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Cold-induced PGC-1[alpha] expression modulates muscle glucose uptake through an insulin receptor/Akt-independent, AMPK-dependent pathway. Am J Physiol Endocrinol Metab 287: E686-E695, 2004. First published May 27, 2004; 10.1152/ ajpendo.00103.2004.--Peroxisome proliferator-activated receptor-[gamma] coactivator-1[alpha] (PGC-1[alpha]) participates in control of expression of genes involved in adaptive thermogenesis, muscle fiber type differentiation, and fuel homeostasis. The objective of the present study was to evaluate the participation of cold-induced PGC-1[alpha] expression in muscle fiber type-specific activity of proteins that belong to the insulin-signaling pathway. Rats were exposed to 4[degrees]C for 4 days and acutely treated with insulin in the presence or absence of an antisense oligonucleotide to PGC-1[alpha] Cold exposure promoted a significant increase of PGC-1[alpha] and uncoupling protein-3 protein expression in type I and type II fibers of gastrocnemius muscle. In addition, cold exposure led to higher glucose uptake during a hyperinsulinemic clamp, which was accompanied by higher expression and membrane localization of GLUT4 in both muscle fiber types. Cold exposure promoted significantly lower insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and [Ser.sup.473] phosphorylation of acute transforming retrovirus thymoma (Akt) and an insulin-independent increase of [Thr.sup.172] phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). Inhibition of PGC-l[alpha] expression in cold-exposed rats by antisense oligonucleotide treatment diminished glucose clearance rates during a hyperinsulinemic clamp and reduced expression and membrane localization of GLUT4. Reduction of PGC-1[alpha] expression resulted in no modification of insulin-induced tyrosine phosphorylation of the IR and [Ser.sup.473] phosphorylation of Akt. Finally, reduction of PGC-1[alpha] resulted in lower [Thr.sup.172] phosphorylation of AMPK. Thus cold-induced hyperexpression of PGC-1[alpha] participates in control of skeletal muscle glucose uptake through a mechanism that controls GLUT4 expression and subcellular localization independent of the IR and Akt activities but dependent on AMPK. acute transforming retrovirus thymoma; adenosine 5'-monophosphate-activated protein kinase; cold exposure

Aging and a high-fat diet are predisposing factors for type 2 diabetes. A study in mice suggests that dietary fat and aging lead to atypical transforming growth factor-β1 signaling in [...]

Abstract Aim The purpose of the present study was to assess the dietary fat intake, glucose, insulin, Homeostasis model assessment for insulin resistance HOMA-IR, and endotoxin levels and correlate them with adipokine serum concentrations in obese adolescents who had been admitted to long-term interdisciplinary weight-loss therapy. Design The present study was a longitudinal clinical intervention of interdisciplinary therapy. Adolescents (n = 18, aged 15–19 y) with a body mass index > 95th percentile were admitted and evaluated at baseline and again after 1 year of interdisciplinary therapy. We collected blood samples, and IL-6, adiponectin, and endotoxin concentrations were measured by ELISA. Food intake was measured using 3-day diet records. In addition, we assessed glucose and insulin levels as well as the homeostasis model assessment for insulin resistance (HOMA-IR). Results The most important finding from the present investigation was that the long-term interdisciplinary lifestyle therapy decreased dietary fat intake and endotoxin levels and improved HOMA-IR. We observed positive correlations between dietary fat intake and endotoxin levels, insulin levels, and the HOMA-IR. In addition, endotoxin levels showed positive correlations with IL-6 levels, insulin levels and the HOMA-IR. Interestingly, we observed a negative correlation between serum adiponectin and both dietary fat intake and endotoxin levels. Conclusions The present results indicate an association between dietary fat intake and endotoxin level, which was highly correlated with a decreased pro-inflammatory state and an improvement in HOMA-IR. In addition, this benefits effect may be associated with an increased adiponectin level, which suggests that the interdisciplinary therapy was effective in improving inflammatory pathways.

Abstract Background Nanogold has been investigated in a wide variety of biomedical applications because of the anti-inflammatory properties. The purpose of this study was to evaluate the effects of TPU (Therapeutic Pulsed Ultrasound) with gold nanoparticles (GNP) on oxidative stress parameters and the expression of pro-inflammatory molecules after traumatic muscle injury. Materials and methods Animals were divided in nine groups: sham (uninjured muscle); muscle injury without treatment; muscle injury + DMSO; muscle injury + GNP; muscle injury + DMSO + GNP; muscle injury + TPU; muscle injury + TPU + DMSO; muscle injury + TPU + GNP; muscle injury + TPU + DMSO + GNP. The ROS production was determined by concentration of superoxide anion, modulation of antioxidant defenses was determined by the activity of superoxide dismutase, catalase and glutathione peroxidase enzymes, oxidative damage determined by formation of thiobarbituric acid-reactive substance and protein carbonyls. The levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were measured as inflammatory parameters. Results Compared to muscle injury without treatment group, the muscle injury + TPU + DMSO + GNP gel group promoted a significant decrease in superoxide anion production and lipid peroxidation levels (p < 0.050). It also showed a significant decrease in TNF-α and IL-1β levels (p < 0.050) when compared to muscle injury without treatment group. Conclusions Our results suggest that TPU + DMSO + GNP gel presents beneficial effects on the muscular healing process, inducing a reduction in the production of ROS and also the expression of pro-inflammatory molecules.

Obesity is a worldwide epidemic and is one of the factors involved in the etiology of type 2 diabetes mellitus. Obesity induces low-grade inflammation and oxidative stress. The treatment for obesity involves changes in diet, physical activity, and even medication and surgery. Currently, the use of nutraceutical compounds is associated with health benefits. Ginger and avocado are used for many people all around the world; however, its effect as a nutraceutical compound is less known by the general population. For this reason, we searched information of the literature to point its effects on distinct mechanisms of defense against the obesity its comorbidities. The present review aimed showing that these nutraceuticals may be useful in obesity treatment. Reports have shown that ginger and avocado induce antioxidant and anti-inflammatory effects by improving enzymatic activity and modulating obesity-related impairments in the anti-inflammatory system in different tissues, without side effects. Furthermore, ginger and avocado were found to be effective in reversing the harmful effects of obesity on blood lipids. In conclusion, on the basis of the positive effects of ginger and avocado in in vitro, animal, and human studies, these nutraceuticals may be useful in obesity treatment. [ABSTRACT FROM AUTHOR]

The aim of this study was to verify the effects of running overtraining protocols performed in downhill, uphill, and without inclination on the proteins related to hypertrophy signaling pathway in extensor digitorum longus (EDL) and soleus of C57BL/6 mice. We also performed histological and stereological analyses. Rodents were divided into control (CT; sedentary mice), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up), and overtrained by running without inclination (OTR). The incremental load, exhaustive, and grip force tests were used as performance evaluation parameters. 36 h after the grip force test, EDL and soleus were removed and immediately used for immunoblotting analysis or stored at −80°C for histological and stereological analyses. For EDL, OTR/down decreased the protein kinase B (Akt) and tuberous sclerosis protein 2 (TSC2) phosphorylation (p), and increased myostatin, receptor-activated Smads (pSMAD2-3), and insulin receptor substrate-1 (pIRS-1; Ser307/636). OTR/down also presented low and high relative proportions of cytoplasm and connective tissue, respectively. OTR/up increased the mammalian target of rapamycin (pmTOR), 70-kDa ribosomal protein S6 kinase 1 (pS6K1) and pSMAD2-3, and decreased pTSC2. OTR decreased pTSC2 and increased pIRS-1 (Ser636). For soleus, OTR/down increased S6 ribosomal protein (pS6RP) and pSMAD2-3, and decreased pIRS-1 (Ser639). OTR/up decreased pS6K1, pS6RP and pIRS-1 (Ser639), and increased pTSC2 (Ser939), and pSMAD2-3. OTR increased pS6RP, 4E-binding protein-1 (p4E-BP1), pTSC2 (Ser939), and pSMAD2-3, and decreased pIRS-1 (Ser639). In summary, OTR/down inhibited the skeletal muscle hypertrophy with concomitant signs of atrophy in EDL. The effects of OTR/up and OTR depended on the analyzed skeletal muscle type. J. Cell. Physiol. 231: 1045-1056, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Recent papers reported that tyrosine kinase inhibitors used for cancer treatment may improve insulin sensitivity in type 2 diabetes. However, the molecular mechanism by which these drugs improve insulin sensitivity has not yet been established. In this study, six-week-old male Swiss mice were divided into four groups with similar body weights and assigned to receive a standard rodent chow (C) or a high fat diet (HF). After 2 months, HF-mice were treated with PD153035 (30 mg/kg) (HFPD) or vehicle (HFV) by gavage once a day for 7 day. Insulin signaling was investigated by using immunoprecipitation/immunoblotting assays. PD153035 did not change the body weight, but reduced serum insulin and plasma glucose levels compared to HF and HFV groups. Intraperitoneal GTT and ITT demonstrated improvement of insulin sensitivity in HFPD group compared to HF and HFV. Adiponectin serum levels were higher and leptin and free fatty acids serum levels were lower in HFPD group compared to HF/HFV groups. These results were associated with an increase in insulin-induced PI3-K/Akt pathway in liver, muscle and adipose tissue. In parallel we investigated the expression of pro-inflammatory cytokines and serine/kinases involved in the pathogenesis of insulin resistance. PD153035 significantly decreased tissue expression of TNFα IL-6, p-JNK and IRS-1[sup ser307] in liver, muscle and adipose tissue and TNFα and IL-6 serum levels of DIO mice. There was also a decrease in NFκB[sub 65] linked to DNA in these tissues of HFPD-mice compared to HF and HFV groups. In summary, these results demonstrate that treatment with PD153035 improve insulin sensitivity, reduces hyperglicemia and increase PI-3K/Akt pathway, in parallel to a reduction in the expression of pro-inflammatory cytokines and serine kinases involved in the pathogenesis of insulin resistance. [ABSTRACT FROM AUTHOR]

Background: Studies have demonstrated that exercise in hypoxia situations induces a cytotoxicity effects. However, the cytokines participation in this condition is remaining unknown. Thus, the aim the present study was to evaluate physiological parameters and inflammatory profiles in response to acute exercise after five hours of hypoxic conditions., Methods: Fourteen healthy men were distributed randomly into two groups: normoxic exercise (N.=7) and hypoxic exercise (N.=7). All volunteers were blinded to the protocol. Initially, all subjects were submitted to chamber normobaric in a room fitted for altitude simulations of up to 4500 m, equivalent to a barometric pressure of 433 mmHg. All analyses began at 7:00 a.m. and was maintained for 5 hours; the fraction of inspired oxygen (FiO2) was 13.5%. The groups began a 60-minute session of physical exercise starting at 11:00 a.m., at 50% of peak VO2 (50% VO2peak). Blood was collected for cytokine analysis in the morning upon waking, before the 60-minute exercise session and immediately thereafter., Results: The heart rate during 60 minutes' exercise training was significantly increased in both exercise groups (P<0.05), and the oxygen saturation was reduced under hypoxic conditions during exercise (P<0.05). After exercise, significant increases were found for IL-1ra and IL-10 under hypoxic conditions (P<0.05) and for IL-6 for both groups (P<0.05). TNF-α was not altered under either environmental condition., Conclusions: Our data demonstrate that acute exercise performance in hypoxic conditions can promotes early inflammatory response, leads for immunosuppression state.

The purpose of this study was to verify the effects of overtraining (OT) on insulin, inflammatory and gluconeogenesis signaling pathways in the livers of mice. Rodents were divided into control (CT), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up) and overtrained by running without inclination (OTR). Rotarod, incremental load, exhaustive and grip force tests were used to evaluate performance. Thirty-six hours after a grip force test, the livers were extracted for subsequent protein analyses. The phosphorylation of insulin receptor beta (pIRbeta), glycogen synthase kinase 3 beta (pGSK3beta) and forkhead box O1 (pFoxo1) increased in OTR/down versus CT. pGSK3beta was higher in OTR/up versus CT, and pFoxo1 was higher in OTR/up and OTR versus CT. Phosphorylation of protein kinase B (pAkt) and insulin receptor substrate 1 (pIRS-1) were higher in OTR/up versus CT and OTR/down. The phosphorylation of IκB kinase alpha and beta (pIKKalpha/beta) was higher in all OT protocols versus CT, and the phosphorylation of stress-activated protein kinases/Jun amino-terminal kinases (pSAPK-JNK) was higher in OTR/down versus CT. Protein levels of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) and hepatocyte nuclear factor 4alpha (HNF-4alpha) were higher in OTR versus CT. In summary, OTR/down improved the major proteins of insulin signaling pathway but up-regulated TRB3, an Akt inhibitor, and its association with Akt.

Hypothalamic inflammation is associated with insulin and leptin resistance, hyperphagia, and obesity. In this scenario, hypothalamic protein tyrosine phosphatase 1B (PTP1B) has emerged as the key phosphatase induced by inflammation that is responsible for the central insulin and leptin resistance. Here, we demonstrated that acute exercise reduced inflammation and PTP1B protein level/activity in the hypothalamus of obese rodents. Exercise disrupted the interaction between PTP1B with proteins involved in the early steps of insulin (IRβ and IRS-1) and leptin (JAK2) signaling, increased the tyrosine phosphorylation of these molecules, and restored the anorexigenic effects of insulin and leptin in obese rats. Interestingly, the anti-inflammatory action and the reduction of PTP1B activity mediated by exercise occurred in an interleukin-6 (IL-6)-dependent manner because exercise failed to reduce inflammation and PTP1B protein level after the disruption of hypothalamic-specific IL-6 action in obese rats. Conversely, intracerebroventricular administration of recombinant IL-6 reproduced the effects of exercise, improving hypothalamic insulin and leptin action by reducing the inflammatory signaling and PTP1B activity in obese rats at rest. Taken together, our study reports that physical exercise restores insulin and leptin signaling, at least in part, by reducing hypothalamic PTP1B protein level through the central anti-inflammatory response.

Exercise training has demonstrated cardioprotection effects. However, the exact mechanism behind this effect is not is clear. The present study evaluated the effects of 12 weeks of previous treadmill training on the levels of oxidative damage, antioxidant enzyme activity and injury in the myocardium of rats submitted to infarction induced by isoproterenol (ISO). Isoproterenol treatment (80 mg/kg given over 2 days in two equal doses) caused arrhythmias and 60% mortality within 24 h of the last injection in the control group (C + ISO) group when compared with the saline control group (saline). Creatine Kinase--MB levels were markedly increased in hearts from ISO-treated animals in the C + ISO group. Twelve weeks of treadmill training reduced superoxide production, lipid peroxidation levels and protein carbonylation in these animals, as well as increasing the activities and expressions of SOD and CAT. Previous training also reduced CK-MB levels and numbers of deaths by 40%, preventing the deleterious effects of ISO. Based on the data obtained in this study, it is suggested that 12-week treadmill training increases antioxidant enzymes, decreases oxidative damage and reduces the degree of infarction induced by ISO in the hearts of male rats.