Daily Oral Oleoyl‐Estrone Gavage Induces a Dose‐Dependent Loss of Fat in Wistar Rats

Objective: 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. Research Methods and Procedures: The effects of a daily oral gavage of oleoyl‐estrone (0, 0.2, 0.5, 1, 2, 5, 10, and 20 μmol/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. Results: 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. Discussion: 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.     

Tamoxifen does not prevent the mobilization of body lipids elicited by oleoyl-estrone

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.     

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 mol/dayúkg 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.     

Improvements in cardiovascular risk profile with large-volume liposuction: a pilot study

In this study, the authors investigated the physiologic effects of the altered body composition that results from surgical removal of large amounts of subcutaneous adipose tissue. Fourteen women with body mass indexes of greater than > 27 kg/m2 underwent measurements of fasting plasma insulin, triglycerides, cholesterol, body composition by dual-energy x-ray absorptiometry (DXA), resting energy expenditure, and blood pressure before and after undergoing large-volume ultrasound-assisted liposuction.There were no significant intraoperative complications. Body weight had decreased by 5.1 kg (p < 0.0001) by 6 weeks after liposuction, with an additional 1.3-kg weight loss (p < 0.05) observed between 6 weeks and 4 months after surgery, for a total weight loss of 6.5 kg (p < 0.00006). Body mass index decreased from (mean +/- SEM) 28.8 +/- 2.3 to 26.8 +/- 1.5 kg/m2 (p < 0.0001). This change in body weight was primarily the result of decreases in body fat mass: as assessed by DXA, lean body mass did not change (43.8 +/- 3.1 kg to 43.4 +/- 3.6 kg, p = 0.80), whereas DXA total body fat mass decreased from 35.7 +/- 6.3 to 30.1 +/- 6.5 kg (p < 0.0001). There were significant decreases in fasting plasma insulin levels (14.9 +/- 6.5 mIU/ml before liposuction versus 7.2 +/- 3.2 mIU/ml 4 months after liposuction, p < 0.007), and systolic blood pressure (132.1 +/- 7.2 versus 120.5 +/- 7.8 mmHg, p < 0.0002). Total cholesterol, high-density lipoprotein cholesterol, plasma triglycerides, and resting energy expenditure values were not significantly altered after liposuction.In conclusion, over a 4-month period, large-volume liposuction decreased weight, body fat mass, systolic blood pressure, and fasting insulin levels without detrimental effects on lean body mass, bone mass, resting energy expenditure, or lipid profiles. Should these improvements be maintained over time, liposuction may prove to be a valuable tool for reducing the comorbid conditions associated with obesity.     

Restrained Eating Behavior and the Metabolic Response to Dietary Energy Restriction in Women

Objective: To determine whether prior eating behavior characterized by dietary restraint alters responses in energy expenditure and substrate oxidation associated with a short‐term, energy‐restricted diet. Research Methods and Procedures: A repeated‐measures, 3‐day diet‐intervention study of adequate (125 kJ/kg of body weight) or restricted (62.5 kJ/kg) energy intake was conducted with 30 women, 20 to 46 years, BMI 25 to 45 kg/m², whose prior eating behavior was “restrained” or “unrestrained.” The Eating Inventory (cognitive restraint subscale) was used to measure restrained eating behavior. Energy expenditure and substrate oxidation were measured after a 12‐hour fast and during the first and fourth hours after a standard meal. Plasma glucose, nonesterified fatty acids, and insulin were measured at corresponding times. Body composition was determined by total body electrical conductivity. Results: Resting energy expenditure was not affected by 3 days of energy restriction. Short‐term energy restriction resulted in lower respiratory‐exchange ratios, higher rates of fat oxidation, and lower rates of carbohydrate oxidation. Subjects classified as restrained eaters had higher postprandial respiratory‐exchange ratios and carbohydrate‐oxidation rates compared with unrestrained eaters. Fasting insulin concentrations were lower in restrained eaters. These effects associated with prior eating behavior were independent of the diet intervention. Discussion: Metabolic outcomes associated with a 3‐day energy‐restricted diet (i.e., increased fat oxidation and decreased carbohydrate oxidation) were not affected by prior restrained eating behavior. However, restrained eating behavior was associated with increased carbohydrate oxidation after a mixed meal. This effect of restrained eating behavior may be attributable to increased insulin sensitivity.     

Oleoyl-estrone is a precursor of an estrone-derived ponderostat signal

Oleoyl-estrone (OE) is a powerful anti-obesity compound that decreases food intake, decreases insulin resistance and circulating cholesterol. OE stimulates a severe loss of body fat by decreasing adipose tissue lipid synthesis and maintaining lipolysis. Therefore, the body economy loses lipid energy because energy expenditure is maintained. This study analyses the discrepancy between OE effects and the distribution of labelled OE in plasma. Estrone radioimmunoassay of organic solvent plasma extracts of rats treated with OE showed the massive presence of acyl-estrone, but saponification did not release estrone, but containing similar unknown compound. Analysis of label distribution in plasma after oral gavages of (3)H-OE showed the presence of a more hydrophilic compound than OE or any estrogen as well as (3)H(2)O, formed from (3)H-OE in the acidic stomach medium. OE was not attached to a specific transporter in plasma. Through serum HPLC analysis we found W, a labelled derivative more hydrophilic than OE or estrone. The results were confirmed using (14)C-OE. HPLC-MS/MS studies showed that plasma OE levels were one order of magnitude lower than those of W. When liver cell cytosols from rats laden with (3)H-OE were incubated with nuclei from untreated rats, the OE-derived label (i.e., Ws) was found attached to nuclear DNA. Neither estradiol nor estrone interfered with its binding. W is a fairly hydrophilic compound of low molecular weight containing the estrone nucleus, but it is not an ester because saponification or esterases do not yield estrone as OE does. It is concluded that OE acts through its conversion to W, its active form; which binds to a nuclear receptor different from that of estrogen. The estimated W serum levels are proportional to the pharmacological OE effects in vivo. We postulate W as a new type of hormone that exerts the full range of in vivo effects thus far attributed to OE. The full identification of W is anticipated to open the way for the development of new OE-like anti-obesity drugs.     

Profiling of Energy Metabolism in Olanzapine‐Induced Weight Gain in Rats and Its Prevention by the CB1‐Antagonist AVE1625

This is the first study to examine the effect of subchronic olanzapine (OLZ) on energy homeostasis in rats, covering all aspects of energy balance, including energy intake as metabolizable energy, storage, and expenditure. We further analyzed whether, and by which mechanism, the CB1‐antagonist AVE1625 might attenuate OLZ‐induced body weight gain. For this purpose, we selected juvenile female Hanover Wistar rats that robustly and reproducibly demonstrated weight gain on OLZ treatment, accepting limitations to model the aberrations on lipid and carbohydrate metabolism. Rats received 2 mg/kg OLZ orally twice daily for 12 days. Body weight and body composition were analyzed. Moreover daily food intake, energy expenditure, and substrate oxidation were determined in parallel to motility and body core temperature. OLZ treatment resulted in substantial body weight gain, in which lean and fat mass increased significantly. OLZ‐treated rats showed hyperphagia that manifested in increased carbohydrate oxidation and lowered fat oxidation (FO). Energy expenditure was increased, motility decreased, but there was no indication for hypothermia in OLZ‐treated rats. Coadministration of OLZ and AVE1625 (10 mg/kg orally once daily) attenuated body weight gain, diminishing the enhanced food intake while maintaining increased energy expenditure and decreased motility. Our data reveal that energy expenditure was enhanced in OLZ‐treated rats, an effect not critically influenced by motility. Energy uptake, however, exceeded energy expenditure and led to a positive energy balance, confirming hyperphagia as the major driving factor for OLZ‐induced weight gain. Combination of OLZ treatment with the CB1‐antagonist AVE1625 attenuated body weight gain in rats.     

Oleoyl-estrone induces the massive loss of body weight in Zucker fa/fa rats fed a high-energy hyperlipidic diet

To test whether oleoyl-estrone plus a hyperlipidic diet affects body weight in Zucker fa/fa rats, 13-week-old male Zucker obese (fa/fa) rats initially weighing 440-470 g were used. They 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% was protein-derived energy and containing 1.23 +/- 0.39 μmol/kg of fatty-acyl esters of estrone. This diet was supplemented with added oleoyl-estrone to produce a diet with 33.3 μmol/kg of fatty-acyl estrone. Oral administration of oleoyl-estrone in a hyperlipidic diet (at a mean dose of 0.5 μmol. kg(-1).d(-1)) resulted in significant losses of fat, energy and, ultimately, weight. Treatment induced the maintenance of energy expenditure combined with lower food intake, creating an energy gap that was filled with internal fat stores while preserving body protein, in contrast with the marked growth of controls fed the hyperlipidic diet. Treatment of genetically obese rats with a hyperlipidic diet containing additional oleoyl-estrone resulted in the loss of fat reserves with scant modification of other metabolic parameters, except for lower plasma glucose and insulin levels. The results agree with the postulated role of oleoyl-estrone as a ponderostat signal.     

Pharmacological actions of the peptide hormone amylin in the long-term regulation of food intake, food preference, and body weight

The ability of amylin to reduce acute food intake in rodents is well established. Longer-term administration in rats (up to 24 days) shows a concomitant reduction in body weight, suggesting energy intake plays a significant role in mediating amylin-induced weight loss. The current set of experiments further explores the long-term effects of amylin (4-11 wk) on food preference, energy expenditure, and body weight and composition. Furthermore, we describe the acute effect of amylin on locomotor activity and kaolin consumption to test for possible nonhomeostatic mechanisms that could affect food intake. Four-week subcutaneous amylin infusion of high-fat fed rats (3-300 microg.kg(-1).day(-1)) dose dependently reduced food intake and body weight gain (ED(50) for body weight gain = 16.5 microg.kg(-1).day(-1)). The effect of amylin on body weight gain was durable for up to 11 wks and was associated with a specific loss of fat mass and increased metabolic rate. The body weight of rats withdrawn from amylin (100 microg.kg(-1).day(-1)) after 4 wks of infusion returned to control levels 2 wks after treatment cessation, but did not rebound above control levels. When self-selecting calories from a low- or high-fat diet during 11 wks of infusion, amylin-treated rats (300 microg.kg(-1).day(-1)) consistently chose a larger percentage of calories from the low-fat diet vs. controls. Amylin acutely had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. These results demonstrate pharmacological actions of amylin in long-term body weight regulation in part through appetitive-related mechanisms and possibly via changes in food preference and energy expenditure.     

Longitudinal associations of the endocrine environment on fat partitioning in postmenopausal women

Among postmenopausal women, declining estrogen may facilitate fat partitioning from the periphery to the intra-abdominal space. Furthermore, it has been suggested that excess androgens contribute to a central fat distribution pattern in women. The objective of this longitudinal study was to identify independent associations of the hormone milieu with fat distribution in postmenopausal women. Fifty-three healthy postmenopausal women, either using or not using hormone replacement therapy (HRT) were evaluated at baseline and 2 years. The main outcomes were intra-abdominal adipose tissue (IAAT), subcutaneous abdominal adipose tissue, and total thigh fat analyzed by computed tomography scanning and leg fat and total body fat mass measured by dual-energy X-ray absorptiometry. Serum estradiol, estrone, estrone sulfate, total testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate), sex hormone-binding globulin (SHBG), and cortisol were assessed. On average, in all women combined, IAAT increased by 10% (10.5 cm(2)) over 2 years (P < 0.05). Among HRT users, estradiol was inversely associated with, and estrone was positively associated with, 2-year gain in IAAT. Among HRT nonusers, free testosterone was inversely associated with, and SHBG was positively associated with, 2-year gain in IAAT. These results suggest that in postmenopausal women using HRT, greater circulating estradiol may play an integral role in limiting lipid deposition to the intra-abdominal cavity, a depot associated with metabolically detrimental attributes. However, a high proportion of weak estrogens may promote fat partitioning to the intra-abdominal cavity over time. Furthermore, among postmenopausal women not using HRT, greater circulating free testosterone may limit IAAT accrual.     

Effect of plastoquinone derivative 10-(6′-Plastoquinonyl) decyltriphenylphosphonium (SkQ1) on estrous cycle and 17β-estradiol level in rats

Administration of the plastoquinone derivative 10-(6??-plastoquinonyl)decyltriphenylphosphonium (SkQ1) to female Wistar rats with regular estrous cycle once a day for two weeks at doses of 25 nmol/kg (but not 250 nmol/kg) leads to increase in proestrus duration by reducing the phase of diestrus and metestrus. Neither dose caused significant changes in serum 17??-estradiol level for any stage of the cycle. However, relative elongation of the proestrus stage leads to an increase in average per cycle estradiol levels by 20%.     

Retention of estradiol negative feedback relationship to LH predicts ovulation in response to caloric restriction and weight loss in obese patients with polycystic ovary syndrome

The present study tests the hypothesis that specific endocrine, metabolic, and anthropometric features distinguish obese women with polycystic ovary syndrome (PCOS) who resume ovulation in response to calorie restriction and weight loss from those who do not. Fifteen obese (body mass index 39 +/- 7 kg/m(2)) hyperandrogenemic oligoovulatory patients undertook a very low calorie diet (VLCD), wherein each lost > or =10% of body weight over a mean of 6.25 mo. Body fat distribution was quantitated by magnetic resonance imaging. Hormones were measured in the morning at baseline, after 1 wk of VLCD, and after 10% weight loss. To monitor LH release, blood was sampled for 24 h at 10-min intervals before intervention and after 7 days of VLCD. Responders were defined a priori as individuals exhibiting two or more ovulatory cycles in the course of intervention, as corroborated by serum progesterone concentrations > or =18 nmol/l followed by vaginal bleeding. At baseline, responders had a higher sex hormone-binding globulin (SHBG) concentration but were otherwise indistinguishable from nonresponders. Body weight, the size of body fat depots, and plasma insulin levels declined to a similar extent in responders and nonresponders. Also, SHBG increased, and the free testosterone index decreased comparably. However, responders exhibited a significant decline of circulating estradiol concentrations (from 191 +/- 82 to 158 +/- 77 pmol/l, means +/- SD, P = 0.037) and a concurrent increase in LH secretion (from 104 +/- 42 to 140 +/- 5 U.l(-1).day(-1), P = 0.006) in response to 7 days of VLCD, whereas neither parameter changed significantly in nonresponders. We infer that evidence of retention of estradiol-dependent negative feedback on LH secretion may forecast follicle maturation and ovulation in obese patients with PCOS under dietary restriction.     

胰岛素强化治疗对胃癌围手术期营养代谢的影响：随机对照研究

目的:探讨胃癌围手术期能量及营养物质的代谢特点,研究强化胰岛素治疗对围手术营养代谢的影响.方法:选取胃中、下部癌病理诊断明确并且外科病房ICU住院时间不少于24h的患者64例,取得知情同意后随机分到强化胰岛素治疗(IIT)血糖控制在4.4～6.1 mmol/L.和传统治疗(CIT)组血糖控制在10mmol/L以下;应用CCM营养代谢监测系统测定围手术期静息能量消耗(REE),呼吸商(RQ),每公斤体重静息能量消耗(REE/kg)和脂肪氧化比率,应用多频人体生物电阻抗分析仪测定围手术期人体组分的变化及应用稳态模式评估法计算胰岛素抵抗指数(HOMA-IR).结果:64例病人入选,每组32例,手术创伤引起术后第1、3天REE水平增加约22%和12%,呼吸商降低至0.759和0.791,REE/kg增加28 kcal/kg和26 kcal/kg,脂肪氧化比率增加至78%和65%,Ln-HOMA-IR明显增加(P<0.05);IIT治疗能降低术后第1、3天Ln-HOMA-IR和REE/kg水平;术后人体指标如细胞内液、脂肪组织、蛋白组织、肌肉组织、瘦体组织和体质量较术前水平明显降低(P<0.05);IIT能明显减少脂肪组织、蛋白组织和细胞内液的消耗量(P=0.009,t=0.026).结论:IIT能够有效降低胃癌围手术期胰岛素抵抗程度、降低静息能量消耗的水平和减少脂肪及蛋白质的消耗.     

Body fat loss and compensatory mechanisms in response to different doses of aerobic exercise--a randomized controlled trial in overweight sedentary males

The amount of weight loss induced by exercise is often disappointing. A diet-induced negative energy balance triggers compensatory mechanisms, e.g., lower metabolic rate and increased appetite. However, knowledge about potential compensatory mechanisms triggered by increased aerobic exercise is limited. A randomized controlled trial was performed in healthy, sedentary, moderately overweight young men to examine the effects of increasing doses of aerobic exercise on body composition, accumulated energy balance, and the degree of compensation. Eighteen participants were randomized to a continuous sedentary control group, 21 to a moderate-exercise (MOD; 300 kcal/day), and 22 to a high-exercise (HIGH; 600 kcal/day) group for 13 wk, corresponding to ～30 and 60 min of daily aerobic exercise, respectively. Body weight (MOD: -3.6 kg, P < 0.001; HIGH: -2.7 kg, P = 0.01) and fat mass (MOD: -4.0 kg, P < 0.001 and HIGH: -3.8 kg, P < 0.001) decreased similarly in both exercise groups. Although the exercise-induced energy expenditure in HIGH was twice that of MOD, the resulting accumulated energy balance, calculated from changes in body composition, was not different (MOD: -39.6 Mcal, HIGH: -34.3 Mcal, not significant). Energy balance was 83% more negative than expected in MOD, while it was 20% less negative than expected in HIGH. No statistically significant changes were found in energy intake or nonexercise physical activity that could explain the different compensatory responses associated with 30 vs. 60 min of daily aerobic exercise. In conclusion, a similar body fat loss was obtained regardless of exercise dose. A moderate dose of exercise induced a markedly greater than expected negative energy balance, while a higher dose induced a small but quantifiable degree of compensation.     

Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial

Coronary heart disease (CHD) risk factors and the risk of CHD increase with increased adiposity. Fat loss induced by negative energy balance improves all metabolic CHD risk factors. To determine whether fat loss induced by long-term calorie restriction (CR) or increased energy expenditure induced by exercise (EX) has different effects on CHD risk factors in nonobese subjects, we conducted a 1-yr controlled trial involving 48 nonobese subjects who were randomly assigned to one of three groups: CR, 20% CR diet (n = 18); EX, 20% increase in energy expenditure through daily exercise with no increase in energy intake (n = 18); or HL, healthy lifestyle guidelines (n = 10). Subjects were 29 women and 17 men aged 57 +/- 3 yr, with BMI 27.3 +/- 2.0 kg/m(2). Assessments included total body fat by DEXA, lipoproteins, blood pressure, HOMA-IR, C-reactive protein (CRP), and estimated 10-yr CHD risk score. Body fat decreased by 6.3 +/- 3.8 kg in CR, 5.6 +/- 4.4 kg in EX, and 0.4 +/- 1.7 kg in HL, which corresponded to reductions of 24.9, 22.3, and 1.2% of baseline body fat mass, respectively. These CR- and EX-induced energy deficits were accompanied by reductions in most of the major CHD risk factors, including plasma LDL-cholesterol, total cholesterol/HDL ratio, HOMA-IR index, and CRP concentrations that were similar in the two intervention groups. Data from the present study provide evidence that CR- and EX-induced negative energy balance result in substantial and similar improvements in the major risk factors for CHD in normal-weight and overweight middle-aged adults.     

MSG lesions decrease body mass of suckling-age rats by attenuating circadian decreases of energy expenditure

Suckling-age rats display endogenous circadian rhythmicity of metabolic rate (MR) with energy-saving, torpor-like decreases, which are sympathetically controlled and suppressed by leptin treatment. We investigated whether neonatal monosodium glutamate (MSG) treatment, known to cause arcuate nucleus damage and adult-age obesity, alters energy balance in the first two postnatal weeks. Continuously recorded MR and core temperatures (T(c)) show that MSG treatment disinhibits the periodic, sympathetically controlled, energy-saving drops of T(c) and MR. Increased energy expenditure thus explains reduced body fat at normal lean body mass found in MSG-treated pups artificially nourished identically to controls. In MSG-treated mother-reared pups, lean body mass is additionally reduced, suggesting that MSG also reduces suckling. Plasma leptin levels are similar in controls and MSG-treated pups but higher per unit of fat mass in the latter. We conclude that the postweaning development of MSG obesity and depressed thermogenesis are preceded by an early phase of increased energy expenditure with decreased fat deposition during suckling age and hypothesize cell damage in the arcuate nucleus to be involved in both.     

Effect of oral oleoyl-estrone on the energy balance of diabetic rats.

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.     

Comparison of the metabolic effects of GIP receptor antagonism and PYY(3-36) receptor activation in high fat fed mice

Glucose-dependent insulinotropic polypeptide (GIP) and peptide YY (PYY) are secreted from the intestinal K- and L-cells, respectively, following a meal. Both peptides are believed to play a key role in glucose homeostasis and energy expenditure. This study investigated the effects of daily administration of the stable and specific GIP-R antagonist, (Pro(3))GIP (25 nmol/kg) and the endogenous truncated form of PYY, PYY(3-36) (50 nmol/kg), in mice fed with a high fat diet. Daily i.p. injection of (Pro(3))GIP, PYY(3-36) or combined peptide administration over 24 days significantly (P<0.05-0.01) decreased body weight compared with saline-treated controls without change in food intake. Plasma glucose levels and glucose tolerance were significantly (P<0.05) lowered by (Pro(3))GIP treatment alone, and in combination with PYY(3-36). These changes were accompanied by a slight improvement of insulin sensitivity in all of the treatment groups. (Pro(3))GIP treatment significantly reduced plasma corticosterone (P<0.05), while combined administration with PYY(3-36) significantly lowered serum glucagon (P<0.05). No appreciable changes were observed in either circulating or glucose-stimulated insulin secretion in all treatment groups. (Pro(3))GIP-treated mice had significantly (P<0.01) lowered fasting glucose levels and an improved (P<0.05) glycemic response to feeding. These comparative data indicate that chemical ablation of GIP receptor action using (Pro(3))GIP provides an especially effective means of countering obesity and related abnormalities induced by consumption of high fat energy rich diet.     

Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol x kg(-1) x day(-1) using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia.