Physical Exercise Reduces Circulating Lipopolysaccharide and TLR4 Activation and Improves Insulin Signaling in Tissues of DIO Rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)OBJECTIVE-Insulin resistance in diet-induced obesity (DIO) is associated with a chronic systemic low-grade inflammation, and Toll-like receptor 4 (TLR4) plays an important role in the link among insulin resistance, inflammation, and obesity. The current study aimed to analyze the effect of exercise on TLR4 expression and activation in obese rats and its consequences on insulin sensitivity and signaling. RESEARCH DESIGN AND METHODS-The effect of chronic and acute exercise was investigated on insulin sensitivity, insulin signaling, TLR4 activation, c-Jun NH(2)-terminal kinase (JNK) and I kappa B kinase (IKK beta) activity, and lipopolysaccharide (LPS) serum levels in tissues of DIO rats. RESULTS-The results showed that chronic exercise reduced TLR4 mRNA and protein expression in liver, muscle, and adipose tissue. However, both acute and chronic exercise blunted TLR4 signaling in these tissues, including a reduction in JNK and IKK beta phosphorylation and IRS-1 serine 307 phosphorylation, and, in parallel, improved insulin-induced IR, IRS-1 tyrosine phosphorylation, and Akt serine phosphorylation, and reduced LPS serum levels. CONCLUSIONS-Our results show that physical exercise in DIO rats, both acute and chronic, induces an important suppression in the TLR4 signaling pathway in the liver, muscle, and adipose tissue, reduces LPS serum levels, and improves insulin signaling and sensitivity. These data provide considerable progress in our understanding of the molecular events that link physical exercise to an improvement in inflammation and insulin resistance. Diabetes 60:784-796, 2011603784796Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de PesquisaINCT-Obesidade e DiabetesFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

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β-Hydroxy-β-methylbutyrate (HMβ) supplementation stimulates skeletal muscle hypertrophy in rats via the mTOR pathway

β-Hydroxy-β-methylbutyrate (HMβ) supplementation is used to treat cancer, sepsis and exercise-induced muscle damage. However, its effects on animal and human health and the consequences of this treatment in other tissues (e.g., fat and liver) have not been examined. The purpose of this study was to evaluate the effects of HMβ supplementation on skeletal muscle hypertrophy and the expression of proteins involved in insulin signalling. Rats were treated with HMβ (320 mg/kg body weight) or saline for one month. The skeletal muscle hypertrophy and insulin signalling were evaluated by western blotting, and hormonal concentrations were evaluated using ELISAs. HMβ supplementation induced muscle hypertrophy in the extensor digitorum longus (EDL) and soleus muscles and increased serum insulin levels, the expression of the mammalian target of rapamycin (mTOR) and phosphorylation of p70S6K in the EDL muscle. Expression of the insulin receptor was increased only in liver. Thus, our results suggest that HMβ supplementation can be used to increase muscle mass without adverse health effects

Long-term effects of moderate physical exercise during early childhood on insulin sensitivity in rats during adulthood

It is of great importance to investigate the effects of physical exercise for metabolic health when performed in early life, and what the adulthood response would be. The aim of this study is to analyse the effects of moderate intensity physical exercise protocol during childhood on the adipose tissue and insulin sensitivity of rats during adulthood. Twenty weaned Wistar (28 days old) were divided into control and trained groups. The Control Group was kept sedentary, and the Trained group was submitted to swimming exercise at 80% of the anaerobic threshold (determined by the lactate minimum test) for 1 hour/day, 5 days/week from 28 to 90 days of age. At the end of the experiment, the body weight, adiposity (adipose tissue weight), insulin sensitivity, glycemia, insulinemia, pancreatic insulin, lipogenic activity in mesenteric fat, lipogenic activity and glycogen store in gastrocnemius and glucose uptake by soleus were analyzed. Trained group showed lower body weight gain, fat acumulation, lipid synthesis, glycemia, insulinemia and pancreatic insulin level. Kitt, HOMA-IR, glycogen store in gastrocnemius and glucose uptake by soleus were higher in this group. Therefore, we conclude that the moderate physical exercise performed during childhood can contribute to the reduction of body fat and insulin resistance during adulthood in Wistar rats.É de grande importância a investigação dos efeitos do exercício para a saúde metabólica quando realizado no início da vida, e quais seriam as respostas durante a fase adulta. O objetivo desse estudo é analisar os efeitos do exercício físico de intensidade moderada durante a infância na adiposidade e sensibilidade à insulina de ratos durante a fase adulta. Vinte ratos Wistar desmamados de 28 dias de vida foram divididos em grupos Controle e Treinado. O grupo Controle permaneceu sedentário, enquanto o grupo Treinado realizou exercício de natação a 80% do limiar anaeróbio (determinado pelo teste de lactato mínimo) por 1hora/dia, 5dias/semana do 28º até o 90º dia de vida. No fim do experimento, a massa corporal, adiposidade, sensibilidade à insulina, glicemia, insulinemia, insulina pancreática, atividade lipogênica do tecido adiposo mesentérico, atividade lipogênica e estoques de glicogênio no músculo gastrocnêmio e captação de glicose pelo músculo sóleo foram analizadas. O grupo Treinado apresentou menor ganho de massa corporal, acúmulo de gordura, síntese de lipídios, glicemia, insulinemia e insulina pancreática. Kitt, HOMA-IR, estoques de glicogênio no gastrocnêmio e captação de glicose pelo sóleo foram maiores nesse grupo. Portanto, concluímos que o exercício físico moderado realizado durante a infância pode contribuir para a redução da adiposidade corporal e resistência à insulina durante a fase adulta em ratos Wistar

O que influencia o desejo de ter um filho nos jovens adultos

Enquadramento: O Índice Sintético de Fecundidade (ISF) português é dos mais baixos da Europa. No entanto, o desejo de cada individuo jovem ter um filho, sem qualquer restrição é superior ao valor de referência para a substituição de gerações. Objectivos: Compreender a relação entre as variáveis sociodemográficas, as variáveis de contexto sexual e reprodutivo e as variáveis psicológicas com o desejo de ter um filho. Métodos: Estudo quantitativo, descritivo-correlacional. A amostra é não probabilistica por conveniência com uma média de idade de 20,79 anos (dp=2,785). O protocolo de investigação foi um questionário que caracteriza o perfil sociodemográfico, sexual e reprodutivo da amostra. Foi incluído o “QVPM” (Matos& Costa, 2001), “QVA” (Matos& Costa, 2001), “Questionário de desejo de ter um filho” (Leal, 1999) e escala de Auto estima de (Rosenberg, 1965, adaptado 1999). Resultados: É no sexo feminino e no grupo etário ≤ 19 anos que o desejo de ter um filho é maior. O desejo de ter um filho diminui com a idade. Ter namorado(a), pertencer a uma família alargada, não ter irmãos e ser proveniente de uma zona rural estão relacionados com maior desejo de ter um filho, no entanto sem diferenças estatísticas significativas. Os estudantes do primeiro ano apresentam maior desejo de ter um filho no futuro e este diminui conforme a progressão no ensino (ano de curso) e aproximação do mercado de trabalho. Os que apresentam maior desejo de ser pais com base em sentimentos relativos à parentalidade frequentam menos a consulta de planeamento familiar. Observaram-se diferenças estatísticas significativas entre o número de filhos desejado no futuro e o desejo de ter um filho. O nível de conhecimento sobre fertilidade não influencia o desejo de ter um filho. Quanto maior a ansiedade de separação da mãe (vinculação à mãe), a dependência da vinculação amorosa, a ansiedade de separação do pai (vinculação ao pai) e a auto estima, maior é o desejo de ter um filho. Conclusões: O desejo de ter um filho é um construto ao longo da vida, pelo que os enfermeiros acompanhando o ciclo vital do individuo contribuem para a promoção e capacitação da parentalidade nomeadamente através da: avaliação e promoção do vinculo parental e promoção da saúde sexual e reprodutiva. Palavras chave: Jovem adulto, parentalidade, vinculação amorosa, auto estima.Abstract: Framework: The Portuguese Synthetic Fertility Index (ISF) is among the lowest in Europe. However, the desire of each young individual to have a child without any restriction is higher than the reference value for the replacement of generations. Objective: Understand the relationship between sociodemographic variables, sexual and reproductive health variables, and psychological variables with the desire to have a child. Methods: Quantitative, descriptive-correlational study. A non-probabilistic for convenience sampling with an average age of 20.79 years (sd = 2.785). The research protocol was a questionnaire that characterizes the sociodemographic, sexual and reproductive profile of the sample and includes the “QVPM” (Matos& Costa, 2001), “QVA” (Matos& Costa, 2001), “Questionário de desejo de ter um filho” (Leal, 1999) and Rosenberg Self – esteem scale (Rosenberg, 1965, adap.1999). Results: It is in the female sex and in the age group ≤ 19 years that the desire to have a child is higher. The desire to have a child decreases with age. Having a boyfriend, belonging to an extended family, not having siblings and being from the countryside are related to higher desire to have a child, however without significant statistical differences. In the first year students the desire to have a child is higher and this decreases with the progression in school’s year and the approaching of labor market. Those who are more likely to be parents based on feelings about parenting are less likely to attend family planning visits. Significant statistical differences were observed between the number of children desired in the future and the desire to have a child. The level of knowledge about fertility does not influence the desire to have a child. The greater the separation anxiety of the mother (attachment to the mother), the dependence of the love bond, the separation anxiety of the father (attachment to the father) and the self esteem, the greater is the desire to have a child. Conclusions: The desire to have a child is a lifelong construct, so the nurses by accompanying the individual's life cycle contribute to the promotion and training of parenting, namely through: evaluation and promotion of parental attachment and promotion of sexual and reproductive health. Descriptors: Young adult, parenting, attachment, self esteem

Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans.

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 +/- 1.1 years, BMI 33.4 +/- 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 +/- 44 vs. 1,135 +/- 97 mumol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans

Exercise Counterbalances Rho/ROCK2 Signaling Impairment in the Skeletal Muscle and Ameliorates Insulin Sensitivity in Obese Mice

Physical exercise is considered a fundamental strategy in improving insulin sensitivity and glucose uptake in skeletal muscle. However, the molecular mechanisms underlying this regulation, primarily on skeletal muscle glucose uptake, are not fully understood. Recent evidence has shown that Rho-kinase (ROCK) isoforms play a pivotal role in regulating skeletal muscle glucose uptake and systemic glucose homeostasis. The current study evaluated the effect of physical exercise on ROCK2 signaling in skeletal muscle of insulin-resistant obese animals. Physiological (ITT) and molecular analysis (immunoblotting, and RT-qPCR) were performed. The contents of RhoA and ROCK2 protein were decreased in skeletal muscle of obese mice compared to control mice but were restored to normal levels in response to physical exercise. The exercised animals also showed higher phosphorylation of insulin receptor substrate 1 (IRS1 Serine 632/635) and protein kinase B (Akt) in the skeletal muscle. However, phosphatase and tensin homolog (PTEN) and protein-tyrosine phosphatase-1B (PTP-1B), both inhibitory regulators for insulin action, were increased in obesity but decreased after exercise. The impact of ROCK2 action on muscle insulin signaling is further underscored by the fact that impaired IRS1 and Akt phosphorylation caused by palmitate in C2C12 myotubes was entirely restored by ROCK2 overexpression. These results suggest that the exercise-induced upregulation of RhoA-ROCK2 signaling in skeletal muscle is associated with increased systemic insulin sensitivity in obese mice and further implicate that muscle ROCK2 could be a potential target for treating obesity-linked metabolic disorders

Targeted disruption of inducible nitric oxide synthase protects against aging, S-nitrosation, and insulin resistance in muscle of male mice

Accumulating evidence has demonstrated that S-nitrosation of proteins plays a critical role in several human diseases. Here, we explored the role of inducible nitric oxide synthase (iNOS) in the S-nitrosation of proteins involved in the early steps of the insulin-signaling pathway and insulin resistance in the skeletal muscle of aged mice. Aging increased iNOS expression and S-nitrosation of major proteins involved in insulin signaling, thereby reducing insulin sensitivity in skeletal muscle. Conversely, aged iNOS-null mice were protected from S-nitrosation–induced insulin resistance. Moreover, pharmacological treatment with an iNOS inhibitor and acute exercise reduced iNOS-induced S-nitrosation and increased insulin sensitivity in the muscle of aged animals. These findings indicate that the insulin resistance observed in aged mice is mainly mediated through the S-nitrosation of the insulin-signaling pathway