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This study investigates the insulin sensitizer effect of carbenoxolone (CBX) and potentially involved peripheral mechanisms. Taking glucose transporter 4 (GLUT4) as a marker of glucose disposal, we investigated the CBX effects on whole-body insulin sensitivity and solute carrier 2a4 (Slc2a4)/GLUT4 expression in visceral (VAT) and subcutaneous (SAT) adipose tissues and soleus muscle of monosodium glutamate (MSG)-induced obese rats. Sterol regulatory element binding protein (SREBP1), an enhancer of Slc2a4 expression was analyzed through mRNA content and SREBP1-binding to Slc2a4 promoter. Finally, the small ubiquitin-modifier conjugating enzyme 9 (UBC9), whose low content indicates accelerated GLUT4 degradation was analyzed in soleus. Hypercorticosteronemia, hyperinsulinemia and low glucose decay rate in the insulin tolerance test of obese rats were restored by CBX (P < 0.05). Slc2a4 /GLUT4 increased in SAT (P < 0.05) and decreased in VAT (P < 0.01) of obese rats. In soleus, obesity increased Slc2a4 but decreased GLUT4 (P < 0.01), possibly by accelerating GLUT4 degradation, as suggested by decreased UBC9 (P < 0.01). CBX restored both UBC9 and GLUT4 contents. SREBP1 did not participate in the Slc2a4 transcriptional regulation. The insulin sensitizer effect of CBX involves the increase of GLUT4 expression in soleus, indicating an increased glucose disposal in skeletal muscle. This observation reinforces the skeletal muscle as the main site of insulin-induced glucose uptake and sheds new light on the metabolic effects of 11βHSD1 inhibitors, since most of the studies so far have focused on its effects on liver and adipose tissues. [ABSTRACT FROM AUTHOR]

Aims Hypothalamic obesity is a severe condition without any effective therapy. Bariatric operations appear as an alternative treatment, but the effects of this procedure are controversial. We, herein, investigated the effects of duodeno-jejunal bypass (DJB) surgery upon the lipid profile and expression of genes and proteins, involved in the regulation of hepatic lipid metabolism, in hypothalamic obese (HyO) rats. Methods During the first 5 days of life, male newborn Wistar rats received subcutaneous injections of monosodium glutamate [4 g/kg body weight, HyO group] or saline (control, CTL group). At 90 days of life, HyO rats were randomly submitted to DJB (HyO DJB) or Sham-operations (HyO Sham group). Six months after DJB, adiposity, hepatic steatosis and lipid metabolism were verified. Key findings HyO Sham rats were obese, hyperinsulinemic, insulin resistant and dyslipidemic. These rats had higher liver contents of trygliceride (TG) and presented disorganization of the hepatocyte structures, in association with higher hepatic contents of acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase-1 mRNAs and protein. DJB surgery normalized insulinemia, insulin resistance, and dyslipidemia in HyO rats. TG content in the liver and the hepatic microscopic structures were also normalized in HyO DJB rats, while the expressions of ACC and FASN proteins were decreased in the liver of these rodents. Significance The DJB-induced amelioration in hepatic steatosis manifested as a late effect in HyO rats, and was partly associated with a downregulation in hepatic de novo lipogenesis processes, indicating that DJB protects against liver steatosis in hypothalamic obesity. [ABSTRACT FROM AUTHOR]

Aims We investigated whether the chronic intake of monosodium glutamate (MSG) with food affects kidney function, and renal response to glycine. We also established if the NMDA receptors are involved in the changes observed. Main methods Male Wistar rats (5 weeks old) were fed a diet supplemented with MSG (3 g/kg b.w./day), five days a week, and spontaneous ingestion of a 1% MSG solution during 16 weeks. NaCl rats were fed a diet with NaCl (1 g/kg b.w./day) and 0.35% NaCl solution at the same frequency and time. Control group was fed with normal chow and tap water. We utilized clearance techniques to examine glomerular filtration rate (GFR) and cortical renal plasma flow (CRPF) response to glycine and glycine + MK-801 (antagonist NMDA-R), and we determined NMDA-R1 in kidney by immunohistochemistry. Key findings The addition of MSG in the diet of rats increased both GFR and CRPF with an increase of absolute sodium reabsorption. However, hyperfiltration was accompanied with a normal response to glycine infusion. Immunostain of kidney demonstrate that the NMDA receptor is upregulated in rats fed with MSG diet. NMDA-R antagonist MK-801 significantly reduced both the GFR and CRPF; however the percentage of reduction was significantly higher in the group MSG. MK-801 also reduces fractional excretion of water, sodium and potassium in the three groups. Significance Renal NMDAR may be conditioned by the addition of MSG in the diet, favoring the hyperfiltration and simultaneously Na retention in the body. [ABSTRACT FROM AUTHOR]

Cytochromes P450 (CYPs) are enzymes present from bacteria to man involved in metabolism of endogenous and exogenous compounds incl. drugs. Our objective was to assess whether obesity leads to changes in activities and expression of CYPs in the mouse liver, small intestine and colon. Main methods An obese mouse model with repeated injection of monosodium glutamate (MSG) to newborns was used. Controls were treated with saline. All mice were sacrificed at 8 months. In the liver and intestines, levels of CYP mRNA and proteins were analyzed using RT-PCR and Western blotting. Activities of CYP enzymes were measured with specific substrates of human orthologous forms. Key findings At the end of the experiment, body weight, plasma insulin and leptin levels as well as the specific content of hepatic CYP enzymes were increased in obese mice. Among CYP enzymes, hepatic CYP2A5 activity, protein and mRNA expression increased most significantly in obese animals. Higher activities and protein levels of hepatic CYP2E1 and 3A in the obese mice were also found. No or a weak effect on CYPs 2C and 2D was observed. In the small intestine and colon, no changes of CYP enzymes were detected except for increased expression of CYP2E1 and decreased expression of CYP3A mRNAs in the colon of the obese mice. Significance Results of our study suggest that the specific content and activities of some liver CYP enzymes (especially CYP2A5) can be increased in obese mice. Higher activity of CYP2A5 (CYP2A6 human ortholog) could lead to altered metabolism of drug substrates of this enzyme (valproic acid, nicotine, methoxyflurane). [ABSTRACT FROM AUTHOR]

Aims Studies have associated obesity with a wide variety of cancers. Metformin, an anti-diabetic drug, has recently received attention as a potentially useful therapeutic agent for treating cancer. Therefore, the objective of this study was to analyze the mechanisms involved in the increase in tumor development and the reduction of it by metformin in obesity using an experimental breast tumor model. Material and methods Newborn male Wistar rats were subcutaneously injected with 400 mg/kg monosodium glutamate (MSG) (obese) or saline (control) at 2, 3, 4, 5 and 6 days of age. After 16 weeks, 1 × 10 7 Walker-256 tumor cells were subcutaneously injected in the right flank of the rats and concomitantly the treatment with metformin 300 mg/kg/15 days, via gavage, started. The rats were divided into 4 groups: control tumor (CT), control tumor metformin (CTM), obese-MSG tumor (OT) and obese-MSG tumor metformin (OTM). On the 18th week the tumor development and metformin effect were analyzed. Key findings Tumor development was higher in OT rats compared with CT rats. Activation of insulin–IR-ERK1/2 pathway and an anti-apoptotic effect might be the mechanisms involved in the higher development of tumor in obesity. The effect of metformin reducing the tumor development in obese rats might involve increased mRNA expression of pRb and p27, increased activity of AMPK and FOXO3a and decreased expression of p-ERK1/2 (Thr202/Tyr204) in Walker-256 tumor. Significance Our data allow us to suggest that metformin, reducing the stimulatory effect of obesity on tumor development, has a potential role in the management of cancers. [ABSTRACT FROM AUTHOR]

Abstract: Monosodium glutamate (MSG) has been the target of research due to its toxicological effects. Aims: We investigated the depressive- and anxiogenic-like behaviors in rats exposed to neonatal subcutaneous injection of MSG. The involvement of the serotonergic system, by measuring [3H] serotonin (5-HT) uptake in cerebral cortices, and the hypothalamic pituitary adrenal (HPA) axis, by determining serum adrenocorticotropic hormone (ACTH) and corticosterone levels, was also examined. Materials and methods: Male and female newborn Wistar rats were divided into control and MSG groups, which received, respectively, a daily subcutaneous injection of saline (0.9%) or MSG (4g/kg/day) from the 1st to 5th postnatal day. The behavioral tests [spontaneous locomotor activity, contextual fear conditioning, and forced swimming test (FST)] were performed from the 60th to 64th postnatal day. MSG-treated animals showed alteration in the spontaneous locomotor activity, an increase in the number of fecal pellets and the number of animal's vocalizations and urine occurrence, and a decrease in the grooming time. Key findings: The MSG exposure increased the immobility time in the FST and the freezing reaction in the contextual fear conditioning. Additionally, MSG treatment increased the [3H]5-HT uptake in the cerebral cortices of rats and induced a deregulation of HPA axis function (by increasing serum ACTH and corticosterone levels). Significance: In conclusion MSG-treated rats are more susceptible to develop anxiogenic- and depressive-like behaviors, which could be related to a dysfunction in the serotonergic system. [Copyright &y& Elsevier]

Aims: Monosodium glutamate (MSG) is a neuroexcitatory amino acid used in human food to enhance flavor. MSG can affect the morphological and electrophysiological organization of the brain. This effect is more severe during brain development. Here, we investigated the electrophysiological and morphological effects of MSG in the developing rat brain by characterizing changes in the excitability-related phenomenon of cortical spreading depression (CSD) and microglial reaction. Main methods: From postnatal days 1–14, Wistar rat pups received 2 or 4g/kg MSG (groups MSG-2 and MSG-4, respectively; n =9 in each group), saline (n =10) or no treatment (naïve group; n =5) every other day. At 45–60days, CSD was recorded on two cortical points for 4h. The CSD parameters velocity, and amplitude and duration of the negative potential change were calculated. Fixative-perfused brain sections were immunolabeled with anti-IBA-1 antibodies to identify and quantify cortical microglia. Key findings: MSG-4 rats presented significantly higher velocities (4.59±0.34mm/min) than the controls (saline, 3.84±0.20mm/min; naïve, 3.71±0.8mm/min) and MSG-2 group (3.75±0.10mm/min). The amplitude (8.8±2.2 to 11.2±1.9mV) and duration (58.2±7.1 to 73.6±6.0s) of the negative slow potential shift was similar in all groups. MSG-treatment dose-dependently increased the microglial immunolabeling. Significance: The results demonstrate a novel, dose-dependent action of MSG in the developing brain, characterized by acceleration of CSD and significant microglial reaction in the cerebral cortex. The CSD effect indicates that MSG can influence cortical excitability, during brain development, as evaluated by CSD acceleration. Data suggest caution when consuming MSG, especially in developing organisms. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Metformin is an insulin sensitizing agent with beneficial effects in diabetic patients on glycemic levels and in the cardiovascular system. We examined whether the metabolic changes and the vascular dysfunction in monosodium glutamate-induced obese non-diabetic (MSG) rats might be improved by metformin. Main methods: 16week-old MSG rats were treated with metformin for 15days and compared with age-matched untreated MSG and non-obese non-diabetic rats (control). Blood pressure, insulin sensitivity, vascular reactivity and prostanoid release in the perfused mesenteric arteriolar bed as well as nitric oxide production and reactive oxygen species generation in isolated mesenteric arteries were analyzed. Key findings: 18-week-old MSG rats displayed higher Lee index, fat accumulation, dyslipidemia, insulin resistance and hyperinsulinemia. Metformin treatment improved these alterations. The norepinephrine-induced response, increased in the mesenteric arteriolar bed from MSG rats, was corrected by metformin. Indomethacin corrected the enhanced contractile response in MSG rats but did not affect metformin effects. The sensitivity to acetylcholine, reduced in MSG rats, was also corrected by metformin. Indomethacin corrected the reduced sensitivity to acetylcholine in MSG rats but did not affect metformin effects. The sensitivity to sodium nitroprusside was increased in preparations from metformin-treated rats. Metformin treatment restored both the reduced PGI2/TXA2 ratio and the increased reactive oxygen species generation in preparations from MSG rats. Significance: Metformin improved the vascular function in MSG rats through reduction in reactive oxygen species generation, modulation of membrane hyperpolarization, correction of the unbalanced prostanoids release and increase in the sensitivity of the smooth muscle to nitric oxide. [Copyright &y& Elsevier]

Abstract: Aims: P-glycoprotein (P-gp) is an important drug efflux transporter located in many tissues such as the blood–brain barrier, intestines, liver and kidneys. We have previously reported that ileal P-gp expression levels decrease via a nitric oxide synthase (NOS)-mediated pathway in a streptozotocin (STZ)-induced type 1 diabetic mouse model. Herein, our objective was to assess whether there are differences in the expression of intestinal P-gp in an obesity-induced hyperglycemic mouse model versus the type 1 diabetic mouse model. Main methods: The hyperglycemia-accompanied obese mouse model was developed through an injection of monosodium glutamate (MSG). We analyzed intestinal P-gp expression using Western blot analysis. Key findings: Body weight, body mass index, blood glucose levels and serum insulin levels increased significantly with age in the MSG-treated mice. Furthermore, in 24week-old MSG-treated mice, while intestinal P-gp expression levels were tended to increase P-gp expression in the duodenum, it was only significant in the jejunum, but not in the ileum. Additionally, the hyperglycemia-accompanied increase in intestinal NOS activity of STZ-treated mice was not evident in the MSG-treated mice. Significance: Our results suggest that P-gp expression levels in the upper part of the intestine increase with age in a hyperglycemia/hyperinsulinemia (i.e. type 2 diabetes) -associated MSG-treated obese mouse model, and that these results completely differ from those found in the STZ-induced type 1 diabetic mouse model. [Copyright &y& Elsevier]

Abstract: Aims: The objective of this study was to analyze the influence of obesity and insulin resistance on tumor development and, in turn, the effect of insulin sensitizing agents. Main methods: Male offspring of Wistar rats received monosodium glutamate (400mg/kg) (obese) or saline (control) from the second to sixth day after birth. Sixteen-week-old control and obese rats received 5×105 Walker-256 tumor cells, subcutaneously injected into the right flank. Some of the obese and control rats received concomitant treatment with metformin (300mg/kg) by gavage. At the 18th week, obesity was characterized. The percentage of rats that developed tumors, the tumor relative weight and the percentage of cachexia incidence were analyzed. The tumor tissue was evaluated histologically by means of hematoxylin and eosin staining. Key findings: Metformin did not correct the insulin resistance in obese rats. The tumor development was significantly higher in the obese group, whereas metformin treatment reduced it. After pathological analysis, we observed that the tumor tissues were similar in all groups except for adipocytes, which were found in greater quantity in the obese and metformin-treated obese groups. The area of tumor necrosis was higher in the group treated with metformin when compared with the untreated one. Significance: Metformin reduced Walker-256 tumor development but not cachexia in obese rats. The reduction occurred independently of the correction of insulin resistance. Metformin increased the area of necrosis in tumor tissues, which may have contributed to the reduced tumor development. [Copyright &y& Elsevier]

Abstract: Aims: The purpose of the present work was to investigate the effect of cyclooxygenase-2 (COX-2) inhibition on the cardiovascular and inflammatory aspects promoted by monosodium glutamate (MSG)-induced obesity in rats. Main methods: Neonatal Wistar male rats were injected with MSG (4mg/g body weight ID) or equimolar saline (control). Treatment with celecoxib (50mg/kg ip) or saline (0.9% NaCl ip) began at 60days of age. At 90days, all rats were anesthetized for catheterization of the femoral artery, and the mean arterial pressure (MAP) and heart rate (HR) were recorded once consciousness was regained. Key findings: MSG obese rats were hypertensive (MAP=138±4mm Hg) compared with controls (MAP=118±2mm Hg). After treatment with celecoxib, the hypertension was attenuated (MAP=126±2mm Hg) in obese rats without changes in HR. The retroperitoneal and periepididymal fat weighed more in obese rats (Obese: Retro=7.08±0.51, Peri=6.36±0.81, Control: Retro=3.60±0.46; Peri=3.24±0.42), but celecoxib did not alter these parameters. Plasma nitric oxide levels were not different between groups. However, the level of plasma prostaglandins, the immunohistochemical staining of COX-2 in cardiac tissue and plasma lipoperoxidation were higher in obese rats, and celecoxib attenuated these parameters. MSG produced liver steatosis that was also attenuated following celecoxib treatment. Significance: Our data demonstrate an association between increased blood pressure and products of COX-2 in obese rats, suggesting a role for prostaglandins in the hypertensive and inflammatory aspects of MSG-induced obesity. [Copyright &y& Elsevier]

Abstract: Aims: We have recently reported that monosodium glutamate (MSG) induces severe obesity with diabetes mellitus and/or non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) in Crj:CD-1(ICR) neonatal mice. In this study, we investigated the effects of varying the dose of MSG on the resulting obesity and diabetes mellitus. Main methods: Crj:CD-1(ICR) neonatal mice were administered MSG in one of several courses: once-daily subcutaneous injections of 2mg/g for 5 consecutive days (2mg/g×5 group), a single subcutaneous injection of 4mg/g (4mg/g×1 group) and once-daily subcutaneous injections of 4mg/g for 5 consecutive days (4mg/g×5 group). Key findings: In all the MSG treatment groups, severe obesity developed by 29weeks of age. The onset of diabetes mellitus and liver lesions (resembling those of human NAFLD/NASH) were observed before 54weeks of age. The obesity, diabetes mellitus and liver lesions were most severe in the 4mg/g×1 group. In the 4mg/g×5 group, increases in body weight and body length were inhibited by MSG''s severe toxicity. Significance: A single 4mg/g dose of MSG is the most suitable as the obese model and induces not only severe obesity and diabetes mellitus, but also liver changes resembling human NAFLD/NASH. A small amount of MSG in the newborn develops obesity and the other complications without hyperphagia after a long term. [Copyright &y& Elsevier]

Sepsis is a potentially fatal systemic inflammatory response and its underlying pathophysiology is still poorly understood. Studies suggest that obesity, a component of metabolic syndrome (MS), is associated with sepsis survival. Therefore, this study focused on investigating the influence of MS on mortality and cardiovascular dysfunction induced by sublethal cecal ligation and puncture (SL-CLP). Newborn Swiss mice received monosodium glutamate (MSG) (4 mg kg−1 day−1, s.c.) during the first 5 d of life for MS induction, while the control pups received equimolar saline solution. On the 75th day, SL-CLP was used to induce mild sepsis (M-CLP) in the MS (MS-M-CLP) and control (SAL-M-CLP) mice. The effect of MS on sepsis in mice was assessed by determining the survival rate and quantification of nitric oxide (NO) in the plasma, and associating this data with hematological and cardiovascular parameters. MS improved the survival of septic mice, preventing impairment to hematological and cardiovascular parameters. In addition, MS attenuated plasmatic NO increase, which is a typical feature of sepsis. These findings provide new insights into the relationship between obesity and mild sepsis in mice, thus revealing an approach in favor of the "obesity paradox." • Metabolic syndrome protects mice from CLP-induced mild sepsis in mice. • Hypotension during sepsis is blunted in mice with metabolic syndrome. • Metabolic syndrome attenuates NO increase during sepsis. • Hematological profile favors MS animals to survive due to sepsis. [ABSTRACT FROM AUTHOR]

Abstract: This study aimed to evaluate whether maternal obesity leads to the onset of diabetes in adult Wistar rats offspring. MSG solution neonatally administration induced obesity in rats (F1MSG group, n =30); and saline solution was also administrated to control rats (F1CON group, n =13). In 3rd month of age, both control and MSG groups were mated for offspring (generation F2), named as F2CON, n =28 and F2MSG groups, n =15; and so both generations were studied until 7th month of life. Lee Index was measured for experimental obesity validation from 5th to 7th month. Glycemia was weekly determined during pregnancy and monthly from 3rd to 7th month. In the end of experimental period all rats were submitted to oral glucose tolerance test (OGTT), with estimation of total area under the curve (AUC); and insulin tolerance test (ITT). Rats were then anesthetized and killed. Data were statistically analyzed with significance level of p <0.05. Lee Index has confirmed obesity in all MSG rats. Glycemic levels comparisons between generations showed significant maternal interference in control and MSG groups. OGTT analysis showed higher glycemia in obese rats (F1MSG) and their offspring (F2MSG) as compared to their respective controls; and MSG groups increased AUC from OGTT. As regards ITT, F2MSG showed higher glycemia at 30 and 120 min, suggesting a delay of insulin action decreasing. Although glucose intolerance and insulin resistance clinical conditions represent as a factors for type 2 Diabetes mellitus development, this experimental model proposal was not efficient to induce type 2 Diabetes mellitus, but for obesity developing, glucose intolerance and insulin resistance in successive generations of rats. [Copyright &y& Elsevier]

Abstract: Exercise has been recommended as a remedy against a worldwide obesity epidemic; however, the onset of excessive weight gain is not fully understood, nor are the effects of exercise on body weight control. Activity deficits of the sympathetic nervous system, including the sympathoadrenal axis, have been suggested to contribute to high fat accumulation in obesity. In the present work, swim training was used to observe fat accumulation and adrenal catecholamine stocks in hypothalamic-obese mice produced by neonatal treatment with monosodium l-glutamate (MSG). MSG-treated and normal mice swam for 15 min/day, 3 days a week, from weaning up to 90 days old (EXE 21–90); from weaning up to 50 days old (EXE 21–50) and from 60 up to 90 days old (EXE 60–90). Sedentary MSG and normal mice (SED groups) did not exercise at all. Animals were sacrificed at 90 days of age. MSG treatment induced obesity, demonstrated by a 43.08% increase in epididymal fat pad weight; these adult obese mice presented 27.7% less catecholamine stocks in their adrenal glands than untreated mice (p <0.001). Exercise reduced fat accumulation and increased adrenal catecholamine content in EXE 21–90 groups. These effects were more pronounced in MSG-mice than in normal ones. Halting the exercise (EXE 21–50 groups) still changed fat accretion and catecholamine stocks; however, no effects were recorded in the EXE 60–90 groups. We conclude that metabolic changes imposed by early exercise, leading to an attenuation of MSG-hypothalamic obesity onset, are at least in part due to sympathoadrenal activity modulation. [Copyright &y& Elsevier]

Abstract: KP-102 (D-Ala-D-β-Nal-Ala-Trp-D-Phe-Lys-NH2), a new second generation hexapeptide, has a potent growth hormone (GH)-releasing action in vivo and in vitro. Here, we evaluated the GH-releasing action of KP-102 under pentobarbital (PB) anesthesia in neonatally sodium-glutamate-monohydrate-treated low growth (NMSG- LG) rats. The plasma GH level in NMSG-LG rats after i.v. administration of KP- 102 at 100 μg/kg was 1/6.7 (95% CL. 1/14.7–1/3.0) of that in normal rats given the same dose (p &#60; 0.01). However, the increase was significant compared with that in normal rats after saline administration (p &#60; 0.0l). The plasma GH releasing action of KP-102 at 100 μg/kg i.v. in rats with lesions in the bilateral hypothalamic arcuate nuclei (ARC), was about 1/6.3 (95% C.L. 1/12.4–1/3.2) of that in normal rats under PB anesthesia (p &#60; 0.01). When KP-102 was injected into the ARC at doses of 0.0002, 0.02 and 2 μg/rat, GH release was dose-related (p &#60; 0.01) under PB anesthesia. KP-102 at 2 μg i.c.v. also increased the plasma GH levels (p &#60; 0.01) to about 1/8.3 (95% C.L. 1/22.7–1/3.1) of that by systematic administration, at the same potency as the ARC injection (1/13.7 and 95% C.L. 1/37.2–1/5.0). These findings suggest that KP-102 potently stimulates the GH release by a direct or indirect antagonism of somatostatin (SRIF) and growth hormone releasing hormone (GHRH) release in the hypothalamus and by a direct action on the pituitary. Furthermore, the GH-releasing action of KP-102 was similar and additive upon both regions in vivo at the maximum effective dose. Moreover, since the GH-release in response to KP-102 administration differed between NMSG-LG and normal rats, and since KP-102 increased the GH release even in NMSG-LG rats, it should be evaluated in the hypophysial GH secretion tests, and may be used to treat the hypophysial GH secretion insufficiency. [Copyright &y& Elsevier]

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 ∼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. [Copyright &y& Elsevier]

Growth hormone (GH) deficiency is a common cause of late sexual maturation and fertility issues. To determine whether GH-induced effects on reproduction are associated with alterations in hypothalamic kisspeptin system, we studied the male reproduction in two distinct GH deficiency mouse models. In the first model, mice present GH deficiency secondary to arcuate nucleus of the hypothalamus (ARH) lesions induced by posnatal monosodium glutamate (MSG) injections. MSG-induced ARH lesions led to significant reductions in hypothalamic Ghrh mRNA expression and consequently growth. Hypothalamic Kiss1 mRNA expression and Kiss1- expressing cells in the ARH were disrupted in the MSG-treated mice. In contrast, kisspeptin immunoreactivity remained preserved in the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) of MSG-treated mice. Importantly, ARH lesions caused late sexual maturation and infertility in male mice. In our second mouse model, we studied animals profound GH deficiency due to a loss-of-function mutation in the Ghrhr gene (Ghrhr lit/lit mice). Interestingly, although Ghrhr lit/lit mice exhibited late puberty onset, hypothalamic Kiss1 mRNA expression and hypothalamic kisspeptin fiber density were normal in Ghrhr lit/lit mice. Despite presenting dwarfism, the majority of Ghrhr lit/lit male mice were fertile. These findings suggest that spontaneous GH deficiency during development does not compromise the kisspeptin system. Furthermore, ARH Kiss1- expressing neurons are required for fertility, while AVPV/PeN kisspeptin expression is sufficient to allow maturation of the hypothalamic-pituitary-gonadal axis in male mice. • Neonatal-induced ARH lesions compromise the kisspeptin system and the somatotropic axis. • Kisspeptin expression in the rostral hypothalamus is sufficient for HPG axis maturation. • Kisspeptin expression in the arcuate nucleus of the hypothalamus is essential for male fertility. • Growth hormone deficiency does not compromise the kisspeptin system. [ABSTRACT FROM AUTHOR]

Obesity is associated with a spectrum of hepatic abnormalities that can be experimentally induced by injections of monosodium glutamate (MSG) in neonatal rodents. We investigated the protective actions of the repeated therapy with 4-phenylselenyl-7-chloroquinoline (4-PSQ), a quinoline derivative containing selenium, on damage to the liver triggered by early postnatal administration of MSG in male Wistar rats. Neonatal rats received MSG (4 g/kg, subcutaneous route) or saline (1 ml/kg) from 5 to 14 postnatal day (PND) to induce obesity with consequent damages in the liver. 4-PSQ treatment (5 mg/kg) or canola oil (1 ml/kg) was administered from 60 to 76 PND by the intragastric route. On 76 PND, animals were anesthetized for blood and liver collection. Plasma markers of hepatic function, hepatic lipoperoxidation levels and histology analysis of liver tissue were assessed. Our data revealed that treatment with 4-PSQ reverted the increase in plasma transaminases activities observed in MSG rats. Treatment with 4-PSQ reduced plasma lactate levels in obese rats. In the liver, MSG elevated the content of lipoperoxidation which was reverted by 4-PSQ administrations. Lastly, 4-PSQ therapy attenuated the histological alterations induced by MSG. Together, the results indicate a hepatoprotective action of repeated treatment with 4-PSQ in obese rats. • MSG caused hepatic damage in rats. • 4-PSQ treatment attenuated the increase of plasma biochemical markers in rats. • 4-PSQ had hepatoprotective action against the injury caused by exposure to MSG. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is a cluster of metabolic abnormalities. Anatomically restructuring of the gastrointestinal system has recently been an important subject of research in the treatment of MetS and closely related diseases. The aim of this study is to ensure the remission of parameters that define MetS by ileal interposition (IT) and to examine the effect of IT on plasma total GLP-1 and pancreatic GLP-1R expression. To induce MetS, newborn male Wistar albino rats were given MSG (4 g/mg) on days 0, 2, 4, 6, 8, and 10. The control group was injected with saline. In the 5th month, IT or sham surgery was performed on the MetS rats. The lipid levels, abdominal obesity, insulin level, OGTT, Lee index, HOMA-IR, plasma GLP-1 and pancreas GLP-1R expression were evaluated 2 months after surgery. The results showed that IT significantly improved hyperinsulinemia (p = 0.013) and lipid profile (TG p = 0.0001; TCHOL p = 0.018; HDL p = 0.001). Furthermore, it normalized the Lee index (p = 0.006) and insulin resistance. The IT did not affect the secretion of the GLP-1, but the expression levels of pancreas GLP-1R were increased (p = 0.006). IT surgery corrected the MetS parameters in this rat model. The healing effects of IT surgery could be caused by mechanisms in the target tissues of insulin. The decrease in pancreatic GLP-1R levels in the MetS groups might be a compensatory response to the harmful effects of hyperinsulinemia in these groups. These results show that IT can be useful in the treatment of MetS. • The metabolic syndrome includes a constellation of several well-established risk factors, which need to be aggressively treated in order to prevent overt type 2 diabetes and cardiovascular disease. • Gastrointestinal metabolic surgery is becoming the most effective therapy for type 2 diabetes in obese patients and is used extensively nowadays. • The mechanisms of recovery of metabolic syndrome with ileal transposition as a metabolic surgical procedure are investigated. • IT surgery restored most of the metabolic parameters altered in rats with metabolic syndrome. In addition, pancreatic GLP-1R expression was significantly increased with IT surgery. • The return of decreased GLP-1R level to control values with metabolic surgery in metabolic syndrome may provide a new approach in the use of GLP-1 analogues in clinical practice. [ABSTRACT FROM AUTHOR]