Behavioral, metabolic, and lipidomic characterization of the 5xFADxTg30 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is associated with both extracellular amyloid-ß (Aß) plaques and intracellular tau-containing neurofibrillary tangles (NFT). We characterized the behavioral, metabolic and lipidomic phenotype of the 5xFADxTg30 mouse model which contains overexpression of both Aß and tau. Our results independently reproduce several phenotypic traits described previously for this model, while providing additional characterization. This model develops many aspects associated with AD including frailty, decreased survival, initiation of aspects of cognitive decline and alterations to specific lipid classes and molecular lipid species in the plasma and brain. Notably, some sex-specific differences exist in this model and motor impairment with aging in this model does compromise the utility of the model for some movement-based behavioral assessments of cognitive function. These findings provide a reference for individuals interested in using this model to understand the pathology associated with elevated Aß and tau or for testing potential therapeutics for the treatment of AD.

Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease.

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes.

AIMS/HYPOTHESIS: Nitric oxide (NO) has been implicated as an important signalling molecule in the contraction-mediated glucose uptake pathway and may represent a novel strategy for blood glucose control. The current study sought to determine whether acute infusion of the NO donor, sodium nitroprusside (SNP), increases leg glucose uptake at rest in patients with type 2 diabetes. METHODS: Fifteen male patients with type 2 diabetes (aged 54+/-4 years, mean+/-SD) were entered into a randomised, cross-over design study, examining the effect of a 30-min intra-femoral infusion of SNP on leg glucose uptake. Comparison was made with a 30-min infusion of verapamil, titrated to elicit similar leg blood flow responses to SNP. Leg blood flow was measured by thermodilution in the femoral vein, and leg glucose uptake was calculated as the product of leg blood flow and the femoral arterio-venous (A-V) glucose concentration gradient. RESULTS: The two drugs increased leg blood flow to a similar extent (p=0.50). Both leg A-V glucose concentration gradient (SNP 0.12+/-0.05, verapamil -0.06+/-0.04 mmol/l; mean+/- SEM, p=0.03) and leg glucose uptake (SNP 0.17+/-0.09, verapamil -0.09+/-0.06 mmol/min; p=0.03) were higher with the SNP treatment than with verapamil. These results occurred independently of any significant difference in plasma insulin concentration between drugs (p=0.56). CONCLUSIONS/INTERPRETATION: Acute infusion of SNP resulted in greater glucose uptake relative to verapamil. NO may therefore be an important mediator of peripheral glucose disposal and a potential therapeutic target in patients with type 2 diabetes.

Diet but not aerobic exercise training reduces skeletal muscle TNF-alpha in overweight humans.

AIMS/HYPOTHESIS: Our aim was to test the hypothesis that TNF-alpha protein levels in skeletal muscle are important in mediating the improvements in glucose homeostasis that are associated with diet and exercise regimens intended to reduce cardiovascular risk. METHODS: We recruited 20 people with a body mass index of 32.1 +/- 1.2 kg/m2 (mean +/- SEM) and one other component of the metabolic syndrome. The average age was 51.2 +/- 8.1 years (mean +/- SD). Of the 20 subjects, 6 were men and 14 were women. All subjects completed an 8-week control period, followed by randomisation to 8 weeks of moderate cycling exercise (30 min, three times per week) or to a diet with the following characteristics: low in saturated fat, high in fibre, low glycaemic index, rich in complex carbohydrates. RESULTS: Diet induced a small reduction in body mass index (3.0 +/- 0.7%, p<0.05), although weight loss was not intended. Exercise training increased maximum oxygen consumption by 12 +/- 6% (p<0.05). Both interventions reduced fasting plasma insulin levels by about 20%. Diet reduced skeletal muscle TNF-alpha protein by 54 +/- 10% (p<0.05), an effect that was independent (p=0.94 in covariate analysis) of the small concurrent weight loss (-2.8 +/- 0.7 kg). Levels of GLUT4 protein were unchanged in the diet group. In contrast, exercise training did not significantly change TNF-alpha protein expression, but GLUT4 protein expression increased by 105 +/- 37% (p<0.05). CONCLUSIONS/INTERPRETATION: These data indicate that the metabolic benefits of a diet aimed at cardiovascular risk reduction are associated with a decrease in skeletal muscle TNF-alpha protein.