Physical Exercise Introduced After Weaning Enhances Pancreatic Islet Responsiveness To Glucose And Potentiating Agents In Adult Msg-obese Rats

Physical exercise represents an alternative way to prevent and/or ameliorate chronic metabolic diseases. Disruption of sympathetic nervous system (SNS) activity contributes to adiposity in obese subjects. Here, we verified the preventive effect of swimming training upon adiposity, adrenal catecholamine storage, and pancreatic islet function in obese monosodium glutamate (MSG)-treated rats. Male neonatal Wistar rats received MSG (4 mg/g body weight) during the first 5 days of life and, at weaning, half of the rats were submitted to swimming training, 30 min/day, 3 days a week, until 90 days of age (exercised rats: MSGex). Half of the rats were used as controls (sedentary group, MSGsd). Exercise training (ET) decreased insulinemia and fat deposition in MSGex, and increased adrenal catecholamine content, compared with MSGsd rats. Insulinemia during the ivGTT was lower in MSGex rats, despite a lack of difference in glycemia. Swimming training enhanced insulin release in islets challenged by 2.8-8.3 mmol/l glucose, whereas, at supraphysiological glucose concentrations (11.1-16.7 mmol/l), MSGex islets secreted less insulin than MSGsd. No differences in insulin secretion were observed following l-arginine (Arg) or K+ stimuli. In contrast, islets from MSGex rats secreted more insulin when exposed to carbachol (100 μmol/l), forskolin (10 μmol/l), or IBMX (1 mmol/l) at 8.3 mmol/l glucose. Additionally, MSGex islets presented a better epinephrine inhibition upon insulin release. These results demonstrate that ET prevented the onset of obesity in MSG rats, probably by enhancing adrenal catecholamine levels. ET ameliorates islet responsiveness to several compounds, as well as insulin peripheral action. © Georg Thieme Verlag KG Stuttgart · New York.469609614Arrone, L.J., Mackintosh, R., Rosenbaum, M., Leibel, R.L., Hirsch, J., Cardiac autonomic nervous system activity in obese and never-obese young men (1997) Obes Res, 5, pp. 354-359Kahn, S.E., Prigeon, R.L., Schwartz, R.S., Fujimoto, W.Y., Knopp, R.H., Brunzell, J.D., Porte Jr., D., Obesity, body fat distribution, insulin sensitivity and Islet beta-cell function as explanations for metabolic diversity (2001) J Nutr, 131, pp. 354S-360SKahn, S.E., The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes (2003) Diabetologia, 46, pp. 3-19Bray, G.A., York, D.A., Hypothalamic and genetic obesity in experimental animals: An autonomic and endocrine hypothesis (1979) Physiol Rev, 59, pp. 719-809Bray, G.A., York, D.A., The MONA LISA hypothesis in the time of leptin (1998) Recent Prog Horm Res, 53, pp. 95-117. , discussion 117-118Scomparin, D.X., Gomes, R.M., Grassiolli, S., Rinaldi, W., Martins, A.G., De Oliveira, J.C., Gravena, C., De Freitas Mathias, P.C., Autonomic activity and glycemic homeostasis are maintained by precocious and low intensity training exercises in MSG-programmed obese mice (2009) Endocrine, 36, pp. 510-517Atef, N., Ktorza, A., Picon, L., Penicaud, L., Increased islet blood flow in obese rats: Role of the autonomic nervous system (1992) Am J Physiol, 262, pp. E736-E740Leigh, F.S., Kaufman, L.N., Young, J.B., Diminished epinephrine excretion in genetically obese (ob/ob) mice and monosodium glutamate-treated rats (1992) Int J Obes Relat Metab Disord, 16, pp. 597-604Weyer, C., Salbe, A.D., Lindsay, R.S., Pratley, R.E., Bogardus, C., Tataranni, P.A., Exaggerated pancreatic polypeptide secretion in Pima Indians: Can an increased parasympathetic drive to the pancreas contribute to hyperinsulinemia, obesity, and diabetes in humans (2001) Metabolism, 50, pp. 223-230Quilliot, D., Zannad, F., Ziegler, O., Impaired response of cardiac autonomic nervous system to glucose load in severe obesity (2005) Metabolism, 54, pp. 966-974Inoue, S., Bray, G.A., The effects of subdiaphragmatic vagotomy in rats with ventromedial hypothalamic obesity (1977) Endocrinology, 100, pp. 108-114Edvell, A., Lindstrom, P., Vagotomy in young obese hyperglycemic mice: Effects on syndrome development and islet proliferation (1998) Am J Physiol, 274, pp. E1034-E1039Balbo, S.L., Mathias, P.C., Bonfleur, M.L., Alves, H.F., Siroti, F.J., Monteiro, O.G., Ribeiro, F.B., Souza, A.C., Vagotomy reduces obesity in MSG-treated rats (2000) Res Commun Mol Pathol Pharmacol, 108, pp. 291-296Balbo, S.L., Grassiolli, S., Ribeiro, R.A., Bonfleur, M.L., Gravena, C., Brito Mdo, N., Andreazzi, A.E., Torrezan, R., Fat storage is partially dependent on vagal activity and insulin secretion of hypothalamic obese rat (2007) Endocrine, 31, pp. 142-148Scheurink, A.J., Steffens, A.B., Roossien, B., Balkan, B., Sympathoadrenal function in genetically obese Zucker rats (1992) Physiol Behav, 52, pp. 679-685Barnard, R.J., Wen, S.J., Exercise and diet in the prevention and control of the metabolic syndrome (1994) Sports Med, 18, pp. 218-228Olney, J.W., Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate (1969) Science, 164, pp. 719-721Olney, J.W., Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. An electron microscopic study (1971) J Neuropathol Exp Neurol, 30, pp. 75-90Martins, A.C., Souza, K.L., Shio, M.T., Mathias, P.C., Lelkes, P.I., Garcia, R.M., Adrenal medullary function and expression of catecholamine-synthesizing enzymes in mice with hypothalamic obesity (2004) Life Sci, 74, pp. 3211-3222Nardelli, T.R., Ribeiro, R.A., Balbo, S.L., Vanzela, E.C., Carneiro, E.M., Boschero, A.C., Bonfleur, M.L., Taurine prevents fat deposition and ameliorates plasma lipid profile in monosodium glutamate-obese rats (2011) Amino Acids, 41, pp. 901-908Ribeiro, R.A., Balbo, S.L., Roma, L.P., Camargo, R.L., Barella, L.F., Vanzela, E.C., Carneiro, E.M., Bonfleur, M.L., Impaired muscarinic type 3 (M3) receptor/PKC and PKA pathways in islets form MSG-obese rats (2013) Mol Biol Rep, 40, pp. 4521-4528Scomparin, D.X., Grassiolli, S., Marcal, A.C., Gravena, C., Andreazzi, A.E., Mathias, P.C., Swim training applied at early age is critical to adrenal medulla catecholamine content and to attenuate 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Taurine Prevents Fat Deposition And Ameliorates Plasma Lipid Profile In Monosodium Glutamate-obese Rats

The aim of the present study was to evaluate the preventive effects of taurine (TAU) supplementation upon monosodium glutamate (MSG)-induced obesity. Rats treated during the first 5 days of life with MSG or saline were distributed into the following groups: control (CTL), CTL-treated with TAU (CTAU), MSG and MSG-supplemented with TAU (MTAU). CTAU and MTAU received 2.5% of TAU in their drinking water from 21 to 90 days of life. At the end of treatment, MSG and MTAU rats were hyperinsulinemic, glucose intolerant and insulin resistant, as judged by the HOMA index. MSG and MTAU rat islets secreted more insulin at 16.7 mM glucose compared to CTL. MSG rats also showed higher triglycerides (TG) and non-esterified fatty acids (NEFA) plasma levels, Lee Index, retroperitoneal and periepidydimal fat pads, compared with CTL, whereas plasma lipid concentrations and fat depots were lower in MTAU, compared with MSG rats. In addition, MSG rats had a higher liver TG content compared with CTL. TAU decreased liver TG content in both supplemented groups, but fat content only in MTAU rats. TAU supplementation did not change glucose homeostasis, insulin secretion and action, but reduced plasma and liver lipid levels in MSG rats. © Springer-Verlag 2010.414901908Anuradha, C.V., Balakrishnan, S.D., Taurine attenuates hypertension and improves insulin sensitivity in the fructose-fed rat: An animal model of insulin resistance (1999) Can J Physiol Pharmacol, 77, pp. 749-754Balbo, S.L., Mathias, P.C., Bonfleur, M.L., Alves, H.F., Siroti, F.J., Monteiro, O.G., Ribeiro, F.B., Souza, A.C., Vagotomy reduces obesity in MSG-treated rats (2000) Res Commun Mol Pathol Pharmacol, 108, pp. 291-296Balbo, S.L., Grassiolli, S., Ribeiro, R.A., Bonfleur, M.L., Gravena, C., Brito Mdo, N., Andreazzi, A.E., Torrezan, R., Fat storage is partially dependent on vagal activity and insulin secretion of hypothalamic obese rat (2007) Endocrine, 31, pp. 142-148Bernardis, L.L., Patterson, B.D., Correlation between 'Lee index' and carcass fat content in weanling and adult female rats with hypothalamic lesions (1968) J Endocrinol, 40, pp. 527-528Bonora, E., Targher, G., Alberiche, M., Bonadonna, R.C., Saggiani, F., Zenere, M.B., Monauni, T., Muggeo, M., Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: Studies in subjects with various degrees of glucose tolerance and insulin sensitivity (2000) Diabetes Care, 23, pp. 57-63Boujendar, S., Reusens, B., Merezak, S., Ahn, M.T., Arany, E., Hill, D., Remacle, C., Taurine supplementation to a low protein diet during foetal and early postnatal life restores a normal proliferation and apoptosis of rat pancreatic islets (2002) Diabetologia, 45, pp. 856-866Carneiro, E.M., Latorraca, M.Q., Araujo, E., Beltra, M., Oliveras, M.J., Navarro, M., Berna, G., Martin, F., Taurine supplementation modulates glucose homeostasis and islet function (2009) J Nutr Biochem, 20, pp. 503-511Chen, W., Matuda, K., Nishimura, N., Yokogoshi, H., The effect of taurine on cholesterol degradation in mice fed a high-cholesterol diet (2004) Life Sci, 74, pp. 1889-1898Cherif, H., Reusens, B., Dahri, S., Remacle, C., Hoet, J.J., Stimulatory effects of taurine on insulin secretion by fetal rat islets cultured in vitro (1996) J Endocrinol, 151, pp. 501-506Cherif, H., Reusens, B., Ahn, M.T., Hoet, J.J., Remacle, C., Effects of taurine on the insulin secretion of rat fetal islets from dams fed a low-protein diet (1998) J Endocrinol, 159, pp. 341-348Choi, M.J., Kim, J.H., Chang, K.J., The effect of dietary taurine supplementation on plasma and liver lipid concentrations and free amino acid concentrations in rats fed a high-cholesterol diet (2006) Adv Exp Med Biol, 583, pp. 235-242Dashti, N., The effect of low density lipoproteins, cholesterol, and 25-hydroxycholesterol on apolipoprotein B gene expression in HepG2 cells (1992) J Biol Chem, 267, pp. 7160-7169Dawson Jr., R., Acute and long lasting neurochemical effects of monosodium glutamate administration to mice (1983) Neuropharmacology, 22, pp. 1417-1419Duivenvoorden, I., Teusink, B., Rensen, P.C., Romijn, J.A., Havekes, L.M., Voshol, P.J., Apolipoprotein C3 deficiency results in dietinduced obesity and aggravated insulin resistance in mice (2005) Diabetes, 54, pp. 664-671Folch, J., Lees, M., Sloane Stanley, G.H., A simple method for the isolation and purification of total lipides from animal tissues (1957) J Biol Chem, 226, pp. 497-509Huxtable, R.J., Physiological actions of taurine (1992) Physiol Rev, 72, pp. 101-163Kahn, S.E., Prigeon, R.L., Schwartz, R.S., Fujimoto, W.Y., Knopp, R.H., Brunzell, J.D., Porte Jr., D., Obesity, body fat distribution, insulin sensitivity and islet beta-cell function as explanations for metabolic diversity (2001) J Nutr, 131, pp. 354S-360SKaniuk, N.A., Kiraly, M., Bates, H., Vranic, M., Volchuk, A., Brumell, J.H., Ubiquitinated-protein aggregates form in pancreatic betacells during diabetes-induced oxidative stress and are regulated by autophagy (2007) Diabetes, 56, pp. 930-939Kaplan, B., Karabay, G., Zagyapan, R.D., Ozer, C., Sayan, H., Duyar, I., Effects of taurine in glucose and taurine administration (2004) Amino Acids, 27, pp. 327-333Kulakowski, E.C., Maturo, J., Hypoglycemic properties of taurine: Not mediated by enhanced insulin release (1984) Biochem Pharmacol, 33, pp. 2835-2838Macho, L., Fickova, M., Jezova Zorad, S., Late effects of postnatal administration of monosodium glutamate on insulin action in adult rats (2000) Physiol Res, 49 (1 SUPPL.), pp. S79-S85Martins, A.C., Souza, K.L., Shio, M.T., Mathias, P.C., Lelkes, P.I., Garcia, R.M., Adrenal medullary function and expression of catecholamine- synthesizing enzymes in mice with hypothalamic obesity (2004) Life Sci, 74, pp. 3211-3222Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C., Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man (1985) Diabetologia, 28, pp. 412-419Maturo, J., 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Thirunavukkarasu, V., Anuradha, C.V., Taurine modifies insulin signaling enzymes in the fructose-fed insulin resistant rats (2005) Diabetes Metab, 31, pp. 337-344Nishimura, N., Umeda, C., Ona, H., Yokogoshi, H., The effect of taurine on plasma cholesterol concentration in genetic type 2 diabetic GK rats (2002) J Nutr Sci Vitaminol (Tokyo, 48, pp. 483-490Olney, J.W., Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate (1969) Science, 164, pp. 719-721Olney, J.W., Glutamate-induced neuronal necrosis in the infant mouse hypothalamus. An electron microscopic study (1971) J Neuropathol Exp Neurol, 30, pp. 75-90Olofsson, S.O., Boren, J., Apolipoprotein B: A clinically important apolipoprotein which assembles atherogenic lipoproteins and promotes the development of atherosclerosis (2005) J Intern Med, 258, pp. 395-410Ribeiro, R.A., Bonfleur, M.L., Amaral, A.G., Vanzela, E.C., Rocco, S.A., Boschero, A.C., Carneiro, E.M., Taurine supplementation enhances nutrient-induced insulin secretion in pancreatic mice islets (2009) Diabetes Metab Res Rev, 25, pp. 370-379Ribeiro, R.A., Vanzela, E.C., Oliveira, C.A., Bonfleur, M.L., Boschero, A.C., Carneiro, E.M., Taurine supplementation: Involvement of cholinergic/phospholipase C and protein kinase A pathways in potentiation of insulin secretion and Ca2+ handling in mouse pancreatic islets (2010) Br J Nutr, 104 (8), pp. 1148-1155Tas, S., Sarandol, E., Ayvalik, S.Z., Serdar, Z., Dirican, M., Vanadyl sulfate, taurine, and combined vanadyl sulfate and taurine treatments in diabetic rats: Effects on the oxidative and antioxidative systems (2007) Arch Med Res, 38, pp. 276-283Tsuboyama-Kasaoka, N., Shozawa, C., Sano, K., Kamei, Y., Kasaoka, S., Hosokawa, Y., Ezaki, O., Taurine (2-aminoethanesulfonic acid) deficiency creates a vicious circle promoting obesity (2006) Endocrinology, 147, pp. 3276-3284Xiao, C., Giacca, A., Lewis, G.F., Oral taurine but not N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity and beta cell function in obese and overweight, non-diabetic men (2008) Diabetologia, 51, pp. 139-146Yanagita, T., Han, S.Y., Hu, Y., Nagao, K., Kitajima, H., Murakami, S., Taurine reduces the secretion of apolipoprotein B100 and lipids in HepG2 cells (2008) Lipids Health Dis, 7, p. 38Zhang, M., Bi, L.F., Fang, J.H., Su, X.L., Da, G.L., Kuwamori, T., Kagamimori, S., Beneficial effects of taurine on serum lipids in overweight or obese non-diabetic subjects (2004) Amino Acids, 26, pp. 267-27

Lower Expression Of Pkaα Impairs Insulin Secretion In Islets Isolated From Low-density Lipoprotein Receptor (ldlr -/-) Knockout Mice

Hypercholesterolemic low-density lipoprotein receptor knockout mice (LDLR -/-) show normal whole-body insulin sensitivity, but impaired glucose tolerance due to a reduced insulin secretion in response to glucose. Here, we investigate the possible mechanisms involved in such a defect in isolated LDLR -/- mice islets. Low-fat chow-fed female and male mice aged 20 weeks, LDLR -/- mice, and wild-type (WT) mice were used in this study. Static insulin secretion, cytoplasmatic Ca 2+ analysis, and protein expression were measured in islets isolated from LDLR -/- and WT mice. At basal (2.8 mmol/L) and stimulatory (11.1 mmol/L) glucose concentrations, the insulin secretion rates induced by depolarizing agents such as KCl, l-arginine, and tolbutamide were significantly reduced in LDLR -/- when compared with control (WT) islets. In addition, KCl-induced Ca 2+ influx at 2.8 mmol/L glucose was lower in LDLR -/- islets, suggesting a defect downstream of the substrate metabolism step of the insulin secretion pathway. Insulin secretion induced by the protein kinase A (PKA) activators forskolin and 3-isobutyl-1-methyl-xanthine, in the presence of 11.1 mmol/L glucose, was lower in LDLR -/- islets and was normalized in the presence of the protein kinase C pathway activators carbachol and phorbol 12-myristate 13-acetate. Western blotting analysis showed that phospholipase Cβ 2 expression was increased and PKAα was decreased in LDLR -/- compared with WT islets. 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Duodenal-jejunal bypass normalizes pancreatic islet proliferation rate and function but not hepatic steatosis in hypothalamic obese rats

Modifications in life-style and/or pharmacotherapies contribute to weight loss and ameliorate the metabolic profile of diet-induced obese humans and rodents. Since these strategies fail to treat hypothalamic obesity, we have assessed the possible mechanisms by which duodenal-jejunal bypass (DJB) surgery regulates hepatic lipid metabolism and the morphophysiology of pancreatic islets, in hypothalamic obese (HyO) rats. During the first 5 days of life, male Wistar rats received subcutaneous injections of monosodium glutamate (4 g/kg body weight, HyO group), or saline (CTL). At 90 days of age, HyO rats were randomly subjected to DJB (HyO DJB group) or sham surgery (HyO Sham group). HyO Sham rats were morbidly obese, insulin resistant, hypertriglyceridemic and displayed higher serum concentrations of non-esterified fatty acids (NEFA) and hepatic triglyceride (TG). These effects were associated with higher expressions of the lipogenic genes and fatty acid synthase (FASN) protein content in the liver. Furthermore, hepatic genes involved in β-oxidation and TG export were down-regulated in HyO rats. In addition, these rats exhibited hyperinsulinemia, β-cell hypersecretion, a higher percentage of islets and β-cell area/pancreas section, and enhanced nuclear content of Ki67 protein in islet-cells. At 2 months after DJB surgery, serum concentrations of TG and NEFA, but not hepatic TG accumulation and gene and protein expressions, were normalized in HyO rats. Insulin release and Ki67 positive cells were also normalized in HyO DJB islets. In conclusion, DJB decreased islet-cell proliferation, normalized insulinemia, and ameliorated insulin sensitivity and plasma lipid profile, independently of changes in hepatic metabolism

Maternal Roux-en-Y gastric bypass impairs insulin action and endocrine pancreatic function in male F1 offspring

Purpose: Obesity is predominant in women of reproductive age. Roux-en-Y gastric bypass (RYGB) is the most common bariatric procedure that is performed in obese women for weight loss and metabolic improvement. However, some studies suggest that this procedure negatively affects offspring. Herein, using Western diet (WD)-obese female rats, we investigated the effects of maternal RYGB on postnatal body development, glucose tolerance, insulin secretion and action in their adult male F1 offspring. Methods: Female Wistar rats consumed a Western diet (WD) for 18 weeks, before being submitted to RYGB (WD-RYGB) or SHAM (WD-SHAM) operations. After 5 weeks, WD-RYGB and WD-SHAM females were mated with control male breeders, and the F1 offspring were identified as: WD-RYGB-F1 and WD-SHAM-F1. Results: The male F1 offspring of WD-RYGB dams exhibited decreased BW, but enhanced total nasoanal length gain. At 120 days of age, WD-RYGB-F1 rats displayed normal fasting glycemia and glucose tolerance but demonstrated reduced insulinemia and higher glucose disappearance after insulin stimulus. In addition, these rodents presented insulin resistance in the gastrocnemius muscle and retroperitoneal fat, as judged by lower Akt phosphorylation after insulin administration, but an increase in this protein in the liver. Finally, the islets from WD-RYGB-F1 rats secreted less insulin in response to glucose and displayed increased β-cell area and mass. Conclusions: RYGB in WD dams negatively affected their F1 offspring, leading to catch-up growth, insulin resistance in skeletal muscle and white fat, and β-cell dysfunction. Therefore, our data are the first to demonstrate that the RYGB in female rats may aggravate the metabolic imprinting induced by maternal WD consumption, in their male F1 descendants. However, since we only used male F1 rats, further studies are necessary to demonstrate if such effect may also occur in female F1 offspring from dams that underwent RYGB operation.5931067107

Impaired Muscarinic Type 3 (m3) Receptor/pkc And Pka Pathways In Islets From Msg-obese Rats

Monosodium glutamate-obese rats are glucose intolerant and insulin resistant. Their pancreatic islets secrete more insulin at increasing glucose concentrations, despite the possible imbalance in the autonomic nervous system of these rats. Here, we investigate the involvement of the cholinergic/protein kinase (PK)-C and PKA pathways in MSG β-cell function. Male newborn Wistar rats received a subcutaneous injection of MSG (4 g/kg body weight (BW)) or hyperosmotic saline solution during the first 5 days of life. At 90 days of life, plasma parameters, islet static insulin secretion and protein expression were analyzed. Monosodium glutamate rats presented lower body weight and decreased nasoanal length, but had higher body fat depots, glucose intolerance, hyperinsulinemia and hypertrigliceridemia. Their pancreatic islets secreted more insulin in the presence of increasing glucose concentrations with no modifications in the islet-protein content of the glucose-sensing proteins: the glucose transporter (GLUT)-2 and glycokinase. However, MSG islets presented a lower secretory capacity at 40 mM K+ (P < 0.05). The MSG group also released less insulin in response to 100 μM carbachol, 10 μM forskolin and 1 mM 3-isobutyl-1-methyl-xantine (P < 0.05, P < 0.0001 and P < 0.01). These effects may be associated with a the decrease of 46 % in the acetylcholine muscarinic type 3 (M3) receptor, and a reduction of 64 % in PKCα and 36 % in PKAα protein expressions in MSG islets. 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