Hypothalamic α7 nicotinic acetylcholine receptor (α7nAChR) is downregulated by TNFα-induced Let-7 overexpression driven by fatty acids.

The α7nAChR is crucial to the anti-inflammatory reflex, and to the expression of neuropeptides that control food intake, but its expression can be decreased by environmental factors. We aimed to investigate whether microRNA modulation could be an underlying mechanism in the α7nAchR downregulation in mouse hypothalamus following a short-term exposure to an obesogenic diet. Bioinformatic analysis revealed Let-7 microRNAs as candidates to regulate Chrna7, which was confirmed by the luciferase assay. Mice exposed to an obesogenic diet for 3 days had increased Let-7a and decreased α7nAChR levels, accompanied by hypothalamic fatty acids and TNFα content. Hypothalamic neuronal cells exposed to fatty acids presented higher Let-7a and TNFα levels and lower Chrna7 expression, but when the cells were pre-treated with TLR4 inhibitor, Let-7a, TNFα, and Chrna7 were rescued to normal levels. Thus, the fatty acids overload trigger TNFα-induced Let-7 overexpression in hypothalamic neuronal cells, which negatively regulates α7nAChR, an event that can be related to hyperphagia and obesity predisposition in mice.

MicroRNA Let-7 targets AMPK and impairs hepatic lipid metabolism in offspring of maternal obese pregnancies.

Nutritional status during gestation may lead to a phenomenon known as metabolic programming, which can be triggered by epigenetic mechanisms. The Let-7 family of microRNAs were one of the first to be discovered, and are closely related to metabolic processes. Bioinformatic analysis revealed that Prkaa2, the gene that encodes AMPK α2, is a predicted target of Let-7. Here we aimed to investigate whether Let-7 has a role in AMPKα2 levels in the NAFLD development in the offspring programmed by maternal obesity. Let-7 levels were upregulated in the liver of newborn mice from obese dams, while the levels of Prkaa2 were downregulated. Let-7 levels strongly correlated with serum glucose, insulin and NEFA, and in vitro treatment of AML12 with glucose and NEFA lead to higher Let-7 expression. Transfection of Let-7a mimic lead to downregulation of AMPKα2 levels, while the transfection with Let-7a inhibitor impaired both NEFA-mediated reduction of Prkaa2 levels and the fat accumulation driven by NEFA. The transfection of Let-7a inhibitor in ex-vivo liver slices from the offspring of obese dams restored phospho-AMPKα2 levels. In summary, Let-7a appears to regulate hepatic AMPKα2 protein levels and lead to the early hepatic metabolic disturbances in the offspring of obese dams.

Periodized versus non-periodized swimming training with equal total training load: Physiological, molecular and performance adaptations in Wistar rats.

This study investigated the effect of non-periodized training performed at 80, 100 and 120% of the anaerobic threshold intensity (AnT) and a linear periodized training model adapted for swimming rats on the gene expression of monocarboxylate transporters 1 and 4 (MCT1 and 4, in soleus and gastrocnemius muscles), protein contents, blood biomarkers, tissue glycogen, body mass, and aerobic and anaerobic capacities. Sixty Wistar rats were randomly divided into 6 groups (n = 10 per group): a baseline (BL; euthanized before training period), a control group (GC; not exercised during the training period), three groups exercised at intensities equivalent to 80, 100 and 120% of the AnT (G80, G100 and G120, respectively) at the equal workload and a linear periodized training group (GPE). Each training program lasted 12 weeks subdivided into three periods: basic mesocycle (6 weeks), specific mesocycle (5 weeks) and taper (1 week). Although G80, G100 and G120 groups were submitted to monotony workload (i.e. non-modulation at intensity or volume throughout the training program), rodents were evaluated during the same experimental timepoints as GPE to be able comparisons. Our main results showed that all training programs were capable to minimize the aerobic capacity decrease promoted by age, which were compared to control group. Rats trained in periodization model had reduced levels of lipid blood biomarkers and increased hepatic glycogen stores compared to all other trained groups. At the molecular level, only expressions of MCT1 in the muscle were modified by different training regimens, with MCT1 mRNA increasing in rats trained at lower intensities (G80), and MCT1 protein content showed higher values in non-periodized groups compared to pre-training and GPE. Here, training at different intensities but at same total workload promoted similar adaptations in rats. Nevertheless, our results suggested that periodized training seems to be optimize the physiological responses of rats.