The effect of caffeic acid and ferulic acid in metabolic syndrome in mice

A obesidade e uma epidemia mundial e pode levar ao desenvolvimento da sindrome metabolica (SM) que e caracterizada pelo conjunto de diversas alteracoes, tais como hipercolesterolemia, hipertrigliceridemia, hiperglicemia e hiperinsulinemia. Muitos estudos mostram que o Acido Cafeico (AC) e o Acido Ferulico (AF) apresentam propriedades antioxidantes e anti-inflamatorias alem de melhorar as anormalidades relacionadas a SM. Assim, o objetivo deste estudo foi analisar os efeitos do acido cafeico e acido ferulico sobre a sindrome metabolica induzida pela dieta rica em gordura em camundongos. Para tanto, camundongos C57 foram tratados com dieta rica em gordura (40%) e com o AC (0,9 mg/kg/dia e 1,8 mg/kg/dia) e AF (50 mg/kg/dia) combinados por 40 dias. Peso corporal e consumo de racao foram registrados diariamente. Ao final do protocolo foi realizado teste de tolerancia a glicose e insulina e determinaram-se os niveis de colesterol e triglicerides plasmaticos, alem da avaliacao histologica do tecido hepatico e do tecido adiposo branco (TAB). Tambem medimos a expressao genica de fatores de transcricao relacionados ao metabolismo de glicose e metabolismo lipidico atraves dos metodos de PCR em tempo real. Os resultados mostram que o tratamento de AC combinado com o AF melhorou a obesidade induzida pela dieta hipercalorica, o metabolismo de glicose, reduziu a sintese de colesterol, de acidos graxos e de triglicerides, assim como preveniu a esteatose hepatica. Por outro lado, observou-se a infiltracao de neutrofilos e macrofagos no TAB dos animais tratados com o AC e AF. Em conclusao a combinacao do AC e do AF melhorou as alteracoes observadas na SM induzida pela dieta hipercalorica e pode ser utilizada, no futuro, como terapeutica para o tratamento da obesidade, mas mais estudos sao necessarios para se estabelecer seus efeitos sobre processos inflamatorios no TABCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)BV UNIFESP: Teses e dissertaçõe

A Ausência Da Desiodase Tipo 2 Em Astrócitos Resulta No Comportamento Ansioso E Depressivo Em Camundongos

Thyroid hormone is essential for the functioning central of the nervous system. It is well known that hypothyroidism can lead to neuropsychiatric disorders, such as impairments in cognition and mood disorders. About 20% of T3 normally reaches the brain directly from the circulation and 80% is produced locally by type 2 deiodinase (D2) in astrocytes. Here we report that mice with astrocyte-specific Dio2 inactivation (Astro-D2KO) exhibit anxiety-depressive-like behavior as assessed via behavioral tests, such as elevated plus maze, tail-suspension and the forced-swimming tests, despite normal T3 serum levels observed in these animals. Remarkably, daily treadmill exercise sessions during 4-weeks corrected D2 inactivation-induced abnormalities. While no difference was observed in hippocampal neurogenesis, there was a moderate decrease in T3 signaling as shown by decreased expression of 4 genes out of 6 positively regulated by T3: Mbp (~43%), Mag (~34%), Hr (~49%) and Aldh1a1 (~61%) and increased expression in 3 genes out of 12 negatively regulated T3: Dgkg (~17%), Syce2 (~26%) and Col6a1 (~300%). Likewise, Astro-D2KO animals showed decreased mRNA levels of depressionrelated genes: Bdnf (~18%), Ntf3 (~43%), Nmdar (~26%) and GR (~20%), which were also normalized by exercise sessions. Our findings show that T3 generated by D2 in astrocytes is important for a normal T3 brain signaling and, impairments on this pathway appear to be related with pathological depression. In addition, chronic physical exercise corrected all the changes induced by D2 inactivation, confirming its role as potent antidepressive therapy.O hormônio tireoidiano é fundamental para funcionamento adequado do sistema nervoso central. Sabe-se que o hipotireoidismo pode levar a transtornos neuropsiquiátricos, como prejuízos na cognição e flutuações de humor. Cerca de 20% do T3 no cérebro vem diretamente da circulação e 80% é produzido localmente pela atividade da desiodase tipo 2 (D2), expressa em astrócitos. No presente estudo, nós mostramos que inativação específica do Dio2 nos astrócitos (Astro-D2KO) de camundongos induziu ao comportamento ansioso-depressivo demonstrado pelos testes comportamentais, como labirinto em cruz elevado, teste de suspensão de cauda e natação forçada, apesar de apresentarem T3 sérico normal. Apesar de não obervarmos alterações na neurogênese hipocampal, houve redução moderada na sinalização do T3 como demonstrado pela diminuição na expressão de 4 de 6 genes positivamente regulados pelo T3,(Mbp (~43%), Mag (~34%), Hr (~49%) e Aldh1a1 (~61%)) e aumento da expressão de 3 de 12 genes negativamente regulados pelo T3 (Dgkg (~17%), Syce2 (~26%) e Col6a1 (~300%)). Os animais Astro-D2KO também apresentaram redução nos níveis de RNAm de genes envolvidos na depressão (Bdnf (~18%), Ntf3 (~43%), Nmdar (~26%) e GR (~20%)). Surpreendentemente, 4 semanas de sessões diárias de exercícios na esteira corrigiram as alterações comportamentais causadas pela inativação da D2. Todas as alterações na expressão gênica também foram normalizadas pelas sessões diárias de exercícios. Os nossos resultados mostram que o T3 gerado localmente no cérebro é importante para a sinalização adequada de T3 e que prejuízos nessa via de sinalização parecem estar envolvidos na etiologia da depressão. Além disso, o exercício físico crônico corrigiu todas as alterações induzidas pela inativação da D2, confirmando seu papel como potente terapia antidepressiva.Dados abertos - Sucupira - Teses e dissertações (2017

Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis

A mouse with hepatocyte-specific deiodinase type II inactivation (Alb-D2KO) is resistant to diet-induced obesity, hepatic steatosis, and hypertriglyceridemia due to perinatal epigenetic modifications in the liver. This phenotype is linked to low levels of Zfp125, a hepatic transcriptional repressor that promotes liver steatosis by inhibiting genes involved in packaging and secretion of very-low-density lipoprotein.Here, we used chronic and binge ethanol (EtOH) in mice to cause liver steatosis.The EtOH treatment causes a 2.3-fold increase in hepatic triglyceride content; Zfp125 levels were approximately 50% higher in these animals. In contrast, Alb-D2KO mice did not develop EtOH-induced liver steatosis. They also failed to elevate Zfp125 to the same levels, despite being on the EtOH-containing diet for the same period of time. Their phenotype was associated with 1.3- to 2.9-fold up-regulation of hepatic genes involved in lipid transport and export that are normally repressed by Zfp125, that is, Mttp, Abca1, Ldlr, Apoc1, Apoc3, Apoe, Apoh, and Azgp1. Furthermore, genes involved in the EtOH metabolic pathway, that is, Aldh2 and Acss2, were also 1.6- to 3.1-fold up-regulated in Alb-D2KO EtOH mice compared with control animals kept on EtOH.EtOH consumption elevates expression of Zfp125. Alb-D2KO animals, which have lower levels of Zfp125, are much less susceptible to EtOH-induced liver steatosis

Early Developmental Disruption of Type 2 Deiodinase Pathway in Mouse Skeletal Muscle Does Not Impair Muscle Function

Background: Myogenesis is positively regulated by thyroid hormone (triiodothyronine [T3]), which is amplified by the type 2 deiodinase (D2) activation of thyroxine to T3. Global inactivation of the Dio2 gene impairs skeletal muscle (SKM) differentiation and regeneration in response to muscle injury. Given that newborn and adult mice with late developmental SKM Dio2 disruption do not develop a significant phenotype, it was hypothesized that D2 plays an early role in this process. Methods: This was tested in mice with SKM disruption of Dio2 driven by two early developmental promoters: MYF5 and MYOD. Results: MYF5 myoblasts in culture differentiate normally into myotubes, despite loss of almost all D2 activity. Dio2 mRNA levels in developing SKM obtained from MYF5-D2KO embryos (E18.5) were about 54% of control littermates, but the expression of the T3-responsive genes Myh1 and 7 and Atp2a1 and 2 were not affected. In MYF5-D2KO and MYOD-D2KO neonatal hind-limb muscle, the expression of Myh1 and 7 and Atp2a2 remained unaffected, despite 60-70% loss in D2 activity and/or mRNA. Only in MYOD-D2KO neonatal muscle was there a 40% reduction in Atp2a1 mRNA. Postnatal growth of both mouse models and SKM function as assessed by exercise capacity and measurement of muscle strength were normal. Furthermore, an analysis of the adult soleus revealed no changes in the expression of T3-responsive genes, except for an about 18% increase in MYOD-D2KO SOL Myh7 mRNA. Conclusion: Two mouse models of early developmental disruption of Dio2 in myocyte precursor exhibit no significant SKM phenotype.NIDDKBrazilian National Research Council (CNPq)American Thyroid Association (ATA)Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ)Rush Univ, Med Ctr, Div Endocrinol & Metab, 1735 W Harrison St,Suite 363,Cohn Bldg, Chicago, IL 60612 USAUniv Fed Rio de Janeiro, Biophys Inst, Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Sch Phys Educ & Sports, Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Nutr Inst Josue de Castro, Rio De Janeiro, BrazilUniv Fed Sao Paulo, Dept Translat Med, Sao Paulo, BrazilUniv Prebiteriana Mackenzie, Dev Disorders Program, Ctr Biol & Hlth Sci, Sao Paulo, BrazilHungarian Acad Sci, Inst Expt Med, Dept Endocrine Neurobiol, Budapest, HungaryUniv Fed Sao Paulo, Dept Translat Med, Sao Paulo, BrazilNIDDK: R01 65055ACNPq: 202189/2011-2American Thyroid Association (ATA): M1301627Web of Scienc

Type 2 Deiodinase Disruption in Astrocytes Results in Anxiety-Depressive-Like Behavior in Male Mice

Millions of levothyroxine-treated hypothyroid patients complain of impaired cognition despite normal TSH serum levels. This could reflect abnormalities in the type 2 deiodinase (D2)-mediated T-4-to-T-3 conversion, given their much greater dependence on the D2 pathway for T-3 production. T-3 normally reaches the brain directly from the circulation or is produced locally by D2 in astrocytes. Here we report that mice with astrocyte-specific Dio2 inactivation (Astro-D2KO) have normal serum T-3 but exhibit anxiety-depression-like behavior as found in open field and elevated plus maze studies and when tested for depression using the tail-suspension and the forced-swimming tests. Remarkably, 4 weeks of daily treadmill exercise sessions eliminated this phenotype. Microarray gene expression profiling of the Astro-D2KO hippocampi identified an enrichment of three gene sets related to inflammation and impoverishment of three gene sets related to mitochondrial function and response to oxidative stress. Despite normal neurogenesis, the Astro-D2KO hippocampi exhibited decreased expression of four of six known to be positively regulated genes by T-3, ie, Mbp (similar to 43%), Mag (similar to 34%), Hr (similar to 49%), and Aldh1a1 (similar to 61%) and increased expression of 3 of 12 genes negatively regulated by T-3, ie, Dgkg (similar to 17%), Syce2 (similar to 26%), and Col6a1 (similar to 3-fold) by quantitative real-time PCR. Notably, in Astro-D2KO animals, there was also a reduction in mRNA levels of genes known to be affected in classical animal models of depression, ie, Bdnf (similar to 18%), Ntf3 (similar to 43%), Nmdar (similar to 26%), and GR (similar to 20%), which were also normalized by daily exercise sessions. These findings suggest that defects in Dio2 expression in the brain could result in mood and behavioral disorders.National Institute of Diabetes and Digestive and Kidney Diseases [R01 65055]Hungarian Brain Research Program Grant [NAP A I/3-4]Coordination for the Improvement of Higher Education Personnel Grant, Coordination for the Improvement of Higher Education Personnel (CAPES), BrazilRush Univ, Med Ctr, Div Endocrinol & Metab, 1735 West Harrison St, Chicago, IL 60612 USAUniv Fed Sao Paulo, Dept Translat Med, BR-04039002 Sao Paulo, SP, BrazilUniv Fed Rio de Janeiro, Inst Biophys, BR-21941599 Rio De Janeiro, RJ, BrazilUniv Fed Rio de Janeiro, Sch Phys Educ & Sports, BR-21941599 Rio De Janeiro, RJ, BrazilUniv Fed Sao Paulo, Dept Clin Endocrinol, BR-04039032 Sao Paulo, SP, BrazilUniv Prebiteriana Mackenzie, Ctr Biol Sci & Hlth, Dev Disorders Program, Rua Consolacao 930, BR-01302900 Sao Paulo, SP, BrazilHungarian Acad Sci, Inst Expt Med, Dept Endocrine Neurobiol, H-1083 Budapest, HungaryTufts Med Ctr, Tupper Res Inst, Div Endocrinol Diabet & Metab, Dept Med, Boston, MA 02111 USAUniv Paulista, Grad Program Dent, Grad Program Environm & Expt Pathol, BR-04026002 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Translat Med, BR-04039002 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Clin Endocrinol, BR-04039032 Sao Paulo, SP, BrazilNIDDK:R01 65055Web of Scienc

Thyroid hormone activation by type2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-gamma coactivator-1 alpha expression in skeletal muscle

Key points In skeletal muscle, physical exercise and thyroid hormone mediate the peroxisome proliferator-activated receptor- coactivator-1 (PGC-1a) expression that is crucial to skeletal muscle mitochondrial function. The expression of type 2 deiodinase (D2), which activates thyroid hormone in skeletal muscle is upregulated by acute treadmill exercise through a -adrenergic receptor-dependent mechanism. Pharmacological block of D2 or disruption of the Dio2 gene in skeletal muscle fibres impaired acute exercise-induced PGC-1a expression.Dio2 disruption also impaired muscle PGC-1a expression and mitochondrial citrate synthase activity in chronically exercised mice. AbstractThyroid hormone promotes expression of peroxisome proliferator-activated receptor- coactivator-1 (PGC-1a), which mediates mitochondrial biogenesis and oxidative capacity in skeletal muscle (SKM). Skeletal myocytes express the type 2 deiodinase (D2), which generates 3,5,3-triiodothyronine (T-3), the active thyroid hormone. To test whether D2-generated T-3 plays a role in exercise-induced PGC-1a expression, male rats and mice with SKM-specific Dio2 inactivation (SKM-D2KO or MYF5-D2KO) were studied. An acute treadmill exercise session (20min at 70-75% of maximal aerobic capacity) increased D2 expression/activity (1.5- to 2.7-fold) as well as PGC-1a mRNA levels (1.5- to 5-fold) in rat soleus muscle and white gastrocnemius muscle and in mouse soleus muscle, which was prevented by pretreatment with 1mg(100g body weight)(-1) propranolol or 6mg(100g body weight)(-1) iopanoic acid (5.9- vs. 2.8-foldP<0.05), which blocks D2 activity . In the SKM-D2KO mice, acute treadmill exercise failed to induce PGC-1a fully in soleus muscle (1.9-vs. 2.8-foldP<0.05), and in primary SKM-D2KO myocytes there was only a limited PGC-1a response to 1m forskolin (2.2- vs. 1.3-foldP<0.05). Chronic exercise training (6weeks) increased soleus muscle PGC-1a mRNA levels (approximate to 25%) and the mitochondrial enzyme citrate synthase (approximate to 20%). In contrast, PGC-1a expression did not change and citrate synthase decreased by approximate to 30% in SKM-D2KO mice. The soleus muscle PGC-1a response to chronic exercise was also blunted in MYF5-D2KO mice. In conclusion, acute treadmill exercise increases SKM D2 expression through a -adrenergic receptor-dependent mechanism. The accelerated conversion of T-4 to T-3 within myocytes mediates part of the PGC-1a induction by treadmill exercise and its downstream effects on mitochondrial function.National Institute of Diabetes and Digestive and Kidney DiseasesBrazilian National Research Council (CNPq)Carlos Chagas Filho Foundation for Research Support in Rio de Janeiro (FAPERJ)American Thyroid Association (ATA)Hungarian Research Fund (OTKA)Coordination for the Improvement of Higher Education Personnel (CAPES)Rush Univ, Med Ctr, Div Endocrinol & Metab, Chicago, IL 60612 USAUniv Fed Sao Paulo, Dept Translat Med, Sao Paulo, BrazilUniv Fed Rio de Janeiro, Inst Biophys Carlos Chagas Filho, BR-21941 Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Sch Phys Educ & Sports, BR-21941 Rio De Janeiro, BrazilUniv Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USAUniv Prebiteriana Mackenzie, Dev Disorders Program, Ctr Biol & Hlth Sci, Sao Paulo, BrazilHungarian Acad Sci, Dept Endocrine Neurobiol, Inst Expt Med, Budapest, HungaryUniv Fed Sao Paulo, Dept Translat Med, Sao Paulo, BrazilNIH: R01 65055ATA: M1301627OTKA: K109415Web of Scienc

The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia

Liver-specific disruption of the type 2 deiodinase gene (Alb-D2KO) results in resistance to both diet-induced obesity and liver steatosis in mice. Here, we report that this is explained by an similar to 60% reduction in liver zinc-finger protein-125 (Zfp125) expression. Zfp125 is a Foxo1-inducible transcriptional repressor that causes lipid accumulation in the AML12 mouse hepatic cell line and liver steatosis in mice by reducing liver secretion of triglycerides and hepatocyte efflux of cholesterol. Zfp125 acts by repressing 18 genes involved in lipoprotein structure, lipid binding, and transport. The ApoE promoter contains a functional Zfp125-binding element that is also present in 17 other lipid-related genes repressed by Zfp125. While liver-specific knockdown of Zfp125 causes an "Alb-D2KO-like'' metabolic phenotype, liver-specific normalization of Zfp125 expression in Alb-D2KO mice rescues the phenotype, restoring normal susceptibility to diet-induced obesity, liver steatosis, and hypercholesterolemia.NIDDKEUHungarian Brain Research ProgramFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Coordenadoria de Apoio a Pesquisa (CAPES), BrazilRush Univ, Med Ctr, Div Endocrinol & Metab, Chicago, IL 60612 USAUniv Fed Sao Paulo, Program Translat Med, Sao Paulo, BrazilUniv Illinois, Coll Med, Dept Med, Sect Endocrinol Diabet & Metab, Chicago, IL USARush Univ, Div Digest Dis & Nutr, Med Ctr, Chicago, IL 60612 USAHarvard Med Sch, Joslin Diabet Ctr, Boston, MA USAUniv Prebiteriana Mackenzie, Ctr Biol Sci & Hlth, Dev Disorders Program, Sao Paulo, BrazilHungarian Acad Sci, Inst Expt Med, Dept Endocrine Neurobiol, Budapest, HungaryUniv Fed Sao Paulo, Program Translat Med, Sao Paulo, BrazilNIDDK: DK65055, R01DK106193, P30DK036836EU: 666869Hungarian Brain Research Program: KTIA_13_NAP_A_I/4FAPESP: 2011/21847-6Web of Scienc