The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPARα signaling, known to regulate multiple ...metabolic pathways. SIRT6 binds PPARα and its response element within promoter regions and activates gene transcription. Sirt6+/− results in significantly reduced PPARα-induced β-oxidation and its metabolites and reduced alanine and lactate levels, while inducing pyruvate oxidation. Reciprocally, starved SIRT6 transgenic mice show increased pyruvate, acetylcarnitine, and glycerol levels and significantly induce β-oxidation genes in a PPARα-dependent manner. Furthermore, SIRT6 mediates PPARα inhibition of SREBP-dependent cholesterol and triglyceride synthesis. Mechanistically, SIRT6 binds PPARα coactivator NCOA2 and decreases liver NCOA2 K780 acetylation, which stimulates its activation of PPARα in a SIRT6-dependent manner. These coordinated SIRT6 activities lead to regulation of whole-body respiratory exchange ratio and liver fat content, revealing the interactions whereby SIRT6 synchronizes various metabolic pathways, and suggest a mechanism by which SIRT6 maintains healthy liver.
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•PPARα mediates various SIRT6-regulated metabolic pathways•PPARα binds to and is activated by SIRT6 to promote fatty acid beta oxidation•SIRT6 decreases NCOA2 acetylation and induces its co-activation of PPARα•Coordinated SIRT6-PPARα activities control energy production under limited nutrients
How the pro-longevity enzyme SIRT6 coordinates between various metabolic pathways is still obscure. Here, Naiman et al. show that SIRT6 activates PPARα to promote fatty acid beta oxidation and inhibit pyruvate oxidation during fasting. This ultimately decides the energy source under nutrient-limited conditions, promoting fat usage over other energy sources.
The modern lifestyle requires less physical activity and skills during our daily routine, leading to multiple pathologies related to physical disabilities and energy accessibility. Thus, exploring ...the mechanisms underlying the metabolic regulation of exercise is crucial. Here, we characterized the effect of forced and voluntary endurance exercises on three key metabolic signaling pathways, sirtuins, AMPK, and mTOR, across several metabolic tissues in mice: brain, muscles, and liver. Both voluntary and forced exercises induced AMPK with higher intensity in the first. The comparison between those metabolic tissues revealed that the hypothalamus and the hippocampus, two brain parts, showed different metabolic signaling activities. Strikingly, despite the major differences in the physiology of muscles and hypothalamic tissues, the hypothalamus replicates the metabolic response of the muscle in response to physical exercise. Specifically, muscles and hypothalamic tissues showed an increase and a decrease in AMPK and mTOR signaling, respectively. Overall, this study reveals new insight into the relation between the hypothalamus and muscles, which enhances the coordination within the muscle–brain axis and potentially improves the systemic response to physical activity performance and delaying health inactivity disorders.
In this paper, we apply novel techniques for characterizing leg muscle activation patterns via electromyograms (EMGs) and for relating them to changes in electroencephalogram (EEG) activity during ...gait experiments. Specifically, we investigate changes of leg-muscle EMG amplitudes and EMG frequencies during walking, intentional stops, and unintended freezing-of-gait (FOG) episodes. FOG is a frequent paroxysmal gait disturbance occurring in many patients suffering from Parkinson's disease (PD). We find that EMG amplitudes and frequencies do not change significantly during FOG episodes with respect to walking, while drastic changes occur during intentional stops. Phase synchronization between EMG signals is most pronounced during walking in controls and reduced in PD patients. By analyzing cross-correlations between changes in EMG patterns and brain-wave amplitudes (from EEGs), we find an increase in EEG-EMG coupling at the beginning of stop and FOG episodes. Our results may help to better understand the enigmatic pathophysiology of FOG, to differentiate between FOG events and other gait disturbances, and ultimately to improve diagnostic procedures for patients suffering from PD.
The National Health Insurance Law in Israel ensures basic health basket eligibility for all its citizens. A supplemental health insurance plan (SHIP) is offered for an additional fee. Over the years, ...the percentage of supplemental insurance's holders has risen considerably, ranking among the highest in OECD countries. The assumption that consumers implement an informed rational choice based on relevant information is doubtful. Are consumers sufficiently well informed to make market processes work well?
To examine perspectives, preferences and knowledge of Israelis in relation to SHIP.
A telephone survey was conducted with a representative sample of the Israeli adult population. 703 interviews were completed. The response rate was 50.3%.
85% of the sample reported possessing SHIP. This survey found that most of the Israeli public parched additional insurance coverage however did not show a significant knowledge about the benefits provided by the supplementary insurance, at least in the three measurements used in this study.
The scope of SHIP acquisition is very broad and cannot be explained in economic terms alone. Acquiring SHIP became a default option rather than an active decision. It is time to review the goals, achievements and side effects of SHIP and to create new policy for the future.
Highlights • The majority of Israelis voluntarily purchased supplemental health insurance. • The public shows low level of knowledge about the insurance. • Three different measurements were used to ...evaluate knowledge. • Knowledge is a basic condition to an intelligent use of insurance’s benefits.
Parkinson's disease (PD) is characterized by gait disturbances, which become severe during the advanced stages of the disease. Though gait impairments in Parkinson's disease have been extensively ...described in terms of spatiotemporal gait parameters, little is known regarding associated patterns of cortical activity. The objective of the present study is to test if interhemispheric synchronization differs between participants with PD and healthy elderly controls (NPD). We analyzed electroencephalography (EEG) signals recorded during bilateral movements, i.e., locomotion and hand tapping.
Fifteen participants with PD (‘OFF’ their anti-parkinsonian medications) and eight NPD were assessed during quiet standing, straight-line walking, turning, and hand tapping tasks. Using a 32-electrode EEG array, we quantified the synchronization in periodic cortical activation between the brain hemispheres (interhemispheric phase synchronization; inter-PS). Theta, alpha, beta, and gamma bands were evaluated.
In all bands, inter-PS was significantly higher for the PD group as compared with the NPD group during standing and walking (p < 0.001) and during bimanual tasks (p = 0.026).
Persons with PD exhibit increased inter-PS as compared with NPD participants. These findings support previous evidence from animal studies, that bilateral cortical hypersynchronization emerges from the asymmetric neural degeneration that is at the base of the disease. Future studies should elucidate the long-term temporal development of this hypersynchronization and its clinical relevance (e.g., can it ‘serve’ as prodromal marker?).
•EEG signals were recorded during walking in persons with PD.•Inter-hemispheric synchronization was compared between PD and healthy participants.•Excessive PD related inter-hemispheric EEG synchronization was observed.•Hyper synchronization presumably emerges from asymmetrical PD related neurodegeneration.
Abstract Background Endothelial dysfunction is considered an important prognostic factor in atherosclerosis. The aim of this study was to detect the long-term association of peripheral vascular ...endothelial function and clinical outcome in healthy subjects without apparent coronary artery disease (CAD). Methods We prospectively assessed brachial flow-mediated dilation (FMD) in 435 consecutive healthy subjects: 281 (65%) men, mean age 54 ± 12 years and body mass index 28 ± 4 kg/m2 . After overnight fasting and discontinuation of all medications for ≥ 12 h, FMD and endothelium-independent nitroglycerin-mediated vasodilation were assessed using high resolution linear array ultrasound. Results Subjects were divided into 2 groups: below ( n = 221) and above ( n = 214) the median FMD of 10.7%, and were comparable regarding CAD risk factors, lipoproteins, fasting glucose, C-reactive protein, and concomitant medications, with a mean clinical follow-up of 32 ± 2 months. Composite cardiovascular endpoints (all-cause mortality, non-fatal myocardial infarction, heart failure or angina pectoris hospitalization, stroke, coronary artery bypass grafting and percutaneous coronary interventions) were significantly more common in subjects with below median FMD of 10.7%, than above (11.8% vs 4.7%, p = 0.007, respectively). Univariate analysis demonstrated that median FMD significantly predicted cardiovascular events odds ratio (OR) of 2.78 and 95% CI 1.35 to 5.71 ( p = 0.003). After multivariate analysis including conventional CAD risk factors, median FMD was the best independent predictor of long-term cardiovascular adverse events OR of 2.70 and 95% CI 1.16 to 6.32 ( p = 0.011). Conclusions Brachial artery median FMD independently predicts long-term adverse cardiovascular events in healthy subjects in addition to traditional risk factor assessment.
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