Effects of chronic administration of sibutramine on body weight, food intake and motor activity in neonatally monosodium glutamate-treated obese female rats: relationship of antiobesity effect with monoamines.

When the hypothalamic ventromedial nucleus and arcuate nucleus were destroyed in rats by treatment with monosodium glutamate in the neonatal stage, increase in the Lee index (body weight 1/3/body length) and in retroperitoneal fat as well as decreases in spontaneous motor activity, food consumption and growth hormone secretion function associated with hypothalamic low body length obesity (monosodium glutamate-treated obesity; MSG-OB) were observed as these rats grew. Treatment with sibutramine at 3 and 10 mg/kg p.o. once a day continuously for 14 days improved these parameters, and the degree of improvement was dose related. The plasma lipid values in MSG-OB rats, which were the same as those in normal rats, were decreased by consecutive administration of sibutramine. Levels of hypothalamic monoamines (MAs) such as norepinephrine, 5-HT (serotonin) and dopamine and their metabolites DOPAC, HVA and 5-HIAA were decreased in MSG-OB rats, and further decrease in them, though slight, was observed with consecutive daily administration of sibutramine, probably as a result of the feedback attributable to an increase in MA in synapses caused by inhibition of MA uptake by sibutramine. These results suggest that sibutramine can activate the MA nervous system by MA uptake inhibition in regions of the brain such as the lateral hypothalamic area and the paraventricular nucleus, which control food intake and sympathetic nerve activity, and the nigrostriatal area related to the extrapyramidal motor system, and thereby exhibit anti-obesity effects in the MSG-OB rat.     

Differential effect of losartan in female and male spontaneously hypertensive rats

We demonstrated that the decreased response to acetylcholine observed in aorta of male and female spontaneously hypertensive rats is corrected after sustained (15 days) reduction of blood pressure levels by losartan. In order to verify if the same occurs in resistance vessels, vascular diameter changes induced by topical application of acetylcholine and bradykinin (endothelium-dependent vasodilators) and sodium nitroprusside (endothelium-independent vasodilator) to mesenteric arterioles studied in vivo, in situ were determined in rats treated with losartan for 24 h (acute) or 15 days (chronic). Rats that presented similar reduction (in %) of the blood pressure levels after losartan treatment were chosen. Sodium nitroprusside induced similar responses in losartan-treated and untreated male or female SHR. Whereas in female SHR, losartan corrected the diminished arteriolar response to endothelium-dependent vasodilators after acute and chronic treatment, in male SHR this correction only occurred after chronic treatment. Thus, losartan corrected the endothelial dysfunction more easily in female than in male SHR and independently of the normalization or the magnitude of the reduction of the blood pressure levels. In an attempt to explain the difference, we evaluated the losartan effect on nitric-oxide synthase (NOS) activity and angiotensin II AT1 and AT2 receptor gene expression in these animals. In male and female SHR, NOS activity and AT1 receptor expression were not altered by acute or chronic treatment. On the other hand, AT2 receptor expression was augmented only in female SHR by these treatments. Therefore, augmented AT2 receptor expression, but not alteration of NOS activity or AT1 receptor expression, might explain the difference observed.     

GLUT4 protein is differently modulated during development of obesity in monosodium glutamate-treated mice

The aim of the present study was to investigate the GLUT4 protein expression during the development of obesity in monosodium glutamate- (MSG) treated mice. Control (C) and neonatally MSG-treated 2-month-old (2-mo), 4-month-old (4-mo) and 7-month-old (7-mo) mice were analyzed. Anthropometric data, basal glycemia and insulinemia were measured; and the GLUT4 protein was assessed by Western blotting in white adipose tissue (WAT), skeletal muscle gastrocnemius (SM) and heart (H). Compared to age-matched C mice, the 2-mo and 4-mo MSG mice were already obese, but metabolically they showed increased or preserved whole-body insulin sensitivity, respectively. At these ages they showed unchanged total GLUT4 content in SM and H. However, in plasma membrane fraction from WAT, the MSG showed increased GLUT4 content at both 2- (by 60%) and 4-month (by 45%) of age. When the GLUT4 protein was expressed by unit of adipocyte surface area the protein amount was increased by 36 and 220% in 2-mo and 4-mo MSG mice, respectively. At 7 months of age, obesity was fully established in MSG mice, showing a strongly insulin resistant condition. Additionally, in the 7-mo MSG-mice the GLUT4 protein was reduced in SM (by 40%), H (by 28%), PM and M fractions of WAT (by approximately 70%), and PM expressed by unit of adipocyte surface area (by 92%). The data demonstrate that early, during the accelerated development of obesity in MSG-treated mice, the GLUT4 content was increased in WAT, and that may play a key role in the development of obesity. Later on, when obesity is fully established, the GLUT4 protein was reduced in SM, heart and WAT, and that may be involved in the insulin resistance present in this condition.     

双歧醋对大鼠预防性减肥的实验研究

目的探讨双歧醋预防大鼠肥胖的作用及相关机制研究。方法 48只SD大鼠被随机分成双歧醋低剂量组[1.8 mL/(kg.BW)]、中剂量组[3.4 mL/(kg.BW)]、高剂量组[6.8 mL/(kg.BW)]和市售醋组[3.4mL/(kg.BW)]、肥胖模型组以及基础对照组,进行预防性减肥实验,观察双歧醋在大鼠肥胖过程中对大鼠的影响,测定指标包括大鼠体重、体脂、Lee’s指数、脂肪细胞直径、血瘦素、血胰岛素。结果实验结果显示,双歧醋各组所有测定指标值都较肥胖组有明显好转,特别是血瘦素和血胰岛素水平,双歧醋的高、中剂量组与市售醋组差异有统计学意义。结论双歧醋能有效预防血瘦素和血胰岛素的升高,预防体脂、Lee’s指数和体重的增加也有一定作用。     

Differential impact of cocaine on meal patterns in female and male rats

Female rats, relative to males, exhibit greater behavioral activation to cocaine and other psychostimulants, but the effect of sex and the estrous cycle in modulating the hypophagic action of cocaine has not been evaluated. Meal patterns were recorded in automated food hoppers during the first 3 h of the dark phase in adult female and male rats after administration of ascending cocaine doses (0, 7.5, and 15 mg/kg cocaine, i.p.) on successive trials. Cocaine produced a greater suppression of feeding as well as a reduction in meal number over a 3 h test period in female rats during estrus, relative to that noted during diestrus. In contrast, during the 180 min test period, male rats showed minimal hypophagic responses to 7.5 or 15 mg/kg cocaine. These results extend the range of behavioral perturbations induced by cocaine that are modulated by sex and by the estrous cycle and are consistent with the notion that estradiol may modulate the neurochemical actions of cocaine.     

The antiobesity effect of dehydroepiandrosterone in rats.

Initial studies showed that dehydroepiandrosterone (DHEA) treatment in mice resulted in lower body weight gain. Subsequent studies have shown that DHEA treatment in rats has a similar effect. In adult rodents, weight loss is a consequence of DHEA treatment. In general, these effects are independent of changes in food intake and are accompanied by lower body fat. DHEA treatment has been shown in some circumstances to alter a number of serum factors including glucose, insulin, cholesterol, and triacylglycerol. Recent studies have focused on the effects of DHEA on liver metabolism. Studies have been undertaken to determine whether the antiobesity effect of DHEA is mediated by the previously described inhibition of glucose-6-phosphate dehydrogenase by this steroid. It appears that inhibition of glucose-6-phosphate dehydrogenase in liver is not the initial metabolic response to DHEA but may play a contributing role. Inhibition of glucose-6-phosphate dehydrogenase in adipose tissue may affect differentiation of fat cells. A number of other enzymes involved in lipid and carbohydrate metabolism have also been shown to be altered by DHEA treatment, and several futile cycles involving some of these enzymes have been proposed to play a role in DHEA's antiobesity action. In addition, mitochondrial protein content is elevated by DHEA treatment. There appear to be time-dependent changes due to DHEA treatment on hepatic mitochondrial state three rates of respiration. Studies continue to evaluate the role of alterations in mitochondrial metabolism in DHEA's antiobesity action.     

Hormonal responses to female conspecifics in hyperprolactinemic male rats and mice

Exposure to a female results in an acute release of LH and testosterone (T) in normal male rats and mice. This study was conducted to determine whether these hormonal responses are altered in hyperprolactinemic (hyperPRL) male rats in which copulatory behavior is known to be suppressed and in hyperPRL male mice in which it is not. Adult male CDF (F-344) rats were made hyperPRL either by grafting of three anterior pituitaries under the kidney capsule or by treatment with diethylstilbestrol (DES). Exposure of control males to receptive females for 10-15 min produced the expected two- to fourfold statistically significant elevations in plasma LH levels. In contrast, plasma LH levels in pituitary grafted or DES-treated males were not altered by female exposure. Male mice were pituitary grafted (two pituitaries per recipient) or sham-operated and housed individually with a female for 1 week. The resident females were then replaced with novel females in half of the cages and blood samples were taken from the males after 5 min exposure for determination of LH levels or after 45-60 min exposure for T levels. Female-induced LH and T elevations occurred in both hyperPRL and control groups. Failure of hyperPRL male rats to experience an increase in plasma LH levels in response to a female suggests abnormality of mechanisms controlling LHRH release. Suppression of LHRH release may be involved also in the induction of deficits of sexual behavior in these animals.     

Differential responsiveness of LH and prolactin to p-tyramine in male and female rats

The effect of p-tyramine, a natural amine which is found in the rat brain in trace amounts, was evaluated for its capacity to influence LH and prolactin secretion in male and female rats under different hormonal conditions. p-Tyramine (40 mg/kg ip) was ineffective in modifying LH levels in either female or male rats which had been gonadectomized for 2 days, but if the animals were injected with 12.5 micrograms of estradiol benzoate (EB) on the day of castration, p-tyramine was able to release LH in female but not in male rats. To evaluate whether early androgenization of brain structures which control LH secretion was involved in the sexual difference observed, p-tyramine was tested in female androgenized rats (200 micrograms of testosterone propionate on the day of birth), and in male rats castrated at birth. The trace amine was ineffective in altering LH levels in both experimental models, even if rats were pretreated with EB as control females. On the other hand, p-tyramine inhibited prolactin secretion in male rats pretreated with EB, and not in similarly treated female rats. The present results suggest that p-tyramine may be involved not only in prolactin regulation as it has been previously shown, but also in LH control, and that the hormonal response to this amine is sexually differentiated in the rat.     

Resistance training restores metabolic alterations induced by monosodium glutamate in a sex-dependent manner in male and female rats

Despite resistance exercises being associated with health outcomes, numerous issues are still unresolved and further research is required before the exercise can faithfully be prescribed as medicine. The goal of this study was to investigate whether there are sex differences in resistance training effects on metabolic alterations induced by monosodium glutamate (MSG), a model of obesity, in male and female rats. Male and female Wistar rats received MSG (4 g/kg body weight/day, s.c.) from postnatal day 1 to 10. After 10 days from MSG administration, the rats were separated into two groups: MSG-sedentary and MSG-exercised. At postnatal day 60, the animals started a resistance training protocol in an 80 degrees inclined vertical ladder apparatus and performed it for 7 weeks. Control rats received saline solution and were divided in saline-sedentary and saline-exercised. Resistance training restored all plasma biochemical parameters (glucose, cholesterol, triglycerides, aspartate aminotransferase, and alanine aminotransferase) increased in male and female rats treated with MSG. The MSG administration induced hyperglycemia associated with a decrease in the skeletal muscle glucose transporter 4 (GLUT4) levels and accompanied by deregulation in proteins, G-6Pase, and tyrosine aminotransferase, involved in hepatic glucose metabolism of male and female rats. MSG induced dyslipidemia and lipotoxicity in the liver and skeletal muscle of male rats. Regarding female rats, lipotoxicity was found only in the skeletal muscle. The resistance training had beneficial effects against metabolic alterations induced by MSG in male and female rats, through regulation of proteins (GLUT2, protein kinase B, and GLUT4) involved in glucose and lipid pathways in the liver and skeletal muscle.     

Differential gene expression of organic anion transporters in male and female rats.

Sex-related differential gene expression of organic anion transporters (rOAT1, rOAT2, and rOAT3) in rat brain, liver, and kidney was investigated. There were no sex differences in the expression of rOAT1 mRNA. rOAT2 mRNA was abundant in the liver and weakly expressed in the kidney of male rats; however, the OAT2 gene was strongly expressed in both organs of females. The abundance of rOAT2 mRNA markedly increased in castrated male rat kidney; however, treatment of castrated male rats with testosterone led to a decrease of rOAT2 mRNA. Expression of rOAT3 mRNA in intact female rats was found in the kidney and brain, whereas in males rOAT3 mRNA was also found in the liver. rOAT3 mRNA markedly decreased in the liver of castrated male rats but increased in testosterone-treated castrated male rats. Moreover, rOAT3 mRNA increased in the hypophysectomized female rat liver, indicating that rOAT3 is an inducible isoform. The present findings suggest that sex steroids play an important role in the expression and maintenance of OAT2/3 isoforms in the rat liver and kidney. Our results provide information on the differential gene expression of OAT isoforms with sex hormone dependency.     

Prolactin-releasing effect of tryptolines in the developing and adult male and female rats

The developmental prolactin-releasing effect of Tryptoline (T), Methoxytryptoline (MT) and Hydroxytryptoline (OHT) was examined comparatively in male and female rats. A single injection of T 15 mg/Kg increased serum prolactin in both sexes; the increase was significant from day 20 onwards. OHT evoked a sharp rise in 12 day-old rats and the releasing effect increased with age, both in males and females. No significant sex differences were observed in T or OHT treated rats. MT caused an increment in prolactin secretion in male rats and this action increased with age. The releasing effect of MT was not significant in females, even at 38 postnatal days. In adult animals, the tryptolines (15 mg/Kg) were able to increase serum prolactin in males and in females in diestrous; a dose of 5 mg/Kg of T was only effective in adult male rats. The prolactin-releasing effect was drastically reduced by orchidectomy and by ovariectomy. LH, FSH and TSH were not modified by any treatment. The present results show for the first time the ontogeny of the prolactin-releasing effect of tryptolines in male and female rats and that this effect depends on the presence of gonadal secretions in adults.     

Linoleic acid increases chorda tympani nerve responses to and behavioral preferences for monosodium glutamate by male and female rats

Previous studies suggest that the chorda tympani nerve (CT) is important in transmitting fat taste information to the central nervous system. However, the contribution of the CT in this process may depend upon the presence of other taste stimuli and/or differ in males and females. Accordingly, the present study investigated the role of the CT in free fatty acid taste processing by examining electrophysiological activity of the CT in response to the free fatty acid linoleic acid (LA), as well as by measuring behavioral responses to LA-taste mixtures. We recorded whole nerve responses from the CT in response to lingual application of LA with or without monosodium glutamate (MSG) in anesthetized male and female rats. In addition, we examined preferences for MSG + LA taste mixtures in behavioral tests. Although lingual application of LA alone did not produce CT whole nerve responses, coapplication of LA and MSG elicited greater CT responses than did MSG alone. These findings were paralleled by greater preferences for MSG + LA taste mixtures than for MSG alone. In both cases, the effect was particularly pronounced in male rats. Thus LA enhances CT activity and behavioral responses to LA + MSG taste mixtures, although there are sex differences in the effects. These results suggest that CT input is important in mediating behavioral responses to fat taste, but the effects depend upon other taste stimuli and differ in males and females.     

Differential replication of male and female X-chromosomes in Drosophila

The replication patterns of larval salivary gland chromosomes of D. hydei and D. melanogaster were studied by autoradiography with tritiated thymidine injected in mid third instar larvae. The male X chromosome showed a different replication behavior in comparison to that of the female X chromosome and autosomes. It is concluded that the male X chromosome finishes its replication earlier than the female X chromosome. Moreover, the time needed for a complete replication cycle of individual identical replication units was found to be shorter in the male than in the female X chromosome. Although the whole X chromosomes behave different there were no differences observed in the sequence of the discontinuous labeling patterns of the two types of X chromosome. One autosomal replication unit was observed which showed a different replication behavior in males and females. The possible origin of the differential behavior of the two X chromosomes is discussed in terms of their difference in degree of polyteny.     

Potent antiobesity effect of a short-length peptide YY-analogue continuously administered in mice

The gastrointestinal peptide, peptide YY_3–36 (PYY_3–36) and its shorter peptide analogues have been reported to reduce appetite by activating the neuropeptide Y2 receptor (Y2R), which is associated with obesity and other metabolic diseases. A 14-amino acid PYY analogue, Ac-[d-Pro²⁴,Cha^27,28,36,Aib³¹]PYY(23–36) (3), showed high binding affinity and agonist activity for the Y2R, similar to that of PYY_3–36, but had weak anorectic activity upon continuous administration in lean mice. Three amino acid substitutions [Pya(4)²⁶, Aib²⁸, Lys³⁰], which contributed to the decreased hydrophobicity of 3, efficiently increased its anorectic activity. The compound containing these three amino acids, Ac-[d-Pro²⁴,Pya(4)²⁶,Cha^27,36,Aib^28,31,Lys³⁰]PYY(23–36) (22), exerted more potent and durable food intake suppression than that by PYY_3–36 in lean mice, as well as excellent Y2R agonist activity (EC₅₀: 0.20 nM) and good subcutaneous bioavailability (66.6%). The 11-day continuous administration of 22 at 1 mg/kg/day successfully produced antiobese and antidiabetic effects, with more than 20% body weight loss in obese and Type 2 diabetes ob/ob model mice.     

Lack of effect of nicotine on the fertility of male and female mice

Summary Nicotine, administered by sub-cutaneous injection over a period of six weeks, was found to be ineffective in breaking male mouse chromosomes as judged by dominant lethal tests. In addition, no indication of an effect of nicotine on the fertility of female mice, or on the development of the foetusin utero, was found.     

High-glycemic index carbohydrates abrogate the antiobesity effect of fish oil in mice

Fish oil rich in n-3 polyunsaturated fatty acids is known to attenuate diet-induced obesity and adipose tissue inflammation in rodents. Here we aimed to investigate whether different carbohydrate sources modulated the antiobesity effects of fish oil. By feeding C57BL/6J mice isocaloric high-fat diets enriched with fish oil for 6 wk, we show that increasing amounts of sucrose in the diets dose-dependently increased energy efficiency and white adipose tissue (WAT) mass. Mice receiving fructose had about 50% less WAT mass than mice fed a high fish oil diet supplemented with either glucose or sucrose, indicating that the glucose moiety of sucrose was responsible for the obesity-promoting effect of sucrose. To investigate whether the obesogenic effect of sucrose and glucose was related to stimulation of insulin secretion, we combined fish oil with high and low glycemic index (GI) starches. Mice receiving the fish oil diet containing the low-GI starch had significantly less WAT than mice fed high-GI starch. Moreover, inhibition of insulin secretion by administration of nifedipine significantly reduced WAT mass in mice fed a high-fish oil diet in combination with sucrose. Our data show that the macronutrient composition of the diet modulates the effects of fish oil. Fish oil combined with sucrose, glucose, or high-GI starch promotes obesity, and the reported anti-inflammatory actions of fish oil are abrogated. In conclusion, our data indicate that glycemic control of insulin secretion modulates metabolic effects of fish oil by demonstrating that high-GI carbohydrates attenuate the antiobesity effects of fish oil.