Effect of physical activity in a weight loss program on circulating total ANGPTL8 concentrations in northern Americans with obesity: A prospective randomized controlled trial.

BACKGROUND AND AIMS: The primary goals of this study were to clarify 1) the effect of weight loss by lifestyle intervention on circulating total angiopoietin-like protein 8 (ANGPTL8), and 2) the role of physical activity on serum total ANGPTL8 in northern Americans with obesity but without diabetes. METHODS AND RESULTS: A total of 130 subjects with body mass index (BMI) â‰§ 35 kg/m2 but without diabetes were recruited, and 121 subjects completed a weight loss program for data analysis. Abdominal adipose tissue was determined by non-contrast computed tomography (CT). Serum total ANGPTL8 was higher in the group with obesity than in the lean control group. Serum total ANGPTL8 was positively correlated with waist circumference (WC), BMI, fasting insulin, HOMA-IR, HOMA-B, QUICKI, hs-CRP, IL-6, and leptin. Serum total ANGPTL8 did not significantly differ between the two intervention groups at baseline, and it was significantly lower after weight loss, with comparable changes with diet only and diet plus physical activity. CONCLUSION: Among northern Americans with obesity but without diabetes, a lifestyle modification resulted in significant reduction of circulating total ANGPTL8 concentrations in a 6-month weight-loss period. Although addition of physical activity resulted in greater total and liver fat loss, it did not promote further significant decline of serum total ANGPTL8 beyond diet alone.

Persistent vestibular-ocular impairment following concussion in adolescents.

OBJECTIVES: The current study investigated the role of persistent vestibular-ocular symptoms and impairment following sport-related concussion on recovery time and clinical outcomes among adolescents. DESIGN: Prospective cohort. METHODS: 50 (F-22/M-28) adolescents aged 12-20 years completed a vestibular-ocular motor screening, neurocognitive assessment, and the Post-Concussion Symptom Scale (PCSS) at clinical assessments conducted at 0-10 and 11-21 days after concussion. Participants were assigned to: 1) persistent vestibular-ocular (PERSIST), 2) vestibular-ocular improvement (IMPROVE), or 3) no vestibular-ocular impairment (NONE) groups based on vestibular-ocular motor screening conducted during each assessment. A 3 (GROUP) X 2 (TIME) ANOVA was performed on neurocognitive and symptom scores, and a between-subjects ANOVA was performed for recovery time. RESULTS: 49 subjects were identified among the PERSIST (n=17), IMPROVE (n=12) and NONE (n=20) groups. There were no neurocognitive performance differences between groups at 0-10 days post-concussion, but groups differed on PCSS at 11-21 days (p=.001), with the PERSIST (29.0±24.9) group reporting higher symptoms than the NONE (5.45±10.0; p=.005) group. The PERSIST group took significantly longer to recover (34.9±11.6 days) than the NONE (22.9±14.9 days) group (p=.03). All groups improved on verbal (p<.001) and visual memory (p=.028), visual motor speed (p=.005), and reaction time (p=.004) from 0-10 to 11-20 days following SRC and no significant group by time interactions for cognitive scores identified. CONCLUSIONS: Persistent post-concussion vestibular-ocular symptoms and impairment may influence neurocognitive performance and clinical recovery following sport-related concussion.

Preliminary Evidence for Improvement in Symptoms, Cognitive, Vestibular, and Oculomotor Outcomes Following Targeted Intervention with Chronic mTBI Patients.

Introduction: To determine if targeted, active interventions would improve symptoms and impairment in previously intractable patients with chronic mild traumatic brain injury (mTBI). Materials and Methods: Twenty-six (20 males; 6 females) out of 51 (51%) former military and civilian patients with chronic (1-3 yr) mTBI enrolled in the TEAM traumatic brain injury (TBI) study completed both an initial and 6-mo post-intervention comprehensive mTBI assessment including symptoms (Post-concussion Symptom Scale [PCSS], Dizziness Handicap Inventory [DHI]), cognitive (Immediate Post-concussion Assessment and Cognitive Testing [ImPACT]), vestibular/oculomotor (Vestibular/Ocular Motor Screening [VOMS]), balance (Activities-specific Balance Confidence [ABC] scale, Balance Error Scoring System [BESS]), and cervical (Neck Disability Index [NDI]). Patients were prescribed progressive, targeted interventions and therapies (e.g., behavioral, vestibular, vision, and exertion) that matched their mTBI clinical profile. A series of paired t-tests adjusted for multiple corrections were used to compare pre- and post-intervention assessment scores. Results: Patients demonstrated significant improvement from pre- to post-intervention on total symptoms (t = 2.69, p = 0.01), verbal memory (t = -1.96, p = 0.05), ABC balance score (t = -2.05, p = 0.05), smooth pursuits (t = 2.32, p = 0.04), near-point convergence distance (t = -3.58, p = 0.01), vestibular ocular reflex (t = 2.31, p = 0.03), and visual motion sensitivity (t = 2.43, p = 0.03). Conclusions: Previously recalcitrant patients with chronic complex mTBI demonstrated significant improvement in symptoms, cognitive, vestibular, oculomotor, and balance function following targeted interventions.

Effect of high fat diet on phenotype, brain transcriptome and lipidome in Alzheimer's model mice.

We examined the effect of chronic high fat diet (HFD) on amyloid deposition and cognition of 12-months old APP23 mice, and correlated the phenotype to brain transcriptome and lipidome. HFD significantly increased amyloid plaques and worsened cognitive performance compared to mice on normal diet (ND). RNA-seq results revealed that in HFD mice there was an increased expression of genes related to immune response, such as Trem2 and Tyrobp. We found a significant increase of TREM2 immunoreactivity in the cortex in response to HFD, most pronounced in female mice that correlated to the amyloid pathology. Down-regulated by HFD were genes related to neuron projections and synaptic transmission in agreement to the significantly deteriorated neurite morphology and cognition in these mice. To examine the effect of the diet on the brain lipidome, we performed Shotgun Lipidomics. While there was no difference in the total amounts of phospholipids of each class, we revealed that the levels of 24 lipid sub-species in the brain were significantly modulated by HFD. Network visualization of correlated lipids demonstrated overall imbalance with most prominent effect on cardiolipin molecular sub-species. This integrative approach demonstrates that HFD elicits a complex response at molecular, cellular and system levels in the CNS.

Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1 haplo-deficient mice.

ATP-binding cassette transporter A1 (ABCA1) controls cholesterol and phospholipid efflux to lipid-poor apolipoprotein E (APOE) and is transcriptionally controlled by Liver X receptors (LXRs) and Retinoic X Receptors (RXRs). In APP transgenic mice, lack of Abca1 increased Aß deposition and cognitive deficits. Abca1 haplo-deficiency in mice expressing human APOE isoforms, increased level of Aß oligomers and worsened memory deficits, preferentially in APOE4 mice. In contrast upregulation of Abca1 by LXR/RXR agonists significantly ameliorated pathological phenotype of those mice. The goal of this study was to examine the effect of LXR agonist T0901317 (T0) on the phenotype and brain transcriptome of APP/E3 and APP/E4 Abca1 haplo-deficient (APP/E3/Abca1+/- and APP/E4/Abca1+/-) mice. Our data demonstrate that activated LXRs/RXR ameliorated APOE4-driven pathological phenotype and significantly affected brain transcriptome. We show that in mice expressing either APOE isoform, T0 treatment increased mRNA level of genes known to affect brain APOE lipidation such as Abca1 and Abcg1. In both APP/E3/Abca1+/- and APP/E4/Abca1+/- mice, the application of LXR agonist significantly increased ABCA1 protein level accompanied by an increased APOE lipidation, and was associated with restoration of APOE4 cognitive deficits, reduced levels of Aß oligomers, but unchanged amyloid load. Finally, using Gene set enrichment analysis we show a significant APOE isoform specific response to LXR agonist treatment: Gene Ontology categories "Microtubule Based Process" and "Synapse Organization" were differentially affected in T0-treated APP/E4/Abca1+/- mice. Altogether, the results are suggesting that treatment of APP/E4/Abca1+/- mice with LXR agonist T0 ameliorates APOE4-induced AD-like pathology and therefore targeting the LXR-ABCA1-APOE regulatory axis could be effective as a potential therapeutic approach in AD patients, carriers of APOEε4.

Systematic review and meta-analysis of the effects of football heading.

AIM/OBJECTIVE: The objective of this study was to provide a meta-analysis examining the effects of football heading. DESIGN: Meta-analytical review on football heading effects on neurocognitive performance, cognition and symptom reports. DATA SOURCES: Combinations of the key terms were entered into the following electronic database search engines: Cochrane Libraries, PyscARTICLE, PyscINFO, PubMed, ProQuest, SPORTDiscus and Web of Science on 7 July 2016. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: The following inclusion criteria were used to determine eligibility for studies: (1) the study examined and reported on soccer athletes; (2) the population's age, sex and sport position was described; (3) cognitive function, symptoms, balance or other outcomes were quantitatively measured; (4) football heading exposure was quantitatively measured between at least two groups and (5) the study was written in the English language after December 1979. RESULTS: The literature search process identified 467 unique studies. After applying exclusion criteria, 28 studies remained. Included studies had a total of 2288 participants (female participants =933, male participants =1355), aged 13-70 years. The overall results of random effects modelling of football heading were found to be inconclusive across all outcomes, groups and time points. No moderating variables related to methodological, sample or study characteristics were supported in the analysis; age was a potential moderating variable. SUMMARY/CONCLUSIONS: We provide the first meta-analytical review of football heading effects aggregated from multiple studies and extended findings from a recent systematic review of the effects of football heading. Our analysis indicates no overall effect for heading a football on adverse outcomes.

Serum autotaxin is independently associated with hepatic steatosis in women with severe obesity.

OBJECTIVE: Autotaxin (ATX) is an adipocyte-derived lysophospholipase that generates the lipid signaling molecule lysophosphatidic acid (LPA). The aim of this study was to determine the relationship between serum ATX and nonalcoholic fatty liver disease (NAFLD) in females with obesity. METHODS: 101 nondiabetic women with obesity (age: 31.5-55.8 years; BMI: 35.0-64.5 kg/m2) were classified as having NAFLD (36.3%) or not having NAFLD (63.7%) based on the degree of hepatic steatosis on abdominal CT. Subjects were characterized for metabolic phenotype including measures of energy, glucose, and lipid homeostasis. Fasting serum adipokines and inflammatory markers were determined by ELISA. Linear regression analysis was used to determine features independently associated with NAFLD. RESULTS: Subjects with and without NAFLD differed in several key features of metabolic phenotype including BMI, waist circumference, fasting glucose and insulin, HOMA-IR, VLDL, triglycerides, and ALT. Serum adipokines, including ATX and leptin, were higher in subjects with NAFLD. Serum ATX was significantly correlated with alkaline phosphatase, fasting glucose, fasting insulin, and HOMA-IR. Linear regression analysis revealed that serum triglycerides and log-transformed ATX were independently associated with hepatic steatosis. CONCLUSIONS: Serum ATX may be a potential pathogenic factor and/or biomarker for NAFLD in nondiabetic women with obesity.

Serum Autotaxin/ENPP2 correlates with insulin resistance in older humans with obesity.

OBJECTIVE: Autotaxin (ATX) is an adipocyte-derived lysophospholipase D that generates the lipid signaling molecule lysophosphatidic acid (LPA). The ATX/LPA pathway in adipose tissue has recently been implicated in obesity and insulin resistance in animal models, but the role of circulating ATX in humans remains unclear. The aim of the present study was to determine the relationship between serum ATX and insulin resistance. METHODS: Older (60-75 years), nondiabetic human participants with overweight or obesity (BMI 25-37 kg m(-2) ) were characterized for metabolic phenotype including measures of energy, glucose, and lipid homeostasis. The relationship between serum ATX and metabolic parameters was then determined using correlative and predictive statistics. RESULTS: Serum ATX was higher in females than in males. After controlling for sex, serum ATX correlated with multiple measures of adiposity and glucose homeostasis/insulin action. Serum ATX and BMI also independently predicted glucose infusion rate during a hyperinsulinemic euglycemic clamp and homeostatic model assessment of insulin resistance after controlling for sex and medication use. CONCLUSIONS: Serum ATX correlates with and predicts measures of glucose homeostasis and insulin sensitivity in older humans, suggesting that it may be a potential pathogenic factor and/or diagnostic/therapeutic target for insulin resistance in this population.

Obesity and diabetes cause cognitive dysfunction in the absence of accelerated ß-amyloid deposition in a novel murine model of mixed or vascular dementia.

Mid-life obesity and type 2 diabetes mellitus (T2DM) confer a modest, increased risk for Alzheimer's disease (AD), though the underlying mechanisms are unknown. We have created a novel mouse model that recapitulates features of T2DM and AD by crossing morbidly obese and diabetic db/db mice with APPΔNL/ΔNLx PS1P264L/P264L knock-in mice. These mice (db/AD) retain many features of the parental lines (e.g. extreme obesity, diabetes, and parenchymal deposition of ß-amyloid (Aß)). The combination of the two diseases led to additional pathologies-perhaps most striking of which was the presence of severe cerebrovascular pathology, including aneurysms and small strokes. Cortical Aß deposition was not significantly increased in the diabetic mice, though overall expression of presenilin was elevated. Surprisingly, Aß was not deposited in the vasculature or removed to the plasma, and there was no stimulation of activity or expression of major Aß-clearing enzymes (neprilysin, insulin degrading enzyme, or endothelin-converting enzyme). The db/AD mice displayed marked cognitive impairment in the Morris Water Maze, compared to either db/db or APPΔNLx PS1P264L mice. We conclude that the diabetes and/or obesity in these mice leads to a destabilization of the vasculature, leading to strokes and that this, in turn, leads to a profound cognitive impairment and that this is unlikely to be directly dependent on Aß deposition. This model of mixed or vascular dementia provides an exciting new avenue of research into the mechanisms underlying the obesity-related risk for age-related dementia, and will provide a useful tool for the future development of therapeutics.

Transgenic models of Alzheimer's disease: better utilization of existing models through viral transgenesis.

Animal models have been used for decades in the Alzheimer's disease (AD) research field and have been crucial for the advancement of our understanding of the disease. Most models are based on familial AD mutations of genes involved in the amyloidogenic process, such as the amyloid precursor protein (APP) and presenilin 1 (PS1). Some models also incorporate mutations in tau (MAPT) known to cause frontotemporal dementia, a neurodegenerative disease that shares some elements of neuropathology with AD. While these models are complex, they fail to display pathology that perfectly recapitulates that of the human disease. Unfortunately, this level of pre-existing complexity creates a barrier to the further modification and improvement of these models. However, as the efficacy and safety of viral vectors improves, their use as an alternative to germline genetic modification is becoming a widely used research tool. In this review we discuss how this approach can be used to better utilize common mouse models in AD research. This article is part of a Special Issue entitled: Animal Models of Disease.

Lipid rafts, caveolae and GPI-linked proteins.

Lipid rafts and caveolae are specialized membrane microdomains enriched in sphingolipids and cholesterol. They function in a variety of cellular processes including but not limited to endocytosis, transcytosis, signal transduction and receptor recycling. Here, we outline the similarities and differences between lipid rafts and caveolae as well as discuss important components and functions of each.