Alexandre Machado Lehnen

GLUT4 content decreases along with insulin resistance and high levels of inflammatory markers in rats with metabolic syndrome

BackgroundMetabolic syndrome is characterized by insulin resistance, which is closely related to GLUT4 content in insulin-sensitive tissues. Thus, we evaluated the GLUT4 expression, insulin resistance and inflammation, characteristics of the metabolic syndrome, in an experimental model.MethodsSpontaneously hypertensive neonate rats (18/group) were treated with monosodium glutamate (MetS) during 9 days, and compared with Wistar-Kyoto (C) and saline-treated SHR (H). Blood pressure (BP) and lipid levels, C-reactive protein (CRP), interleukin 6 (IL-6), TNF-α and adiponectin were evaluated. GLUT4 protein was analysed in the heart, white adipose tissue and gastrocnemius. Studies were performed at 3 (3-mo), 6 (6-mo) and 9 (9-mo) months of age.ResultsMetS rats were more insulin resistant (p<0.001, all ages) and had higher BP (3-mo: p<0.001, 6-mo: p = 0.001, 9-mo: p = 0.015) as compared to C. At 6 months, CRP, IL-6 and TNF-α were higher (p<0.001, all comparisons) in MetS rats vs H, but adiponectin was lower in MetS at 9 months (MetS: 32 ± 2, H: 42 ± 2, C: 45 ± 2 pg/mL; p<0.001). GLUT4 protein was reduced in MetS as compared to C rats at 3, 6 and 9-mo, respectively (Heart: 54%, 50% and 57%; Gastrocnemius: 37%, 56% and 50%; Adipose tissue: 69%, 61% and 69%).ConclusionsMSG-treated SHR presented all metabolic syndrome characteristics, as well as reduced GLUT4 content, which must play a key role in the impaired glycemic homeostasis of the metabolic syndrome.

The beneficial effects of exercise in rodents are preserved after detraining: a phenomenon unrelated to GLUT4 expression

BackgroundAlthough exercise training has well-known cardiorespiratory and metabolic benefits, low compliance with exercise training programs is a fact, and the harmful effects of physical detraining regarding these adaptations usually go unnoticed. We investigated the effects of exercise detraining on blood pressure, insulin sensitivity, and GLUT4 expression in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY).MethodsStudied animals were randomized into sedentary, trained (treadmill running/5 days a week, 60 min/day for 10 weeks), 1 week of detraining, and 2 weeks of detraining. Blood pressure (tail-cuff system), insulin sensitivity (kITT), and GLUT4 (Western blot) in heart, gastrocnemius and white fat tissue were measured.ResultsExercise training reduced blood pressure (19%), improved insulin sensitivity (24%), and increased GLUT4 in the heart (+34%); gastrocnemius (+36%) and fat (+22%) in SHR. In WKY no change in either blood pressure or insulin sensitivity were observed, but there was an increase in GLUT4 in the heart (+25%), gastrocnemius (+45%) and fat (+36%) induced by training. Both periods of detraining did not induce any change in neither blood pressure nor insulin sensitivity in SHR and WKY. One-week detraining reduced GLUT4 in SHR (heart: -28%; fat: -23%) and WKY (heart: -19%; fat: -22%); GLUT4 in the gastrocnemius was reduced after a 2-week detraining (SHR: -35%; WKY: -25%). There was a positive correlation between GLUT4 (gastrocnemius) and the maximal velocity in the exercise test (r = 0.60, p = 0.004).ConclusionsThe study findings show that in detraining, despite reversion of the enhanced GLUT4 expression, cardiorespiratory and metabolic beneficial effects of exercise are preserved.

A review on effects of conjugated linoleic fatty acid (CLA) upon body composition and energetic metabolism.

Conjugated linoleic acid (CLA) is highly found in fats from ruminants and it appears to favorably modify the body composition and cardiometabolic risk factors. The capacity of CLA to reduce the body fat levels as well as its benefic actions on glycemic profile, atherosclerosis and cancer has already been proved in experimental models. Furthermore, CLA supplementation may modulate the immune function, help re-synthetize of glycogen and potentiate the bone mineralization. CLA supplementation also could increase the lipolysis and reduce the accumulation of fatty acids on the adipose tissue; the putative mechanisms involved may be its action in reducing the lipase lipoprotein activity and to increase the carnitine-palmitoil-transferase-1 (CAT-1) activity, its interaction with PPARγ, and to raise the expression of UCP-1. Although studies made in human have shown some benefits of CLA supplementation as the weight loss, the results are still discordant. Moreover, some have shown adverse effects, such as negative effects on glucose metabolism and lipid profile. The purpose of this article is to review the available data regarding the benefits of CLA on the energetic metabolism and body composition, emphasizing action mechanisms.

Aerobic exercise training induces metabolic benefits in rats with metabolic syndrome independent of dietary changes

OBJECTIVES: We evaluated the effects of aerobic exercise training without dietary changes on cardiovascular and metabolic variables and on the expression of glucose transporter Type 4 in rats with metabolic syndrome. METHODS: Twenty male spontaneously hypertensive rats received monosodium glutamate during the neonatal period. The animals were allocated to the following groups: MS (sedentary metabolic syndrome), MS-T (trained on a treadmill for 1 hour/day, 5 days/week for 10 weeks), H (sedentary spontaneously hypertensive rats) and H-T (trained spontaneously hypertensive rats). The Lee index, blood pressure (tail-cuff system), insulin sensitivity (insulin tolerance test) and functional capacity were evaluated before and after 10 weeks of training. Glucose transporter Type 4 expression was analyzed using Western blotting. The data were compared using analysis of variance (ANOVA) (p<0.05). RESULTS: At baseline, the MS rats exhibited lower insulin sensitivity and increased Lee index compared with the H rats. Training decreased the body weight and Lee index of the MS rats (MS-T vs. MS), but not of the H rats (H-T vs. H). There were no differences in food intake between the groups. At the end of the experiments, the systolic blood pressure was lower in the two trained groups than in their sedentary controls. Whole-body insulin sensitivity increased in the trained groups. Glucose transporter Type 4 content increased in the heart, white adipose tissue and gastrocnemius muscle of the trained groups relative to their respective untrained groups. CONCLUSION: In conclusion, the present study shows that an isolated aerobic exercise training intervention is an efficient means of improving several components of metabolic syndrome, that is, training reduces obesity and hypertension and increases insulin sensitivity.

Cardiovascular changes in animal models of metabolic syndrome.

Metabolic syndrome has been defined as a group of risk factors that directly contribute to the development of cardiovascular disease and/or type 2 diabetes. Insulin resistance seems to have a fundamental role in the genesis of this syndrome. Over the past years to the present day, basic and translational research has used small animal models to explore the pathophysiology of metabolic syndrome and to develop novel therapies that might slow the progression of this prevalent condition. In this paper we discuss the animal models used for the study of metabolic syndrome, with particular focus on cardiovascular changes, since they are the main cause of death associated with the condition in humans.

Progressive cardiovascular autonomic dysfunction in rats with evolving metabolic syndrome

Metabolic syndrome is linked to increased cardiovascular mortality, which may be partially attributed to cardiac sympatho-vagal imbalance. However, autonomic changes were not evaluated during the metabolic syndrome development in a monosodium glutamate-induced animal model. We evaluate temporal changes in cardiovascular autonomic modulation in an animal model of metabolic syndrome. Eighteen neonate male spontaneously hypertensive rats (SHR) were treated with monosodium glutamate (MetS), and compared with Wistar-Kyoto (C) and saline-treated SHR (H). Lee index, insulin resistance and autonomic control (spectral analysis) were evaluated at 3 (3-mo), 6 (6-mo) and 9 (9-mo) months of age (compared by two-way ANOVA, p<0.05). Weight of visceral fat, Lee index and arterial pressure were higher in the MetS vs. C and H groups (p<0.001) at all ages. Heart rate variability (HRV) was decreased in the MetS and H groups at 3-mo and 9-mo vs. C. The LF component of HRV was reduced in the MetS group at 3-mo vs. C (p=0.032), and higher vs. C and H at 9-mo (p<0.001, all comparisons). H and MetS rats had a higher LF/HF index vs. C at 9-mo (p=0.001, all comparisons). The VLF component of systolic arterial pressure variability of the MetS was higher earlier (6-mo) than that of the H group. A reduction of 70%, 98% and 54% in αLF index of H and MetS rats vs. C, was observed at 3, 6 and 9 months, respectively. Metabolic syndrome and hypertension in rats evolve with progressive autonomic dysfunction (worst at 9 months), with specific derangements occurring very early.

Changes in the GLUT4 Expression by Acute Exercise, Exercise Training and Detraining in Experimental Models

There is a direct correlation between an increase in insulin sensitivity and increased cell surface GLUT4 content. Acute exercise promotes glucose-transport stimulation that is independent of AMPK and CaMKII insulin-signaling. In turn, post-exercise glucose uptake occurs through changes in components of the insulin signaling cascade involving alterations in downstream mediators such as TBC1D1, TBC1D4/AS160 and p38 MAPK. However, the effects of acute exercise can be reversed within 18–24 hours and appear to be dependent on muscle glycogen levels. Exercise training results in adaptations that facilitate insulin-mediated glucose uptake and are regulated by different mechanisms. It leads to changes in gene expression and greater blood flow and signaling and changes in GLUT4 protein exocytosis and endocytosis. But when exercise training is discontinued GLUT4 tend to return to baseline levels. We have demonstrated in our laboratory that one-week detraining is sufficient to reduce GLUT4 in the heart and adipocytes while this same effect was seen in the gastrocnemius muscle within 2 weeks of training. The present study aimed to review how acute exercise, exercise training, and detraining affect mainly GLUT4 translocation to the insulin-sensitive cell surface.

Exercise-stimulated GLUT4 expression is similar in normotensive and hypertensive rats.

The effects of exercise training on systolic blood pressure (BP), insulin sensitivity, and plasma membrane GLUT4 protein content in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were compared. 16 SHR and 16 WKY male rats, aged 6 months, were randomized into sedentary and trained (treadmill running, 5 days/week, 60 min/day for 10 weeks) groups (n=8/group). At baseline, SHR had lower insulin sensitivity than WKY rats, however, there were no differences between WKY and SHR GLUT4 expression. The 10-week training reduced BP by ∼19% in SHR, improved insulin sensitivity by ∼24% in SHR, but not in WKY, and increased GLUT4 expression in both animal models. Compared to the sedentary group, there was an increase of GLUT4 in WKY rats by ∼25% in the heart, by ∼23% in the gastrocnemius, and by ∼15% in the fat tissue. Trained SHR presented an increase in GLUT4 of ∼21%, ∼20%, and ∼14%, in the same tissues, respectively. There were no differences between SHR and WKY rats in post-training GLUT4 expression. We conclude that training determined BP and insulin resistance reduction in SHR, and increased GLUT4 expression in both normotensive and hypertensive rats. However, considering the similar rise in GLUT4-induced training in SHR and WKY, it is possible that GLUT4 levels in plasma membrane fraction do not have a pivotal role in the exercise-induced improvement of insulin sensitivity in SHR.

Short-Term Detraining does not Change Insulin Sensitivity and RBP4 in Rodents Previously Submitted to Aerobic Exercise

Elevated serum retinol binding protein 4 (RBP4) levels were previously described in insulin-resistance states. Exercise training can improve insulin sensitivity and RBP4, but the time-response effect of exercise detraining on RBP4 has not been studied. Thus, we examined the effects of exercise training and short-term detraining on insulin resistance, serum RBP4 levels, and GLUT4 expression in spontaneously hypertensive rats (SHR). Thirty-two male SHR, 4 months old, were submitted to 10-week treadmill training, 5 times/week or kept sedentary, followed by a 2- and 4-day detraining period. Body weight, insulin tolerance test, maximum speed in a maximal exercise test, serum RBP4 (ELISA), and epididymal fat GLUT4 expression (Western blot) were measured. Although all rats gained weight (43%, p=0.004) only the trained group showed a reduction (p<0.001) of epididymal fat weight. Detraining did not change these parameters. Exercise training increased insulin sensitivity (26%, p=0.001) and maximum exercise capacity (80%, p<0.001), benefits not lost after detraining. RBP4 levels were reduced in response to exercise training (45%, p<0.001); detraining did not change these benefits. Trained rats had increased GLUT4 expression (microsomal, ~226%; p<0.001 and plasma membrane, ~55%; p=0.011). A slight reduction in GLUT4 expression in the plasma membrane (~28%, p=0.041), but not in the microsomal fraction, was observed after 4 days of detraining. Exercise training is associated with reduced RBP4 levels, increased insulin sensitivity, and epididymal fat GLUT4 expression. Even short periods of detraining (4 days) were shown to be associated with reversal of higher plasma membrane GLUT4.

Aerobic training prior to myocardial infarction increases cardiac GLUT4 and partially preserves heart function in spontaneously hypertensive rats

We assessed cardiac function (echocardiographic) and glucose transporter 4 (GLUT4) expression (Western blot) in response to 10 weeks of aerobic training (treadmill) prior to acute myocardial infarction (AMI) by ligation of the left coronary artery in spontaneously hypertensive rats. Animals were allocated to sedentary+sham, sedentary+AMI, training+sham, and training+AMI. Aerobic training prior to AMI partially preserves heart function. AMI and/or aerobic training increased GLUT4 expression. However, those animals trained prior to AMI showed a greater increase in GLUT4 in cardiomyocytes.