Behavioral, neuroplasticity and metabolic effects of 7,8-dihydroxy-4-methylcoumarin associated with physical activity in mice.

The search for strategies to develop resilience against metabolic and neuropsychiatric disorders has motivated the clinical and experimental assessment of early life interventions such as lifestyle-based and use of unconventional pharmacological compounds. In this study, we assessed the effects of voluntary physical activity and 7,8-Dihydroxy-4-methylcoumarin (DHMC), independently or in combination, over mice physiological and behavioral parameters, adult hippocampal and hypothalamic neurogenesis, and neurotrophic factors expression in the hypothalamus. C57Bl/6J mice were submitted to a 29-day treatment with DHMC and allowed free access to a running wheel. We found that DHMC treatment alone reduced fasting blood glucose levels. Moreover, physical activity showed an anxiolytic effect in the elevated plus maze task and DHMC produced additional anxiolytic behavior, evidenced by reduced activity during the light cycle in the physical activity group. Although we did not find any differences in hypothalamic or hippocampal adult neurogenesis, DHMC increased gene expression levels of VEGF, which was correlated to the reduced fasting glucose levels. In conclusion, our data emphasize the potential of physical activity in reducing development of neuropsychiatric conditions, such as anxiety, and highlights DHMC as an attractive compound to be investigated in future studies addressing neuropsychiatric disorders associated with metabolic conditions.

Metabolic syndrome signs in Wistar rats submitted to different high-fructose ingestion protocols.

In search of an adequate model for the human metabolic syndrome, the metabolic characteristics of Wistar rats were analysed after being submitted to different protocols of high fructose ingestion. First, two adult rat groups (aged 90 d) were studied: a control group (C1; n 6) received regular rodent chow (Labina, Purina) and a fructose group (F1; n 6) was fed on regular rodent chow. Fructose was administered as a 10 % solution in drinking water. Second, two adult rat groups (aged 90 d) were evaluated: a control group (C2; n 6) was fed on a balanced diet (AIN-93G) and a fructose group (F2; n 6) was fed on a purified 60 % fructose diet. Finally, two young rat groups (aged 28 d) were analysed: a control group (C3; n 6) was fed on the AIN-93G diet and a fructose group (F3; n 6) was fed on a 60 % fructose diet. After 4-8 weeks, the animals were evaluated. Glucose tolerance, peripheral insulin sensitivity, blood lipid profile and body fat were analysed. In the fructose groups F2 and F3 glucose tolerance and insulin sensitivity were lower, while triacylglycerolaemia was higher than the respective controls C2 and C3 (P < 0.05). Blood total cholesterol, HDL and LDL as well as body fat showed change only in the second protocol. In conclusion, high fructose intake is more effective at producing the signs of the metabolic syndrome in adult than in young Wistar rats. Additionally, diet seems to be a more effective way of fructose administration than drinking water.

Growth factors and glucose homeostasis in diabetic rats: effects of exercise training.

To investigate the alterations of glucose homeostasis and variables of the insulin-like growth factor-1 (IGF-1) growth system in sedentary and trained diabetic (TD) rats, Wistar rats were divided into sedentary control (SC), trained control (TC), sedentary diabetic (SD), and TD groups. Diabetes was induced by Alloxan (35 mg kg(-1) b.w.). Training program consisted of swimming 5 days week(-1), 1 h day(-1), during 8 weeks. Rats were sacrificed and blood was collected for determinations of serum glucose, insulin, growth hormone (GH), IGF-1, and IGF binding protein-3 (IGFBP-3). Muscle and liver were removed to evaluate glycogen content. Cerebellum was extracted to determinate IGF-1 content. Diabetes decreased serum GH, IGF-1, IGFBP-3, liver glycogen, and cerebellum IGF-1 peptide content in baseline condition. Physical training recovered liver glycogen and increased serum and cerebellum IGF-1 peptide in diabetic rats. Physical training induces important metabolic and hormonal alterations that are associated with an improvement in glucose homeostasis and serum and cerebellum IGF-1 concentrations.

Effects of physical training on serum and pituitary growth hormone contents in diabetic rats.

The present study investigated the effects of moderate physical training on some of the parameters in the GH-IGF axis in experimental diabetic rats. Male Wistar rats were allocated into the following groups: sedentary control, trained control, sedentary diabetic, trained diabetic. Diabetes was induced by alloxan (32 mg/kg, b.w. iv). The physical training protocol consisted of 1 h swimming session/day, 5 days/week for 8 weeks supporting a load corresponding to 90% of maximal lactate steady state. After the experimental period, blood was collected to measure serum glucose, insulin, triglycerides, albumin, insulin-like growth factors-I (IGF-I), and growth hormone (GH). Pituitary gland was removed for GH quantification. Diabetes increased blood glucose and triglycerides and decreased insulin, IGF-I, serum and pituitary GH. Physical training decreased glucose and triglycerides, and also counteracted the reduction of serum IGF-I in diabetic rats. In conclusion, physical training recovered serum IGF-I showing no alteration of serum or pituitary GH levels.

Insulin concentrations in cerebellum and body balance in diabetic male rats: aerobic training effects.

UNLABELLED: Brain insulin has had widespread metabolic, neurotrophic, and neuromodulatory functions and has been involved in the central regulation of food intake and body weight, learning and memory, neuronal development, and neuronal apoptosis. PURPOSE: The present study investigated the role of swimming training on cerebral metabolism on insulin concentrations in cerebellum and the body balance performance of diabetic rats. METHODS: Forty Male Wistar rats were divided in four groups: sedentary control (SC), trained control (TC), sedentary diabetic (SD), and trained diabetic (TD). Diabetes was induced by alloxan (32mgkg b.w.), single dose injection. The mean blood glucose of diabetic groups was 367±40mg/dl. Training program consisted in swimming 5days/week, 1h/day, 8weeks, supporting a workload corresponding to 90% of maximal lactate steady state (MLSS). For the body balance testing rats were trained to traverse for 5min daily for 5-7days. All dependent variables were analyzed by one-way analysis of variance (ANOVA) and a significance level of p<0.05 was used for all comparisons. RESULTS: The body balance testing scores were different between groups. Insulin concentrations in cerebellum were not different between groups. CONCLUSION: It was concluded that in diabetic rats, aerobic training does not induce alterations on cerebellum insulin but induces important metabolic, hormonal and behavioral alterations which are associated with an improvement in glucose homeostasis, serum insulin concentrations and body balance.

Hypothalamic inhibition of acetyl-CoA carboxylase stimulates hepatic counter-regulatory response independent of AMPK activation in rats.

BACKGROUND: Hypothalamic AMPK acts as a cell energy sensor and can modulate food intake, glucose homeostasis, and fatty acid biosynthesis. Intrahypothalamic fatty acid injection is known to suppress liver glucose production, mainly by activation of hypothalamic ATP-sensitive potassium (K(ATP)) channels. Since all models employed seem to involve malonyl-CoA biosynthesis, we hypothesized that acetyl-CoA carboxylase can modulate the counter-regulatory response independent of nutrient availability. METHODOLOGY/PRINCIPAL FINDINGS: In this study employing immunoblot, real-time PCR, ELISA, and biochemical measurements, we showed that reduction of the hypothalamic expression of acetyl-CoA carboxylase by antisense oligonucleotide after intraventricular injection increased food intake and NPY mRNA, and diminished the expression of CART, CRH, and TRH mRNA. Additionally, as in fasted rats, in antisense oligonucleotide-treated rats, serum glucagon and ketone bodies increased, while the levels of serum insulin and hepatic glycogen diminished. The reduction of hypothalamic acetyl-CoA carboxylase also increased PEPCK expression, AMPK phosphorylation, and glucose production in the liver. Interestingly, these effects were observed without modification of hypothalamic AMPK phosphorylation. CONCLUSION/SIGNIFICANCE: Hypothalamic ACC inhibition can activate hepatic counter-regulatory response independent of hypothalamic AMPK activation.