Mutations In Pycr1 Gene In Three Families With Autosomal Recessive Cutis Laxa, Type 2

[No abstract available]566336339Steiner, C.E., Cintra, M.L., Marques-de-Faria, A.P., Cutis laxa with growth and development delay, wrinkly skin syndrome or gerodermia osteodysplastica: report of two unrelated patients and literature review (2005) Genet. Mol. Biol., 28 (2), pp. 181-190Scherrer, D.Z., Alexandrino, F., Cintra, M.L., Sartorato, E.L., Steiner, C.E., Type II autossomal recessive cutis laxa: report of another patient and molecular studies concerning three candidate genes (2008) Am. J. Med. Genet. A, 146 (21), pp. 2740-2745Hennies, H.C., Kornak, U., Zhang, H., Egerer, J., Zhang, X., Seifert, W., Kühnisch, J., Mundlos, S., Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin (2008) Nat. Genet., 40 (12), pp. 1410-1412Reversade, B., Escande-Beillard, N., Dimopoulou, A., Fischer, B., Chng, S.C., Li, Y., Shboul, M., Kornak, U., Mutations in PYCR1 cause cutis laxa with progeroid features (2009) Nat. Genet., 41 (9), pp. 1016-1021Guernsey, D.L., Jiang, H., Evans, S.C., Ferguson, M., Matsuoka, M., Nightingale, M., Rideout, A.L., Samuels, M.E., Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2 (2009) Am. J. Hum. Genet., 85 (1), pp. 120-129Yildirim, Y., Tolun, A., Tüysüz, B., The phenotype caused by PYCR1 mutations corresponds to geroderma osteodysplasticum rather than autosomal recessive cutis laxa type 2 (2010) Am. J. Med. Genet. A, 155 A (1), pp. 134-140Kouwenberg, D., Gardeitchik, T., Wevers, R.A., Häberle, J., Morava, E., Recognizable phenotype with common occurrence of microcephaly, psychomotor retardation, but no spontaneous bone fractures in autosomal recessive cutis laxa type IIB due to PYCR1 mutations (2011) Am. J. Med. Genet. A, 155 A (9), pp. 2331-233

Transcriptome of the wistar audiogenic rat (WAR) strain following audiogenic seizures

FAPEMIG - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE MINAS GERAISFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOThe Wistar Audiogenic Rat (WAR) is a model whose rats are predisposed to develop seizures following acoustic stimulation. We aimed to establish the transcriptional profile of the WAR model, searching for genes that help in understanding the molecular mech1472231FAPEMIG - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE MINAS GERAISFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPEMIG - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE MINAS GERAISFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOEDT -193/092009/53444-

Pioglitazone treatment increases food intake and decreases energy expenditure partially via hypothalamic adiponectin/adipoR1/AMPK pathway

Introduction:Thiazolidinediones (TZDs) enhanced body weight (BW) partially by increased adipogenesis and hyperphagia. Neuronal PPAR\u3b3 knockout mice on high-fat diet (HFD) are leaner because of enhanced leptin response, although it could be secondary to their leanness. Thus, it still is an open question how TZDs may alter energy balance. Multiple factors regulate food intake (FI) and energy expenditure (EE), including anorexigenic hormones as insulin and leptin. Nonetheless, elevated hypothalamic AMPK activity increases FI and TZDs increase AMPK activity in muscle cells. Thus, the aim of the present study was to investigate whether Pioglitazone (PIO) treatment alters hypothalamic insulin and leptin action/signaling, AMPK phosphorylation, and whether these alterations may be implicated in the regulation of FI and EE.Methods:Swiss mice on HFD (2 months) received PIO (25 mg kg-1 per day-gavage) or vehicle for 14 days. AMPK and AdipoR1 were inhibited via Intracerebroventricular injections using Compound C (CompC) and small interference RNA (siRNA), respectively. Western blot, real-time PCR and CLAMS were done.Results:PIO treatment increased BW, adiposity, FI, NPY mRNA and decreased POMC mRNA expression and EE in HFD mice. Despite higher adiposity, PIO treatment improved insulin sensitivity, glucose tolerance, decreased insulin and increased adiponectin serum levels. This result was associated with, improved insulin and leptin action/signaling, decreased \u3b12AMPK Ser491 phosphorylation and elevated Acetyl-CoA carboxylase and AMPK Thr172 phosphorylation in hypothalamus. The inhibition of hypothalamic AMPK with CompC was associated with decreased adiposity, FI, NPY mRNA and EE in PIO-treated mice. The reduced expression of hypothalamic AdipoR1 with siRNA concomitantly with PIO treatment reverted PIO induced obesity development, suggesting that adiponectin may be involved in this effect.Conclusions:These results demonstrated that PIO, despite improving insulin/leptin action in hypothalamus, increases FI and decreases EE, partially, by activating hypothalamic adiponectin/AdipoR1/AMPK axis. Suggesting a novel mechanism in the hypothalamus by which TZDs increase BW

Cdc2-like kinase 2 in the hypothalamus is necessary to maintain energy homeostasis

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOTo investigate whether the Cdc2-like kinase 2 (CLK2) is expressed in hypothalamic neurons and if it is, whether the hypothalamic CLK2 has a role in the regulation of energy balance.Subjects:Swiss mice on chow or high-fat diet (HFD) and db/db mice on chow412268278FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO2012/10338-62015/00343-02013/07607-8481084/2013-

Gene Expression Profiling In Genetic Animal Models Of Provide Elements To Unveil The Molecular Mechanisms Underlying Epileptogenesis In Rodents [a Caracterização Do Perfil De Expressão Gênica Em Larga Escala Em Modelos Genéticos De Epilepsia Fornece Elementos Para Entender Os Mecanismos Envolvidos Na Epileptogênese Em Roedores]

Objective: The objective of this study was to characterize and compare the genetic profile of two rodent models of epilepsy (Wistar Audiogenic Rat - WAR and rats with generalized epilepsy with absence seizures-GEAS) using gene expression analysis Methods: We used microarray technology for gene expression analysis. Results: The analysis of gene expression profiles in WAR showed among genes up-regulated Neurod1, involved in the development of the cochlear duct. In addition, we found significant differences in gene expression of Apbb1, Foxg1 and Scn1A. GEAS rats had differentially expressed genes related to the development of central nervous system, as well as genes involved in the MAPK pathway, transcription factors, neuronal migration and apoptosis. Conclusion: This study may help to clarify the underlying molecular mechanism that leads to the predisposition to seizures in these animals. Our results indicate the activation of distinct molecular pathways in both models.1825052Aicard, J., Course and prognosis of certain chidhood epilepsies with predominantly myoclonic seizures (1980) Advances in Epileptology. The Xth Epilepsy International Symposim, pp. 159-163. , Wada JA, Penry JK e cols. New York: RavemAndré, E.S., Electrophysiological characterization of a new form of spontaneous epilepsy in Wistar rats (1999) Epilepsia, 40 (SUPPL. 2)Bruno-Neto, R., Caracterização de uma nova forma de epilepsia espontânea em ratos Wistar (1999) XIV FESBE, AnaisBruno-Neto, R., André, E.S., Pellarin, L., Hilário, F.K., Valle, A.C., Timo-Iaria, C., Electrophysiological characterization of a new form of spontaneous epilepsy in Wistar rats (1999) 23rd International Epilepsy Congress, Prague, Czech RepublicDoretto, M.C., Fonseca, C.G., Lobo, R.B., Terra, V.C., Oliveira, J.A., Garcia-Cairasco, N., Quantitative study of the response to genetic selection of the WistarAudiogenic Rat strain (WAR) (2003) Behav Genet, 33 (1), pp. 33-42Garcia-Cairasco, N., Sabbatini, R., Role of the substantianigra in audiogenic seizures: A neuroethological analysis in the rat (1983) Braz J Med Biol Res, 16 (2), pp. 171-183Gitaí, D.L., Martinelli, H.N., Valente, V., Pereira, M.G., Oliveira, J.A., Elias, C.F., Bittencourt, J.C., Paçó-Larson, M.L., Increased expression of GluR2-flip in the hippocampus of the Wistaraudiogenic rat strain after acute and kindled seizures (2010) Hippocampus, 20, pp. 125-133Jobe, P.C., Brown, R.D., Dailey, J.W., Effect of Ro 4-1284 on audiogenic seizure susceptibility and intensity in epilepsy-prone rats (1981) Life Sci, 28 (18), pp. 2031-2038Kovács, Z., Suppression of spike-wave discharge activity and c-fos expression by2-methyl-4-oxo-3H-quinazoline-3-acetyl piperidine (Q5) in vivo (2007) Neuroscience Letters, 423, pp. 73-77Mesquita, F., Aguiar, J.F., Oliveira, J.A., Garcia-Cairasco, N., Varanda, W.A., Electrophysiological properties of cultured hippocampal neurons from WistarAudiogenic rats (2005) Brain Res Bul, 65, pp. 177-183Moraes, M.F., Galvis-Alonso, O.Y., Garcia-Cairasco, N., Audiogenic kindling in the Wistar rat: A potential model for recruitment of limbic structures (2000) Epilepsy Research, 39, pp. 251-259Nunes, P.V., Valle, A.C., Timo-Iaria, C., Epileptogenic potentials recorded from the cerebellar cortex in rats (1999) Epilepsia, 40, p. 132. , 23th International Epilepsy Congress, Prague, Czech Republi

Ikk? is key to induction of insulin resistance in the hypothalamus, and its inhibition reverses obesity

IKK epsilon (IKKε) is induced by the activation of nuclear factor-κB (NF-κB). Whole-body IKKε knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKKε is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKKε in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-KB activation in this tissue, relieving the inflammatory environment. Inhibition of IKKε activity, but not TBK1, reduced IRS-1Ser307phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. We suggest that IKKε may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism.IKK epsilon (IKK?) is induced by the activation of nuclear factor-?B (NF-?B). Whole-body IKK? knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKK? is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKK? in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-?B activation in this tissue, relieving the inflammatory environment. Inhibition of IKK? activity, but not TBK1, reduced IRS-1(Ser307) phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. We suggest that IKK? may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism631033343345Belgardt, B.F., Brüning, J.C., CNS leptin and insulin action in the control of energy homeostasis (2010) Ann N Y Acad Sci, 1212, pp. 97-113Carvalheira, J.B., Torsoni, M.A., Ueno, M., Cross-talk between the insulin and leptin signaling systems in rat hypothalamus (2005) Obes Res, 13, pp. 48-57Morton, G.J., Schwartz, M.W., The NPY/AgRP neuron and energy homeostasis (2001) Int J Obes Relat Metab Disord, 25, pp. S56-S62. , Suppl. 5Saad, M.J., Folli, F., Kahn, J.A., Kahn, C.R., Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats (1993) J Clin Invest, 92, pp. 2065-2072Pardini, A.W., Nguyen, H.T., Figlewicz, D.P., Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis (2006) Brain Res, 1112, pp. 169-178Belgardt, B.F., Husch, A., Rother, E., PDK1 deficiency in POMC-expressing cells reveals F0X01 -dependent and -independent pathways in control of energy homeostasis and stress response (2008) Cell Metab, 7, pp. 291-301Fukuda, M., Jones, J.E., Olson, D., Monitoring Fox01 localization in chemically identified neurons (2008) J Neurosci, 28, pp. 13640-13648Kitamura, T., Feng, Y., Kitamura, Y.I., Forkhead protein Fox01 mediates Agrp-dependent effects of leptin on food intake (2006) Nat Med, 12, pp. 534-540Kim, M.S., Pak, Y.K., Jang, P.G., Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis (2006) Nat Neurosci, 9, pp. 901-906Folli, F., Ghidella, S., Bonfanti, L., Kahn, C.R., Merighi, A., The early intracellular signaling pathway for the insulin/insulin-like growth factor receptor family in the mammalian central nervous system (1996) Mol Neurobiol, 13, pp. 155-183Folli, F., Bonfanti, L., Renard, E., Kahn, C.R., Merighi, A., Insulin receptor substrate-1 (IRS-1) distribution in the rat central nervous system (1994) J Neurosci, 14, pp. 6412-6422Velloso, L.A., The hypothalamic control of feeding and thermogenesis: Implications on the development of obesity (2006) Arq Bras Endocrinol Metabol, 50, pp. 165-176. , [in Portuguese]Guo, F., Bakal, K., Minokoshi, Y., Hollenberg, A.N., Leptin signaling targets the thyrotropin-releasing hormone gene promoter in vivo (2004) Endocrinology, 145, pp. 2221-2227Gautron, L., Elmquist, J.K., Sixteen years and counting: An update on leptin in energy balance (2011) J Clin Invest, 121, pp. 2087-2093Myers, M.G., Jr., Outstanding Scientific Achievement Award Lecture 2010: Deconstructing leptin: From signals to circuits (2010) Diabetes, 59, pp. 2708-2714Velloso, L.A., Schwartz, M.W., Altered hypothalamic function in diet-induced obesity (2011) Int J Obes (Lond), 35, pp. 1455-1465Prada, P.O., Zecchin, H.G., Gasparetti, A.L., 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, pp. 1576-1587Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., Cai, D., Hypothalamic IKKbeta/ NF-kappaB and ER stress link overnutrition to energy imbalance and obesity (2008) Cell, 135, pp. 61-73Reilly, S.M., Chiang, S.H., Decker, S.J., An inhibitor of the protein kinases TBK1 and IKK-ε improves obesity-related metabolic dysfunctions in mice (2013) Nat Med, 19, pp. 313-321Clément, J.F., Meloche, S., Servant, M.J., The IKK-related kinases: From innate immunity to oncogenesis (2008) Cell Res, 18, pp. 889-899Bao, X., Indukuri, H., Liu, T., IKKε modulates RSV-induced NF-κB-dependent gene transcription (2010) Virology, 408, pp. 224-231Geng, H., Wittwer, T., Dittrich-Breiholz, O., Kracht, M., Schmitz, M.L., Phosphorylation of NF-kappaB p65 at Ser468 controls its COMMD1 -dependent ubiquitination and target gene-specific proteasomal elimination (2009) EMBO Rep, 10, pp. 381-386Moreno, R., Sobotzik, J.M., Schultz, C., Schmitz, M.L., Specification of the NF-kappaB transcriptional response by p65 phosphorylation and TNF-induced nuclear translocation of IKK epsilon (2010) Nucleic Acids Res, 38, pp. 6029-6044Chiang, S.H., Bazuine, M., Lumeng, C.N., The protein kinase IKKepsilon regulates energy balance in obese mice (2009) Cell, 138, pp. 961-975Prada, P.O., Hirabara, S.M., De Souza, C.T., L-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity (2007) Diabetologia, 50, pp. 1949-1959Prada, P.O., Ropelle, E.R., Mourão, R.H., EGFR tyrosine kinase inhibitor (PD153035) improves glucose tolerance and insulin action in high-fat diet-fed mice (2009) Diabetes, 58, pp. 2910-2919Prada, P.O., Quaresma, P.G., Caricilli, A.M., Tub has a key role in insulin and leptin signaling and action in vivo in hypothalamic nuclei (2013) Diabetes, 62, pp. 137-148Elias, C.F., Bittencourt, J.C., Study of the origins of melanin-concentrating hormone and neuropeptide El immunoreactive projections to the periaqueductal gray matter (1997) Brain Res, 755, pp. 255-271De Souza, C.T., Araujo, E.P., Bordin, S., Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus (2005) Endocrinology, 146, pp. 4192-4199Hotamisligil, G.S., Arner, P., Caro, J.F., Atkinson, R.L., Spiegelman, B.M., Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance (1995) J Clin Invest, 95, pp. 2409-2415García-Cáceres, C., Yi, C.X., Tschöp, M.H., Hypothalamic astrocytes in obesity (2013) Endocrinol Metab Clin North Am, 42, pp. 57-66Clark, K., Peggie, M., Plater, L., Novel cross-talk within the IKK family controls innate immunity (2011) Biochem J, 434, pp. 93-104Arkan, M.C., Hevener, A.L., Greten, F.R., IKK-beta links inflammation to obesity-induced insulin resistance (2005) Nat Med, 11, pp. 191-198Scheja, L., Heese, B., Seedorf, K., Beneficial effects of IKKε-deficiency on body weight and insulin sensitivity are lost in high fat diet-induced obesity in mice (2011) Biochem Biophys Res Commun, 407, pp. 288-294Obici, S., Zhang, B.B., Karkanias, G., Rossetti, L., Hypothalamic insulin signaling is required for inhibition of glucose production (2002) Nat Med, 8, pp. 1376-1382Pocai, A., Morgan, K., Buettner, C., Gutierrez-Juarez, R., Obici, S., Rossetti, L., Central leptin acutely reverses diet-induced hepatic insulin resistance (2005) Diabetes, 54, pp. 3182-3189Morton, G.J., Blevins, J.E., Kim, F., Matsen, M., Figlewicz, D.P., The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling (2009) Am J Physiol Endocrinol Metab, 297, pp. E202-E21