Nociceptive And Histomorphometric Characteristics Of Median Nerves Of Rats With Obesity Induced By Monosodium Glutamate [características Nociceptivas E Histomorfométricas De Nervos Medianos De Ratos Com Obesidade Induzida Pelo Glutamato Monossódico]

Aims: To compare nociception and, histomorphometrically, the transverse section of peripheral nerves (median) of Wistar rats submitted to obesity model induced by monosodium glutamate with control animals. Methods: Fourteen Wistar rats divided into control and obese groups were used. During the five first days since birth the rats from obese group received a daily subcutaneous injection of monosodium glutamate (4 g/kg body weight/day), while the control group received hypertonic saline (1.25 g/kg body weight/day). Nociception was evaluated by the withdrawal threshold of the limb, using digital analgesymeter type Von Frey, with the stimulus given in the palmar region of the right hind paw. The first assessment was carried out about 20 days before euthanasia, and the second assessment was performed on the day before euthanasia. Subsequently the median nerve was dissected in the elbow region and processed with cross sections for histological analysis. The analyzed variables were: number of axons per field; axons, fibers and myelin sheath diameters, and G coefficient. The results were analyzed using the t test for independent samples and paired t test, with a significance level of 5%. RESULTS: Fourteen rats were assessed, being seven of the obese group and seven of control group. The evaluation of nociception showed that the animals of the obese group had lower withdrawal threshold. For histomorphometric data, the results showed no significant differences between the two groups. Conclusions: The obese animals showed lower nociceptive threshold, however, there were no morphometric differences of the median nerves between animals subjected to the model of obesity induced by monosodium glutamate and the control group.24411Luz, D.M.D., Encarnação, J.N., Vantagens e desvantagens da cirurgia bariátrica para o tratamento da obesidade mórbida (2008) Rev Bras Obesidade, Nutr e Emagrecimento., 2 (10), pp. 376-383Molinatti, G.M., Limone, P., Obesity: a challenge for the clinician (1992) Front Diabetes., 11, pp. 7-15Muller, H.L., Bueb, K., Bartels, U., Roth, C., Harz, K., Graf, N., Obesity after childhood craniopharyngioma--German multicenter study on pre-operative risk factors and quality of life (2001) Klin Padiatr., 213 (4), pp. 244-249Sowers, J.R., Draznin, B., Insulin, cation metabolism and insulin resistance (1998) J Basic Clin Physiol Pharmacol., 9 (2-4), pp. 223-233Dobretsov, M., Romanovsky, D., Stimers, J.R., Early diabetic neuropathy: Triggers and mechanisms (2007) World J Gastroenterol., 13 (2), pp. 175-191Kellogg, A.P., Cheng, H.T., Pop-Busui, R., Cyclooxygenase-2 pathway as a potential therapeutic target in diabetic peripheral neuropathy (2008) Curr Drug Targets., 9 (1), pp. 68-76Won, J.C., Kim, S.S., Ko, K.S., Cha, B., Current status of diabetic peripheral neuropathy in Korea: report of a hospital-based study of type 2 diabetic patients in Korea by the diabetic neuropathy study group of the korean diabetes association (2014) Diabetes Metab J., 38 (1), pp. 25-31Callaghan, B.C., Hur, J., Feldman, E.L., Diabetic neuropathy: one disease or two? (2012) Curr Opin Neurol., 25 (5), pp. 536-541Davidson, E.P., Coppey, L.J., Kardon, R.H., Yorek, M.A., Differences and similarities in development of corneal nerve damage and peripheral neuropathy and in diet-induced obesity and type 2 diabetic rats (2014) Invest Ophthalmol Vis Sci., 55 (3), pp. 1222-1230Obrosova, I.G., Diabetic painful and insensate neuropathy: pathogenesis and potential treatments (2009) Neurotherapeutics., 6 (4), pp. 638-647Olney, J.W., Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate (1969) Science (80-), 164 (3880), pp. 719-721Macho, L., Ficková, M., Jezová, D., Zórad, S., Late effects of postnatal administration of monosodium glutamate on insulin action in adult rats (2000) Physiol Res., 49, pp. S79-85Nagata, M., Suzuki, W., Iizuka, S., Tabuchi, M., Maruyama, H., Takeda, S., Type 2 diabetes mellitus in obese mouse model induced by monosodium glutamate (2006) Exp Anim., 55 (2), pp. 109-115Balbo, S.L., Grassiolli, S., Ribeiro, R.A., Bonfleur, M.L., Gravena, C., Brito, M.N., Fat storage is partially dependent on vagal activity and insulin secretion of hypothalamic obese rat (2007) Endocrine., 31 (2), pp. 142-148Balbo, S.L., Gravena, C., Bonfleur, M.L., Mathias, P.C.F., Insulin secretion and acetylcholinesterase activity in monosodium L-glutamate-induced obese mice (2000) Horm Res., 54 (4), pp. 186-191Roman-Ramos, R., Almanza-Perez, J.C., Garcia-Macedo, R., Blancas-Flores, G., Fortis-Barrera, A., Jasso, E.I., Monosodium glutamate neonatal intoxication associated with obesity in adult stage is characterized by chronic inflammation and increased mRNA expression of peroxisome proliferator-activated receptors in mice (2011) Basic Clin Pharmacol Toxicol., 108 (6), pp. 406-413Marcioli, M.A.R., Coradini, J.G., Kunz, R.I., Ribeiro, L.D.F.C., Brancalhão, R.M.C., Bertolini, G.R.F., Nociceptive and histomorphometric evaluation of neural mobilization in experimental injury of the median nerve (2013) ScientificWorldJournalVivancos, G.G., Verri, W.A., Jr., Cunha, T.M., Schivo, I.R.S., Parada, C.A., Cunha, F.Q., An electronic pressure-meter nociception paw test for rats (2004) Braz J Med Biol Res., 37 (3), pp. 391-399Bernardis, 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. 527-528Hernández-Bautista, R.J., Alarcón-Aguilar, F.J., Escobar-Villanueva, M.D.C., Almanza-Pérez, J.C., Merino-Aguilar, H., Fainstein, M.K., Biochemical alterations during the obese-aging process in female and male monosodium glutamate (MSG)-treated mice (2014), pp. 11473-11494Miranda, R.A., Agostinho, A.R., Trevenzoli, I.H., Barella, L.F., Franco, C.C.S., Trombini, A.B., Insulin oversecretion in MSG-obese rats is related to alterations in cholinergic muscarinic receptor subtypes in pancreatic islets (2014) Cell Physiol Biochem., 33 (4), pp. 1075-1086De Souza, F., Marchesini, J.B., Campos, A.C.L., Malafaia, O., Monteiro, O.G., Ribeiro, F.B., Efeito da vagotomia troncular em ratos injetados na fase neonatal com glutamato monossódico: estudo biométrico (2001) Acta Cir Bras., 16 (1), pp. 32-45Soares, A., Schoffen, J.P.F., De Gouveia, E.M., Natali, M.R.M., Effects of the neonatal treatment with monosodium glutamate on myenteric neurons and the intestine wall in the ileum of rats (2006) J Gastroenterol., 41 (7), pp. 674-680De Sá, J.M.R., Mazzer, N., Barbieri, C.H., Barreira, A.A., The end-to-side peripheral nerve repair Functional and morphometric study using the peroneal nerve of rats (2004) J Neurosci Methods., 136 (1), pp. 45-53Lopes-Filho, J.D., Caldas, H.C., Santos, F.C.A., Mazzer, N., Simões, G.F., Kawasaki-Oyama, R.S., Microscopic evidences that bone marrow mononuclear cell treatment improves sciatic nerve regeneration after neurorrhaphy (2011) Microsc Res Tech., 74 (4), pp. 355-363Mendonça, A.C., Barbieri, C.H., Mazzer, N., Directly applied low intensity direct electric current enhances peripheral nerve regeneration in rats (2003) J Neurosci Methods., 129 (2), pp. 183-19

Taurine Supplementation: Involvement Of Cholinergic/phospholipase C And Protein Kinase A Pathways In Potentiation Of Insulin Secretion And Ca 2+ Handling In Mouse Pancreatic Islets

Taurine (TAU) supplementation increases insulin secretion in response to high glucose concentrations in rodent islets. This effect is probably due to an increase in Ca2+ handling by the islet cells. Here, we investigated the possible involvement of the cholinergic/phospholipase C (PLC) and protein kinase (PK) A pathways in this process. Adult mice were fed with 2% TAU in drinking water for 30d. The mice were killed and pancreatic islets isolated by the collagenase method. Islets from TAU-supplemented mice showed higher insulin secretion in the presence of 83mm-glucose, 100μm-carbachol (Cch) and 1mm-3-isobutyl-1-methyl-xanthine (IBMX), respectively. The increase in insulin secretion in response to Cch in TAU islets was accompanied by a higher intracellular Ca2+ mobilisation and PLCβ2 protein expression. The Ca2+ uptake was higher in TAU islets in the presence of 83mm-glucose, but similar when the islets were challenged by glucose plus IBMX. TAU islets also showed an increase in the expression of PKA protein. This protein may play a role in cation accumulation, since the amount of Ca 2+ in these islets was significantly reduced by the PKA inhibitors: N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide (H89) and PK inhibitor-(6-22)-amide (PKI). In conclusion, TAU supplementation increases insulin secretion in response to glucose, favouring both influx and internal mobilisation of Ca2+, and these effects seem to involve the activation of both PLC-inositol-1,4,5-trisphosphate and cAMP-PKA pathways. © The Authors 2010.104811481155Jones, P.M., Persaud, S.J., Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic β-cells (1998) Endocr Rev, 19, pp. 429-461Tengholm, A., Gylfe, E., Oscillatory control of insulin secretion (2009) Mol Cell Endocrinol, 297, pp. 58-72Rorsman, P., Renström, E., Insulin granule dynamics in pancreatic b cells (2003) Diabetologia, 46, pp. 1029-1045Gromada, J., Høy, M., Renström, E., CaM kinase II-dependent mobilization of secretory granules underlies acetylcholine-induced stimulation of exocytosis in mouse pancreatic B-cells (1999) J Physiol, 518, pp. 745-759Leech, C.A., Castonguay, M.A., Habener, J.F., Expression of adenylyl cyclase subtypes in pancreatic β-cells (1999) Biochem Biophys Res Commun, 254, pp. 703-706Delmeire, D., Flamez, D., Hinke, S.A., Type VIII adenylyl cyclase in rat b cells: Coincidence signal detector/generator for glucose and GLP-1 (2003) Diabetologia, 46, pp. 1383-1393Rhee, S.G., Regulation of phosphoinositide-specific phospholipase C (2001) Annu Rev Biochem, 70, pp. 281-312Thore, S., Dyachok, O., Gylfe, E., Feedback activation of phospholipase C via intracellular mobilization and storeoperated influx of Ca2+ in insulin-secreting β-cells (2005) J Cell Sci, 118, pp. 4463-4471Thore, S., Wuttke, A., Tengholm, A., Rapid turnover of phosphatidylinositol-4,5-bisphosphate in insulin-secreting cells mediated by Ca2+ and the ATP-to-ADP ratio (2007) Diabetes, 56, pp. 818-826Liu, Y.J., Gylfe, E., Store-operated Ca2+ entry in insulinreleasing pancreatic β-cells (1997) Cell Calcium, 22, pp. 277-286Berridge, M.J., Bootman, M.D., Roderick, H.L., Calcium signalling: Dynamics, homeostasis and remodelling (2003) Nat Rev Mol Cell Biol, 4, pp. 517-529Ammala, C., Eliasson, L., Bokvist, K., Exocytosis elicited by action potentials and voltage-clamp calcium currents in individual mouse pancreatic B-cells (1993) J Physiol, 472, pp. 665-688Leiser, M., Fleischer, N., CAMP-dependent phosphorylation of the cardiac-type a1 subunit of the voltage-dependent Ca2+ channel in a murine pancreatic β-cell line (1996) Diabetes, 45, pp. 1412-1418Gao, T., Yatani, A., Dell'Acqua, M.L., CAMPdependent regulation of cardiac L-type Ca2+ channels requires membrane targeting of PKA and phosphorylation of channel subunits (1997) Neuron, 19, pp. 185-196Dyachok, O., Gylfe, E., Ca2+-induced Ca2+ release via inositol 1,4,5-trisphosphate receptors is amplified by protein kinase A and triggers exocytosis in pancreatic β-cells (2004) J Biol Chem, 279, pp. 45455-45461Grapengiesser, E., Gylfe, E., Hellman, B., Cyclic AMP as a determinant for glucose induction of fast Ca2+ oscillations in isolated pancreatic β-cells (1991) J Biol Chem, 266, pp. 12207-12210Seino, S., Shibasaki, T., PKA-dependent and PKAindependent pathways for cAMP-regulated exocytosis (2005) Physiol Rev, 85, pp. 1303-1342Hatakeyama, H., Kishimoto, T., Nemoto, T., Rapid glucose sensing by protein kinase A for insulin exocytosis in mouse pancreatic islets (2006) J Physiol, 570, pp. 271-282Schaffer, S., Takahashi, K., Azuma, J., Role of osmoregulation in the actions of taurine (2000) Amino Acids, 19, pp. 527-546Satoh, H., Cardiac actions of taurine as a modulator of the ion channels (1998) Adv Exp Med Biol, 442, pp. 121-128Satoh, H., Sperelakis, N., Review of some actions of taurine on ion channels of cardiac muscle cells and others (1998) Gen Pharmacol, 30, pp. 451-463Palmi, M., Youmbi, G.T., Fusi, F., Potentiation of mitochondrial Ca2+ sequestration by taurine (1999) Biochem Pharmacol, 58, pp. 1123-1131Lee, S.H., Lee, H.Y., Kim, S.Y., Enhancing effect of taurine on glucose response in UCP2-overexpressing β cells (2004) Diabetes Res Clin Pract, 66 (SUPPL. 1), pp. S69-S74Park, E.J., Bae, J.H., Kim, S.Y., Inhibition of ATPsensitive K+ channels by taurine through a benzamido-binding site on sulfonylurea receptor 1 (2004) Biochem Pharmacol, 67, pp. 1089-1096Cherif, H., Reusens, B., Dahri, S., Stimulatory effects of taurine on insulin secretion by fetal rat islets cultured in vitro (1996) J Endocrinol, 151, pp. 501-506Carneiro, E.M., Latorraca, M.Q., Araujo, E., Taurine supplementation modulates glucose homeostasis and islet function (2009) J Nutr. Biochem, 20, pp. 503-511Ribeiro, R.A., Bonfleur, M.L., Amaral, A.G., Taurine supplementation enhances nutrient-induced insulin secretion in pancreatic mice islets (2009) Diabetes Metab Res Rev, 25, pp. 370-379Loizzo, A., Carta, S., Bennardini, F., Neonatal taurine administration modifies metabolic programming in male mice (2007) Early Hum Dev, 83, pp. 693-696Dyachok, O., Idevall-Hagren, O., Sagetorp, J., Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion (2008) Cell Metab, 8, pp. 26-37Scott, A.M., Atwater, I., Rojas, E., A method for the simultaneous measurement of insulin release and B cell membrane potential in single mouse islets of Langerhans (1981) Diabetologia, 21, pp. 470-475Bidlingmeyer, B.A., Cohen, S.A., Tarvin, T.L., A new, rapid, high-sensitivity analysis of amino acids in food type samples (1987) J Assoc Off Anal Chem, 70, pp. 241-247Bradford, M.M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding (1976) Anal Biochem, 72, pp. 248-254Bustamante, J., Lobo, M.V., Alonso, F.J., An osmoticsensitive taurine pool is localized in rat pancreatic islet cells containing glucagon and somatostatin (2001) Am J Physiol Endocrinol Metab, 281, pp. E1275-E1285Niwa, T., Matsukawa, Y., Senda, T., Acetylcholine activates intracellular movement of insulin granules in pancreatic β-cells via inositol trisphosphate-dependent [correction of triphosphate-dependent] mobilization of intracellular Ca2+ (1998) Diabetes, 47, pp. 1699-1706Dyachok, O., Isakov, Y., Sagetorp, J., Oscillations of cyclic AMP in hormone-stimulated insulin-secreting β-cells (2006) Nature, 439, pp. 349-352Rajan, A.S., Hill, R.S., Boyd III, A.E., Effect of rise in cAMP levels on Ca2+ influx through voltage-dependent Ca2+ channels in HIT cells second-messenger synarchy in β-cells (1989) Diabetes, 38, pp. 874-880Mundina-Weilenmann, C., Chang, C.F., Gutierrez, L.M., Demonstration of the phosphorylation of dihydropyridine- sensitive calcium channels in chick skeletal muscle and the resultant activation of the channels after reconstitution (1991) J Biol Chem, 266, pp. 4067-4073Bourinet, E., Charnet, P., Tomlinson, W.J., Voltagedependent facilitation of a neuronal a1C L-type calcium channel (1994) Embo J, 13, pp. 5032-5039Kamp, T.J., Hell, J.W., Regulation of cardiac L-type calcium channels by protein kinase A and protein kinase C (2000) Circ Res, 87, pp. 1095-110

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 monosodium L-glutamate-obesity onset in mice (2006) Life Sci, 79, pp. 2151-2156Andreazzi, A.E., Scomparin, D.X., Mesquita, F.P., Balbo, S.L., Gravena, C., De Oliveira, J.C., Rinaldi, W., Mathias, P.C., Swimming exercise at weaning improves glycemic control and inhibits the onset of monosodium L-glutamate-obesity in mice (2009) J Endocrinol, 201, pp. 351-359Scomparin, D.X., Grassiolli, S., Gomes, R.M., Torrezan, R., De Oliveira, J.C., Gravena, C., Pera, C.C., Mathias, P.C., Low-Intensity swimming training after weaning improves glucose and lipid homeostasis in MSG hypothalamic obese mice (2011) Endocr Res, 36, pp. 83-90Delghingaro-Augusto, V., Decary, S., Peyot, M.L., Latour, M.G., Lamontagne, J., Paradis-Isler, N., Lacharite-Lemieux, M., Bergeron, R., Voluntary running exercise prevents beta-cell failure in susceptible islets of the Zucker diabetic fatty rat (2012) Am J Physiol Endocrinol Metab, 302, pp. E254-E264Balbo, S.L., Bonfleur, M.L., Carneiro, E.M., Amaral, M.E., Filiputti, E., Mathias, P.C., Parasympathetic activity changes insulin response to glucose and neurotransmitters (2002) Diabetes Metab, 28, pp. 3S13-3S17. , discussion 13S108-13S112Harms, P.G., Ojeda, S.R., A rapid and simple procedure for chronic cannulation of the rat jugular vein (1974) J Appl Physiol, 36, pp. 391-392Ribeiro, 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, pp. 1148-1155Bernardis, 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. 527-528Pollard, H.B., Ornberg, R., Levine, M., Brocklehurst, K., Forsberg, E., Lelkes, P.I., Morita, K., Regulation of secretion from adrenal chromaffin cells (1985) Physiologist, 28, pp. 247-254Gautam, D., Han, S.J., Hamdan, F.F., Jeon, J., Li, B., Li, J.H., Cui, Y., Wess, J., A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo (2006) Cell Metab, 3, pp. 449-461Theintz, G.E., The endocrine impact of sports (1986) Schweiz Med Wochenschr, 116, pp. 413-418Nonogaki, K., New insights into sympathetic regulation of glucose and fat metabolism (2000) Diabetologia, 43, pp. 533-549Holloszy, J.O., Exercise-induced increase in muscle insulin sensitivity (2005) J Appl Physiol, 99, pp. 338-343. , (1985)Frosig, C., Richter, E.A., Improved insulin sensitivity after exercise: Focus on insulin signaling (2009) Obesity (Silver Spring), 17, pp. S15-S20. , 03Corcoran, M.P., Lamon-Fava, S., Fielding, R.A., Skeletal muscle lipid deposition and insulin resistance: Effect of dietary fatty acids and exercise (2007) Am J Clin Nutr, 85, pp. 662-677Miranda, R.A., Branco, R.C., Gravena, C., Barella, L.F., Da Silva Franco, C.C., Andreazzi, A.E., De Oliveira, J.C., De Freitas Mathias, P.C., Swim training of monosodium L-glutamate-obese mice improves the impaired insulin receptor tyrosine phosphorylation in pancreatic islets (2013) Endocrine, 43, pp. 571-578Zoppi, C.C., Calegari, V.C., Silveira, L.R., Carneiro, E.M., Boschero, A.C., Exercise training enhances rat pancreatic islets anaplerotic enzymes content despite reduced insulin secretion (2011) Eur J Appl Physiol, 111, pp. 2369-2374Calegari, V.C., Zoppi, C.C., Rezende, L.F., Silveira, L.R., Carneiro, E.M., Boschero, A.C., Endurance training activates AMP-activated protein kinase, increases expression of uncoupling protein 2 and reduces insulin secretion from rat pancreatic islets (2011) J Endocrinol, 208, pp. 257-264Tsuchiya, M., Manabe, Y., Yamada, K., Furuichi, Y., Hosaka, M., Fujii, N.L., Chronic exercise enhances insulin secretion ability of pancreatic islets without change in insulin content in non-diabetic rats (2013) Biochem Biophys Res Commun, 430, pp. 676-682Wang, Y.H., Hu, H., Wang, S.P., Tian, Z.J., Zhang, Q.J., Li, Q.X., Li, Y.Y., Zang, W.J., Exercise benefits cardiovascular health in hyperlipidemia rats correlating with changes of the cardiac vagus nerve (2010) Eur J Appl Physiol, 108, pp. 459-468Urano, Y., Sakurai, T., Ueda, H., Ogasawara, J., Sakurai, T., Takei, M., Izawa, T., Desensitization of the inhibitory effect of norepinephrine on insulin secretion from pancreatic islets of exercise-trained rats (2004) Metabolism, 53, pp. 1424-143

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., Kulakowski, E.C., Taurine binding to the purified insulin receptor (1988) Biochem Pharmacol, 37, pp. 3755-3760Mizushima, S., Nara, Y., Sawamura, M., Yamori, Y., Effects of oral taurine supplementation on lipids and sympathetic nerve tone (1996) Adv Exp Med Biol, 403, pp. 615-622Murakami, S., Kondo, Y., Nagate, T., Effects of long-term treatment with taurine in mice fed a high-fat diet: Improvement in cholesterol metabolism and vascular lipid accumulation by taurine (2000) Adv Exp Med Biol, 483, pp. 177-186Murakami, S., Kondo, Y., Toda, Y., Kitajima, H., Kameo, K., Sakono, M., Fukuda, N., Effect of taurine on cholesterol metabolism in hamsters: Up-regulation of low density lipoprotein (LDL) receptor by taurine (2002) Life Sci, 70, pp. 2355-2366Nakaya, Y., Minami, A., Harada, N., Sakamoto, S., Niwa, Y., Ohnaka, M., Taurine improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous type 2 diabetes (2000) Am J Clin Nutr, 71, pp. 54-58Nandhini, A.T., 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. Results indicate that the lower insulin secretion observed in islets from LDLR -/- mice at postprandial levels of glucose can be explained, at least in part, by the reduced expression of PKAα in these islets. © 2011 Elsevier Inc.60811581164Fujimoto, W.Y., Background and recruitment data for the U.S. Diabetes Prevention Program (2000) Diabetes Care, 23, pp. 11-B13Wilson, P.W., Diabetes mellitus and coronary heart disease (1998) Am J Kidney Dis, 32, pp. 89-100Haffner, S.M., Management of dyslipidemia in adults with diabetes (1998) Diabetes Care, 21 (1), pp. 160-178Ginsberg, H.N., Zhang, Y.-L., Hernandez-Ono, A., Regulation of plasma triglycerides in insulin resistance and diabetes (2005) Archives of Medical Research, 36 (3), pp. 232-240. , DOI 10.1016/j.arcmed.2005.01.005, PII S0188440905000068, Current Trends in DiabetesGinsberg, H.N., Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis (1991) Diabetes Care, 14, pp. 839-855Caparevic, Z., Kostic, N., Ilic, S., Oxidized LDL and C-reactive protein as markers for detection of accelerated atherosclerosis in type 2 diabetes (2006) Med Pregl, 59, pp. 160-164Cohen, M.P., Jin, Y., Lautenslager, G.T., Increased plasma glycated low-density lipoprotein concentrations in diabetes: A marker of atherogenic risk (2004) Diabetes Technology and Therapeutics, 6 (3), pp. 348-356. , DOI 10.1089/152091504774198043Breslow, J.L., Mouse models of atherosclerosis (1996) Science, 272 (5262), pp. 685-688Ishibashi, S., Brown, M.S., Goldstein, J.L., Gerard, R.D., Hammer, R.E., Herz, J., Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery (1993) Journal of Clinical Investigation, 92 (2), pp. 883-893Merat, S., Casanada, F., Sutphin, M., Palinski, W., Reaven, P.D., Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet (1999) Arteriosclerosis, Thrombosis, and Vascular Biology, 19 (5), pp. 1223-1230Schreyer, S.A., Vick, C., Lystig, T.C., LDL receptor but not apolipoprotein e deficiency increases diet-induced obesity and diabetes in mice (2002) Am J Physiol Endocrinol Metab, 282, pp. 207-E214Bonfleur, M.L., Vanzela, E.C., Ribeiro, R.A., Primary hypercholesterolaemia impairs glucose homeostasis and insulin secretion in low-density lipoprotein receptor knockout mice independently of high-fat diet and obesity (2010) Biochim Biophys Acta, 1801, pp. 183-190Scott, A.M., Atwater, I., Rojas, E., A method for the simultaneous measurement of insulin release and B cell membrane potential in single mouse islets of Langerhans (1981) Diabetologia, 21 (5), pp. 470-475Bradford, M.M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding (1976) Anal Biochem, 72, pp. 248-254Newton, A.C., Protein kinase C: Structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions (2001) Chemical Reviews, 101 (8), pp. 2353-2364. , DOI 10.1021/cr0002801Xia, F., Gao, X., Kwan, E., Lam, P.P.L., Chan, L., Sy, K., Sheu, L., Tsushima, R.G., Disruption of pancreatic β-cell lipid rafts modifies K v2.1 channel gating and insulin exocytosis (2004) Journal of Biological Chemistry, 279 (23), pp. 24685-24691. , DOI 10.1074/jbc.M314314200Schulla, V., Renstrom, E., Feil, R., Feil, S., Franklin, I., Gjinovci, A., Jing, X.-J., Hofmann, F., Impaired insulin secretion and glucose tolerance in β cell-selective Ca v1.2 Ca 2+ channel null mice (2003) EMBO Journal, 22 (15), pp. 3844-3854. , DOI 10.1093/emboj/cdg389Iwashima, Y., Abiko, A., Ushikubi, F., Hata, A., Kaku, K., Sano, H., Eto, M., Downregulation of the voltage-dependent calcium channel (VDCC) β-subunit mRNAs in pancreatic islets of type 2 diabetic rats (2001) Biochemical and Biophysical Research Communications, 280 (3), pp. 923-932. , DOI 10.1006/bbrc.2000.4122Straub, S.G., Sharp, G.W.G., Glucose-stimulated signaling pathways in biphasic insulin secretion (2002) Diabetes/Metabolism Research and Reviews, 18 (6), pp. 451-463. , DOI 10.1002/dmrr.329Gembal, M., Detimary, P., Gilon, P., Gao, Z.-Y., Henquin, J.-C., Mechanisms by which glucose can control insulin release independently from its action on adenosine triphosphate-sensitive K + channels in mouse B cells (1993) Journal of Clinical Investigation, 91 (3), pp. 871-880Gembal, M., Gilon, P., Henquin, J.C., Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells (1992) J Clin Invest, 89, pp. 1288-1295Sato, Y., Aizawa, T., Komatsu, M., Dual functional role of membrane depolarization/Ca2+ influx in rat pancreatic B-cell (1992) Diabetes, 41, pp. 438-443Jones, P.M., Persaud, S.J., Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic β-cells (1998) Endocrine Reviews, 19 (4), pp. 429-461Boschero, A.C., Szpak-Glasman, M., Carneiro, E.M., Oxotremorine-m potentiation of glucose-induced insulin release from rat islets involves M3 muscarinic receptors (1995) Am J Physiol, 268, pp. 336-E342Malaisse, W.J., Pipeleers, D.G., Levy, J., The stimulus-secretion coupling of glucose-induced insulin release. XVI. A glucose-like and calcium-independent effect of cyclic AMP (1974) Biochim Biophys Acta, 362, pp. 121-128Dyachok, O., Idevall-Hagren, O., Sagetorp, J., Tian, G., Wuttke, A., Arrieumerlou, C., Akusjarvi, G., Tengholm, A., Glucose-Induced Cyclic AMP Oscillations Regulate Pulsatile Insulin Secretion (2008) Cell Metabolism, 8 (1), pp. 26-37. , DOI 10.1016/j.cmet.2008.06.003, PII S1550413108001745Thorens, B., GLP-1 and the control of insulin secretion (1994) Journ Annu Diabetol Hotel Dieu, pp. 33-46Szecowka, J., Grill, V., Sandberg, E., Efendic, S., Effect of GIP on the secretion of insulin and somatostatin and the accumulation of cyclic AMP in vitro in the rat (1982) Acta Endocrinologica, 99 (3), pp. 416-421Huypens, P., Ling, Z., Pipeleers, D., Schuit, F., Glucagon receptors on human islet cells contribute to glucose competence of insulin release (2000) Diabetologia, 43 (8), pp. 1012-1019. , DOI 10.1007/s001250051484Seino, S., Shibasaki, T., PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis (2005) Physiological Reviews, 85 (4), pp. 1303-1342. , DOI 10.1152/physrev.00001.2005Hatakeyama, H., Kishimoto, T., Nemoto, T., Rapid glucose sensing by protein kinase A for insulin exocytosis in mouse pancreatic islets (2006) J Physiol, 570, pp. 271-282Chheda, M.G., Ashery, U., Thakur, P., Rettig, J., Sheng, Z.-H., Phosphorylation of Snapin by PKA modulates its imteraction with the SNARE complex (2001) Nature Cell Biology, 3 (4), pp. 331-338. , DOI 10.1038/35070000Nagy, G., Reim, K., Matti, U., Brose, N., Binz, T., Rettig, J., Neher, E., Sorensen, J.B., Regulation of Releasable Vesicle Pool Sizes by Protein Kinase A-Dependent Phosphorylation of SNAP-25 (2004) Neuron, 41 (3), pp. 417-429. , DOI 10.1016/S0896-6273(04)00038-8Wang, X., Zhou, J., Doyle, M.E., Egan, J.M., Glucagon-like peptide-1 causes pancreatic duodenal homeobox-1 protein translocation from the cytoplasm to the nucleus of pancreatic β-cells by a cyclic adenosine monophosphate/protein kinase A-dependent mechanism (2001) Endocrinology, 142 (5), pp. 1820-1827. , DOI 10.1210/en.142.5.1820Ferreira, F., Barbosa, H.C.L., Stoppiglia, L.F., Delghingaro-Augusto, V., Pereira, E.A., Boschero, A.C., Carneiro, E.M., Decreased Insulin Secretion in Islets from Rats Fed a Low Protein Diet Is Associated with a Reduced PKAα Expression (2004) Journal of Nutrition, 134 (1), pp. 63-67Milanski, M., Arantes, V.C., Ferreira, F., De Barros Reis, M.A., Magalhaes Carneiro, E., Boschero, A.C., Collares-Buzato, C.B., Queiroz Latorraca, M., Low-protein diets reduce PKAα expression in islets from pregnant rats (2005) Journal of Nutrition, 135 (8), pp. 1873-1878Takahashi, N., Kadowaki, T., Yazaki, Y., Ellis-Davies, G.C.R., Miyashita, Y., Kasai, H., Post-priming actions of ATP on Ca 2+-dependent exocytosis in pancreatic beta cells (1999) Proceedings of the National Academy of Sciences of the United States of America, 96 (2), pp. 760-765. , DOI 10.1073/pnas.96.2.760Henquin, J.C., Cellular mechanisms of the control of insulin secretion (1990) Arch Int Physiol Biochim, 98, pp. 61-A80Kasai, H., Suzuki, T., Liu, T.T., Fast and cAMP-sensitive mode of Ca(2+)-dependent exocytosis in pancreatic beta-cells (2002) Diabetes, 51, pp. 19-S2

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

Early Onset Of Obesity Induces Reproductive Deficits In Female Rats

The incidence of obesity is increasing rapidly all over the world and results in numerous health detriments, including disruptions in reproduction. However, the mechanisms by which excess body fat interferes with reproductive functions are still not fully understood. After weaning, female rats were treated with a cafeteria diet or a chow diet (control group). Biometric and metabolic parameters were evaluated in adulthood. Reproductive parameters, including estradiol, progesterone, LH and prolactin during the proestrus afternoon, sexual behavior, ovulation rates and histological analysis of ovaries were also evaluated. Cafeteria diet was able to induce obesity in female rats by increasing body and fat pad weight, which resulted in increased levels of triglycerides, total cholesterol, LDL and induced insulin resistance. The cafeteria diet also negatively affected female reproduction by reducing the number of oocytes and preantral follicles, as well as the thickness of the follicular layer. Obese females did not show preovulatory progesterone and LH surges, though plasma estradiol and prolactin showed preovulatory surges similar to control rats. Nevertheless, sexual receptiveness was not altered by cafeteria diet. Taken together, our results suggest that the cafeteria diet administered from weaning age was able to induce obesity and reduce the reproductive capability in adult female rats, indicating that this obesity model can be used to better understand the mechanisms underlying reproductive dysfunction in obese subjects. © 2012 Elsevier Inc.105511041111Spiegelman, B.M., Flier, J.S., Obesity and the regulation of energy balance (2001) Cell, 104, pp. 531-543Mayes, J.S., Watson, G.H., Direct effects of sex steroids hormones on adipose tissues and obesity (2004) Obes Rev, 5, pp. 197-216Rogers, J., Mitchell, G.W., The relation of obesity to menstrual disturbances (1952) N Engl J Med, 247 (2), pp. 53-55Pasquali, R., Casimirri, F., The impact of obesity on hyperandrogenism and polycystic ovary syndrome in premenopausal women (1993) Clin Endocrinol, 39 (1), pp. 1-16Tortoriello, D.V., McMinn, J., Chua, S.C., Dietary-induced obesity and hypothalamic infertility in female DBA/2J mice (2004) Endocrinology, 45 (3), pp. 1238-1247Hall, L.F., Neubert, A.G., Obesity and pregnancy (2005) Obstet Gynecol Surv, 60 (4), pp. 253-260Brannian, J.D., Furman, G.M., Diggins, M., Declining fertility in the lethal yellow mouse is related to progressive hyperleptinemia and leptin resistance (2005) Reprod Nutr Dev, 45 (2), pp. 143-150Rittmaster, R.S., Desewal, M., Lehman, L., The role of adrenal hyperandrogenism, insulin resistance, and obesity in the pathogenesis of polycystic ovarian syndrome (1993) J Clin Endocrinol Metab, 76, pp. 1295-1300Douchi, T., Kuwahata, R., Yamamoto, S., Oki, T., Yamasaki, H., Nagata, Y., Relationship of upper obesity to menstrual disorders (2002) Acta Obstet Gynecol Scand, 81, pp. 147-150Chopra, M., Galbraith, S., Damton-Hill, I., A global response to a global problem: the epidemic of overnutrition (2002) Bull World Health Organ, 80 (12), pp. 952-958Yura, S., Ogawa, Y., Sagawa, N., Masuzaki, H., Itoh, H., Ebihara, K., Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin (2000) J Clin Invest, 105 (6), pp. 749-755Lake, J.K., Power, C., Cole, T.J., Women's reproductive health: the role of body mass index in early and adult life (1997) Int J Obes Relat Metab Disord, 21 (6), pp. 432-438Prada, P.O., Zecchin, H.G., Gasparetti, A.L., Torsoni, M.A., Ueno, M., Hirata, A.E., Western diet modulates insulin signaling, c-Jun N-terminal kinase activity, and insulin receptor substrate-1ser307 phosphorylation in a tissue-specific fashion (2005) Endocrinology, 146 (3), pp. 1576-1587Freeman, M.E., The neuroendocrine control of the ovarian cycle of the rat (1994) Physiology of reproduction, 45, pp. 613-658. , Raven Press, New York, E. Knobil, Neill (Eds.)Gomes, C.M., Raineki, C., Ramos de Paula, P., Severino, G.S., Helena, C.V., Anselmo-Franci, J.A., Neonatal handling and reproductive function in female rats (2005) J Endocrinol, 184 (2), pp. 435-445Sodersten, P., Hansen, S., Effects of oestradiol and progesterone on the induction and duration of sexual receptivity in cyclic female rats (1977) J Endocrinol, 74 (3), pp. 477-485Pfaus, J.G., Shadiack, A., Van Soest, T., Tse, M., Molinoff, P., Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist (2004) Proc Natl Acad Sci U S A, 101 (27), pp. 10201-10204Poletini, M.O., Szawka, R.E., Freitas Marcon, R.M., Veiga, M.D., Franci, C.R., Anselmo-Franci, J.A., A method to study preovulatory surges of gonadotropins (2003) Brain Res Brain Res Protoc, 12 (1), pp. 41-48. , Endocrinology 146(3): 1576-1587Harms, P.G., Ojeda, S.R., A rapid and simple procedure for chronic cannulation of the rat jugular vein (1974) J Appl Physiol, 36 (3), pp. 391-392Matthews, 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 (7), pp. 412-419Lara, H.E., Dissen, G.A., Leyton, V., Paredes, A., Fuenzalida, H., Fieldler, J.L., An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovary in the rat (2000) Endocrinology, 141 (3), pp. 1059-1072Richards, J.S., Maturation of ovarian follicles: actions and interactions of pituitary and ovarian hormones on follicular cell differentiation (1980) Physiol Rev, 60 (1), pp. 51-89Bao, B., Kumar, N., Karp, R.M., Garverick, H.A., Sundaram, K., Estrogen receptor-beta expression in relation to the expression of luteinizing hormone receptor and cytochrome P450 enzymes in rat ovarian follicles (2000) Biol Reprod, 63 (6), pp. 1747-1755Micevych, P., Sinchak, K., Mills, R.H., Tao, L., LaPolt, P., Lu, J.K., The luteinizing hormone surge is preceded by an estrogen-induced increase of hypothalamic progesterone in ovariectomized and adrenalectomized rats (2003) Neuroendocrinology, 78 (1), pp. 29-35Wildt, L., Hausler, A., Hutchison, J.S., Marshall, G., Knobil, E., Estradiol as a gonadotropin releasing hormone in the rhesus monkey (1981) Endocrinology, 108 (5), pp. 2011-2013Moenter, S.M., Caraty, A., Karsch, F.J., The estradiol-induced surge of gonadotropin-releasing hormone in the ewe (1990) Endocrinology, 127 (3), pp. 1375-1384Freeman, M.E., Kanyicska, B., Lerant, A., Nagy, G., Prolactin: structure, function, and regulation of secretion (2000) Physiol Rev, 80 (4), pp. 1523-1631. , ReviewMcNatty, K.P., Sawers, R.S., McNeilly, A.S., A possible role for prolactin in control of steroid secretion by the human Graafian follicle (1974) Nature, 250 (5468), pp. 653-655Uilenbroek, J.T., van der Schoot, P., den Besten, D., Lankhorst, R.R., A possible direct effect of prolactin on follicular activity (1982) Biol Reprod, 27 (5), pp. 1119-1125Oktem, O., Oktay, K., The ovary: anatomy and function throughout human life (2008) Ann N Y Acad Sci, 1127, pp. 1-9. , ReviewMattioli, M., Barboni, B., Turriani, M., Galeati, G., Zannoni, A., Castellani, G., Follicle activation involves vascular endothelial growth factor production and increased blood vessel extension (2001) Biol Reprod, 65 (4), pp. 1014-1019Kretschmer, B.D., Schelling, P., Beier, N., Liebscher, C., Treutel, S., Krüger, N., Modulatory role of food, feeding regime and physical exercise on body weight and insulin resistance (2005) Life Sci, 76 (14), pp. 1553-1573Fried, S.K., Rao, S.P., Sugars, hypertriglyceridemia, and cardiovascular disease (2003) Am J Clin Nutr, 78 (4), pp. 873S-880SMortola, J.F., Sathanandan, M., Pavlou, S., Dahl, K.D., Hsueh, A.J., Rivier, J., Suppression of bioactive and immunoreactive follicle-stimulating hormone and luteinizing hormone levels by a potent gonadotropin-releasing hormone antagonist: pharmacodynamic studies (1989) Fertil Steril, 51 (6), pp. 957-963Poretsky, L., Cataldo, N.A., Rosenwaks, Z., Giudice, L.C., The insulin-related ovarian regulatory system in health and disease (1999) Endocr Rev, 20 (4), pp. 535-582Billig, H., Furuta, I., Hsueh, A.J., Estrogens inhibit and androgens enhance ovarian granulosa cell apoptosis (1993) Endocrinology, 133 (5), pp. 2204-2212Willis, D., Mason, H., Gilling-Smith, C., Franks, S., Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries (1996) J Clin Endocrinol Metab, 81 (1), pp. 302-309Brüning, J.C., Gautam, D., Burks, D.J., Gillette, J., Schubert, M., Orban, P.C., Role of brain insulin receptor in control of body weight and reproduction (2000) Science, 289 (5487), pp. 2122-2125Gosman, G.G., Katcher, H.I., Legro, R.S., Obesity and the role of gut and adipose hormones in female reproduction (2006) Hum Reprod Update, 12 (5), pp. 585-601. , ReviewMaffei, M., Halaas, J., Ravussin, E., Pratley, R.E., Lee, G.H., Zhang, Y., Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects (1995) Nat Med, 11, pp. 1155-1161Moschos, S., Chan, J.L., Mantzoros, C.S., Leptin and reproduction: a review (2002) Fertil Steril, 77 (3), pp. 433-444. , ReviewBajari, T.M., Nimpf, J., Schneider, W.J., Role of leptin in reproduction (2004) Curr Opin Lipidol, 15 (3), pp. 315-319. , ReviewDuggal, P.S., Van Der Hoek, K.H., Milner, C.R., Ryan, N.K., Armstrong, D.T., Magoffin, D.A., The in vivo and in vitro effects of exogenous leptin on ovulation in the rat (2000) Endocrinology, 141 (6), pp. 1971-1976Spicer, L.J., Francisco, C.C., The adipose obese gene product, leptin: evidence of a direct inhibitory role in ovarian function (1997) Endocrinology, 138 (8), pp. 3374-3379Agarwal, S.K., Vogel, K., Weitsman, S.R., Magoffin, D.A., Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogenesis in granulosa and theca cells of the human ovary (1999) J Clin Endocrinol Metab, 84 (3), pp. 1072-1076Pasquali, R., Gambineri, A., Polycystic ovary syndrome: a multifaceted disease from adolescence to adult age (2006) Ann N Y Acad Sci, 1092, pp. 158-174. , ReviewSaigal, C.S., Obesity and erectile dysfunction: common problems, common solution? (2004) JAMA, 291 (24), pp. 3011-3012Esposito, K., Di Palo, C.C., Marfella, R., Giugliano, D., The effect of weight loss on endothelial functions in obesity: response to Sciacqua et al (2003) Diab Care, 26 (10), pp. 2968-2969Kolotkin, R.L., Binks, M., Crosby, R.D., Østbye, T., Gress, R.E., Adams, T.D., Obesity and sexual quality of life (2006) Obesity (Silver Spring), 14 (3), pp. 472-479Bajos, N., Wellings, K., Laborde, C., Moreau, C., Sexuality and obesity, a gender perspective: results from French national random probability survey of sexual behaviours (2010) BMJ, 340, pp. c2573. , CSF GroupKarkanias, G.B., Morales, J.C., Li, C.S., Deficits in reproductive behavior in diabetic female rats are due to hypoinsulinemia rather than hyperglycemia (1997) Horm Behav, 32 (1), pp. 19-29Levi, J.E., Weinberg, T., Pregnancy in alloxan diabetic rats (1949) Proc Soc Exp Biol Med, 72 (3), pp. 658-662McEwen, B.S., Neural gonadal steroid actions (1981) Science, 211 (4488), pp. 1303-1311. , ReviewEtgen, A.M., Chu, H.P., Fiber, J.M., Karkanias, G.B., Morales, J.M., Hormonal integration of neurochemical and sensory signals governing female reproductive behavior (1999) Behav Brain Res, 105 (1), pp. 93-103Mathews, D., Edwards, D.A., The ventromedial nucleus of the hypothalamus and the hormonal arousal of sexual behaviors in the female rat (1977) Horm Behav, 8 (1), pp. 40-51Pleim, E.T., Brown, T.J., MacLusky, N.J., Etgen, A.M., Barfield, R.J., Dilute estradiol implants and progestin receptor induction in the ventromedial nucleus of the hypothalamus: correlation with receptive behavior in female rats (1989) Endocrinology, 124 (4), pp. 1807-1812Auger, A.P., Ligand-independent activation of progestin receptors: relevance for female sexual behaviour (2001) Reproduction, 122 (6), pp. 847-855Flanagan-Cato, L.M., Calizo, L.H., Daniels, D., The synaptic organization of VMH neurons that mediate the effects of estrogen on sexual behavior (2001) Horm Behav, 40 (2), pp. 178-182Witcher, J.A., Freeman, M.E., The proestrus surge of prolactin enhances sexual receptivity in the rat (1985) Biol Reprod, 32 (4), pp. 834-83

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. Our data suggest that MSG islets, whilst showing a compensatory increase in glucose-induced insulin release, demonstrate decreased islet M3/PKC and adenylate cyclase/PKA activation, possibly predisposing these prediabetic rodents to the early development of β-cell dysfunction. © 2013 Springer Science+Business Media Dordrecht.40745214528Tengholm, A., Gylfe, E., Oscillatory control of insulin secretion (2009) Mol Cell Endocrinol, 297 (1-2), pp. 58-72. , 18706473 10.1016/j.mce.2008.07.009 1:CAS:528:DC%2BD1cXhsFajt7rNCnop, M., Welsh, N., Jonas, J.C., Jorns, A., Lenzen, S., Eizirik, D.L., Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: Many differences, few similarities (2005) Diabetes, 54 (SUPPL. 2), pp. 97-S107. , 16306347 10.2337/diabetes.54.suppl-2.S97 1:CAS:528:DC%2BD2MXht12gs7nFRibeiro, R.A., Santos-Silva, J.C., Vettorazzi, J.F., Cotrim, B.B., Mobiolli, D.D., Boschero, A.C., Carneiro, E.M., Taurine supplementation prevents morpho-physiological alterations in high-fat diet mice pancreatic beta-cells (2012) Amino Acids, 43 (4), pp. 1791-1801. , 22418865 10.1007/s00726-012-1263-5 1:CAS:528:DC%2BC38XhtlOls77NAhren, B., Autonomic regulation of islet hormone secretion-implications for health and disease (2000) Diabetologia, 43 (4), pp. 393-410. , 10819232 10.1007/s001250051322 1:CAS:528:DC%2BD3cXit12hsLk%3DOlney, J.W., Sharpe, L.G., Brain lesions in an infant rhesus monkey treated with monsodium glutamate (1969) Science, 166 (3903), pp. 386-388. , 5812037 10.1126/science.166.3903.386 1:CAS:528:DyaE3cXhtFSrtw%3D%3DMaiter, D., Underwood, L.E., Martin, J.B., Koenig, J.I., Neonatal treatment with monosodium glutamate: Effects of prolonged growth hormone (GH)-releasing hormone deficiency on pulsatile GH secretion and growth in female rats (1991) Endocrinology, 128 (2), pp. 1100-1106. , 1989848 10.1210/endo-128-2-1100 1:CAS:528:DyaK3MXpvFentg%3D%3DMartins, 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 (26), pp. 3211-3222. , 15094322 10.1016/j.lfs.2003.10.034 1:CAS:528:DC%2BD2cXjt1Sitr0%3DBalbo, 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 (2), pp. 142-148. , 17873325 10.1007/s12020-007-0021-z 1:CAS:528:DC%2BD2sXhtVSgtb%2FOLucinei Balbo, S., Gravena, C., Bonfleur, M.L., De Freitas Mathias, P.C., Insulin secretion and acetylcholinesterase activity in monosodium l-glutamate-induced obese mice (2000) Horm Res, 54 (4), pp. 186-191. , 11416236 10.1159/000053257 1:STN:280:DC%2BD3Mzlt1SjtQ%3D%3DBalbo, S.L., Bonfleur, M.L., Carneiro, E.M., Amaral, M.E., Filiputti, E., Mathias, P.C., Parasympathetic activity changes insulin response to glucose and neurotransmitters (2002) Diabetes Metab, 28 (6 PART 2), pp. 13-17. , discussion 13S108-112Nardelli, 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 (4), pp. 901-908. , 21042817 10.1007/s00726-010-0789-7 1:CAS:528:DC%2BC3MXhtFKitLbKPaes, A.M., Carniatto, S.R., Francisco, F.A., Brito, N.A., Mathias, P.C., Acetylcholinesterase activity changes on visceral organs of VMH lesion-induced obese rats (2006) Int J Neurosci, 116 (11), pp. 1295-1302. , 17000530 10.1080/00207450600920910 1:CAS:528:DC%2BD28XhtFOrsLbIMitrani, P., Srinivasan, M., Dodds, C., Patel, M.S., Autonomic involvement in the permanent metabolic programming of hyperinsulinemia in the high-carbohydrate rat model (2007) Am J Physiol Endocrinol Metab, 292 (5), pp. 1364-E1377. , 17227957 10.1152/ajpendo.00672.2006 1:CAS:528:DC%2BD2sXls1yisL8%3DScomparin, 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 (3), pp. 510-517. , 19856134 10.1007/s12020-009-9263-2 1:CAS:528:DC%2BD1MXhsVaksrbEAndreazzi, A.E., Scomparin, D.X., Mesquita, F.P., Balbo, S.L., Gravena, C., De Oliveira, J.C., Rinaldi, W., Mathias, P.C., Swimming exercise at weaning improves glycemic control and inhibits the onset of monosodium l-glutamate-obesity in mice (2009) J Endocrinol, 201 (3), pp. 351-359. , 19297408 10.1677/JOE-08-0312 1:CAS:528:DC%2BD1MXntFGnsb0%3DBernardis, 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 (4), pp. 527-528. , 4868415 10.1677/joe.0.0400527 1:STN:280:DyaF1c7ptFWgsg%3D%3DRibeiro, 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 Ca 2+ handling in mouse pancreatic islets (2010) Br J Nutr, 104 (8), pp. 1148-1155. , 20591207 10.1017/S0007114510001820 1:CAS:528:DC%2BC3cXht1Oms7fPHarms, P.G., Ojeda, S.R., A rapid and simple procedure for chronic cannulation of the rat jugular vein (1974) J Appl Physiol, 36 (3), pp. 391-392. , 4814312 1:STN:280:DyaE2c7gsleltg%3D%3DBergmeyer, H.U., Bernt, E., Determination of glucose with glucose oxidase and peroxidase (1974) Methods of Enzymatic Analysis, pp. 1105-1212. , H.U. Bergeyer (eds) Verlag Chemie WeinheinBonora, 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 (1), pp. 57-63. , 10857969 10.2337/diacare.23.1.57 1:STN:280:DC%2BD3czpsVyisA%3D%3DMatthews, 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 (7), pp. 412-419. , 3899825 10.1007/BF00280883 1:CAS:528:DyaL2MXlslKnu7k%3DStraub, S.G., Sharp, G.W., Glucose-stimulated signaling pathways in biphasic insulin secretion (2002) Diabetes Metab Res Rev, 18 (6), pp. 451-463. , 12469359 10.1002/dmrr.329 1:CAS:528:DC%2BD3sXotFensw%3D%3DGrassiolli, S., Bonfleur, M.L., Scomparin, D.X., De Freitas Mathias, P.C., Pancreatic islets from hypothalamic obese rats maintain K+ ATP channel-dependent but not-independent pathways on glucose-induced insulin release process (2006) Endocrine, 30 (2), pp. 191-196. , 17322578 10.1385/ENDO:30:2:191 1:CAS:528:DC%2BD2sXhslKjtL4%3DWu, G., Morris, Jr.S.M., Arginine metabolism: Nitric oxide and beyond (1998) Biochem J, 336 (PART 1), pp. 1-17. , 9806879 1:CAS:528:DyaK1cXotVGltrs%3DGilon, P., Henquin, J.C., Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function (2001) Endocr Rev, 22 (5), pp. 565-604. , 11588141 10.1210/er.22.5.565 1:CAS:528:DC%2BD3MXotVWmu7o%3DGrassiolli, S., Gravena, C., De Freitas Mathias, P.C., Muscarinic M2 receptor is active on pancreatic islets from hypothalamic obese rat (2007) Eur J Pharmacol, 556 (1-3), pp. 223-228. , 17174301 10.1016/j.ejphar.2006.11.022 1:CAS:528:DC%2BD2sXls1GisA%3D%3DGautam, D., Han, S.J., Hamdan, F.F., Jeon, J., Li, B., Li, J.H., Cui, Y., Wess, J., A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo (2006) Cell Metab, 3 (6), pp. 449-461. , 16753580 10.1016/j.cmet.2006.04.009 1:CAS:528:DC%2BD28Xmt1eku7k%3DLeech, C.A., Castonguay, M.A., Habener, J.F., Expression of adenylyl cyclase subtypes in pancreatic beta-cells (1999) Biochem Biophys Res Commun, 254 (3), pp. 703-706. , 9920805 10.1006/bbrc.1998.9906 1:CAS:528:DyaK1MXhtVegtL4%3DDelmeire, D., Flamez, D., Hinke, S.A., Cali, J.J., Pipeleers, D., Schuit, F., Type VIII adenylyl cyclase in rat beta cells: Coincidence signal detector/generator for glucose and GLP-1 (2003) Diabetologia, 46 (10), pp. 1383-1393. , 13680124 10.1007/s00125-003-1203-8 1:CAS:528:DC%2BD3sXnvVCgurY%3DLeiser, M., Fleischer, N., CAMP-dependent phosphorylation of the cardiac-type alpha 1 subunit of the voltage-dependent Ca2+ channel in a murine pancreatic beta-cell line (1996) Diabetes, 45 (10), pp. 1412-1418. , 8826979 10.2337/diabetes.45.10.1412 1:CAS:528:DyaK28XmtFCnt74%3DSeino, S., Shibasaki, T., PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis (2005) Physiol Rev, 85 (4), pp. 1303-1342. , 16183914 10.1152/physrev.00001.2005 1:CAS:528:DC%2BD2MXhtFeqsr3LDolz, M., Bailbe, D., Giroix, M.H., Calderari, S., Gangnerau, M.N., Serradas, P., Rickenbach, K., Portha, B., Restitution of defective glucose-stimulated insulin secretion in diabetic GK rat by acetylcholine uncovers paradoxical stimulatory effect of beta-cell muscarinic receptor activation on cAMP production (2005) Diabetes, 54 (11), pp. 3229-3237. , 16249449 10.2337/diabetes.54.11.3229 1:CAS:528:DC%2BD2MXht1Shsr7OToft-Nielsen, M.B., Damholt, M.B., Madsbad, S., Hilsted, L.M., Hughes, T.E., Michelsen, B.K., Holst, J.J., Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients (2001) J Clin Endocrinol Metab, 86 (8), pp. 3717-3723. , 11502801 10.1210/jc.86.8.3717 1:CAS:528:DC%2BD3MXlvFektLc%3DFerreira, F., Barbosa, H.C., Stoppiglia, L.F., Delghingaro-Augusto, V., Pereira, E.A., Boschero, A.C., Carneiro, E.M., Decreased insulin secretion in islets from rats fed a low protein diet is associated with a reduced PKAalpha expression (2004) J Nutr, 134 (1), pp. 63-67. , 14704294 1:CAS:528:DC%2BD2cXitlCmtA%3D%3DBonfleur, M.L., Ribeiro, R.A., Balbo, S.L., Vanzela, E.C., Carneiro, E.M., De Oliveira, H.C., Boschero, A.C., Lower expression of PKAalpha impairs insulin secretion in islets isolated from low-density lipoprotein receptor (LDLR(-/-)) knockout mice (2011) Metabolism, 60 (8), pp. 1158-1164. , 21306750 10.1016/j.metabol.2010.12.010 1:CAS:528:DC%2BC3MXptlCntb0%3DWajchenberg, B.L., Beta-cell failure in diabetes and preservation by clinical treatment (2007) Endocr Rev, 28 (2), pp. 187-218. , 17353295 10.1210/10.1210/er.2006-0038 1:CAS:528:DC%2BD2sXkvFentr0%3