zucker rats. MEASUREMENTS: Aortic and interscapular brown adipose tissue (BAT) temperature; plasma NA, 3OHB, glucose and insulin levels during infusion. RESULTS: The NA-induced increase in aortic and BAT temperature was more marked in lean than in obese rats. In lean rats, the rise was arrested by 3OHB; but in obese rats 3OHB had no effect. Infusion of saline, glucose or 3OHB in the absence of NA did not induce changes in either temperature. NA infusion resulted in a rapid increase in plasma NA to 45-50 nM in both groups; this plateau was maintained for up to 60 min. The presence of 3OHB decreased the plasma NA of lean rats, but did not affect the plasma NA of the obese rats. Blood 3OHB rose to 1.2 mM during 3OHB infusion in both groups, and decreased on cessation of infusion. Blood glucose levels increased with NA infusion in both groups; the presence of high 3OHB levels decreased glucose levels only in lean rats. CONCLUSION: The changes in NA levels induced by 3OHB may help explain the effects observed on temperature and glucose. The defective thermogenic system of obese rats cannot be modulated by 3OHB, unlike thermogenesis in lean rats, on which 3OHB has a marked effect.

3-Hydroxybutyric Acid↗

PubMed1998

Effect of adrenalectomy on the slimming activity of liposome-carried oleoyl-estrone in the rat.

OBJECTIVE: To determine the extent of glucocorticoid counter-regulatory control in the slimming action of oleoylestrone. DESIGN: Control and adrenalectomized rats were subjected to a seven-day treatment with 3.5 micromol/kg/d oleoylestrone in liposomes injected i.v. continuously by implanted osmotic minipumps. SUBJECTS: Sham-operated control and adrenalectomized lean Zucker rats. MEASUREMENTS: Body weight and food intake; plasma glucose, urea, insulin, leptin and corticosterone; liver glycogen. RESULTS: Treatment with oleoyl-estrone resulted in decreases in body weight and in food intake, as well as in circulating glucose, insulin and leptin. Combined adrenalectomy and oleoyl-estrone treatment resulted in a loss of almost 15% body weight in only seven days, with a severe drop in circulating glucose and insulin, almost total disappearance of plasma leptin and liver glycogen and a 3-fold rise in circulating urea. Food intake decreased sharply, which resulted in the exhaustion of energy reserves. CONCLUSION: The results presented here, strongly support the hypothesis that glucocorticoids play an important role in the modulation of oleoyl-estrone-induced imbalance of energy intake and expenditure. The large effect of oleoyl-estrone on glucose, glycogen- and protein-derived (urea levels) energy in adrenalectomized rats, provides more evidence for the assumed protective role of glucocorticoids against the oleoyl-estrone-induced net loss of energy reserves. The results also show the powerful destabilizing effects of unchecked oleoyl-estrone on energy balance.

Adrenalectomy↗

PubMed1998

Increased leptin production in vivo and insulin cleavage by the omental adipose tissue of morbidly obese patients.

OBJECTIVE: The aim of this investigation was to assess the insulin cleavage capacity in obese humans. Increased insulin degradation by visceral adipose tissue has previously been demonstrated in obese rats and could be interpreted as a physiological response to hyperinsulinaemia. The recent characterization of leptin receptors in pancreatic beta cells, liver and muscle suggests that leptin may influence insulin function and metabolism. Our study focuses on the possible relationship between leptin secretion and adipose tissue insulin-degrading capacity. DESIGN AND PATIENTS: Insulin and leptin were measured in arterial blood and in the epiploic vein of morbidly obese (n = 7) and non-obese patients (n = 7) who were undergoing abdominal surgery. Arteriovenous insulin difference (AV insulin) was considered an in vivo marker of insulin degradation by the omental fat tissue. Statistical comparison between venous and arterial leptin was used to assess endogenous leptin production. MEASUREMENTS: Insulin was measured using an oligoclonal IRMA and leptin levels were determined by using a specific radioimmunoassay. RESULTS: Morbidly obese patients were hyperinsulinaemic compared to non-obese patients according to arterial insulin levels (P = 0.049) but not to venous levels. Insulin cleavage capacity, nil in the control group, was clearly significant in the morbidly obese patients (P = 0.001). In the morbidly obese group, leptin levels in venous epiploic samples were significantly higher (P = 0.028) than in the arterial samples, confirming in situ the synthesis of leptin by human white adipose tissue. We also observed a correlation between insulin arterial levels and venous leptin concentrations (P = 0.009) which supports the chronic leptinogenic effect of insulin suggested in previous works. Finally, our results show that venous leptin levels are correlated with the extent of insulin cleavage by omental tissue (P = 0.033). CONCLUSIONS: Morbidly obese patients have a higher white adipose tissue insulin cleavage capacity, which could partially diminish hyperinsulinaemia-derived adverse effects. High leptin production, a consequence of high insulin levels, may act as a signal to the insulin-degrading tissues in order to lower insulinaemia.

Adipose Tissue↗

PubMed1998

Corticosterone binding to tissues of adrenalectomized lean and obese Zucker rats.

The binding of corticosterone, dexamethasone and aldosterone was investigated in plasma and in homogenates of liver, kidney, brain, brown adipose tissue and visceral (periovaric) and subcutaneous white adipose tissues of Zucker lean and obese rats: intact controls, adrenalectomized and sham-operated. Corticosterone-binding globulin (CBG) accounted for most of the binding, whereas that of glucocorticoid and mineralocorticoid receptors was much lower. Plasma corticosterone levels increased in sham-operated and obviously decreased in the adrenalectomized animals. Sham-operated and adrenalectomized lean rats showed decreased plasma CBG; in the obese, CBG levels were lower than in controls and were not affected by either surgery. No variation with obesity or surgery was observed either in dexamethasone or aldosterone binding, the latter being practically zero in most samples. When expressed per unit of tissue protein, CBG activity was maximal in adipose tissues, with lowest values in brain and liver. In lean rats, tissue CBG activity decreased with either surgical treatment; no changes were observed in the obese, which also had lower CBG tissue levels. The relative lack of changes in CBG of obese rats suggests that they have lost -- at least in part -- the ability to counter-modulate the changes in glucocorticoid levels through CBG modulation, thus relying only on the control of corticosterone levels. This interpretation agrees with the postulated role of CBG modulating the availability of glucocorticoids to target cells.

Adipose Tissue↗