Little evidence of systemic and adipose tissue inflammation in overweight individuals†

Context: The effect of weight loss by diet alone or diet in conjunction with exercise on low-grade inflammation in non-obese (overweight) individuals is not known. Objective: Test the hypothesis that 24 weeks of moderate calorie restriction (CR; 25%) by diet only or with aerobic exercise would reduce markers of systemic inflammation and attenuate inflammation gene expression in subcutaneous adipose tissue. Design: Randomized controlled trial. Setting: Institutional Research Center. Participants: Thirty-five overweight (body mass index: 27.8 ± 0.7 kg/m2) but otherwise healthy participants (16M/19F) completed the study. Intervention: Participants were randomized to either CR (25% reduction in energy intake, n = 12), caloric restriction + exercise (CR + EX: 12.5% reduction in energy intake + 12.5% increase in exercise energy expenditure, n = 12), or control (healthy weight-maintenance diet, n = 11) for 6 months. Main outcome measures: Fasting serum markers of inflammation [leptin, highly sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), adiponectin] and inflammation-related genes [CD68, IL-6, TNF-α, macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1), adiponectin, plasminogen activator inhibitor-1 (PAI-1)] in subcutaneous adipose tissue. Results: CR and CR + EX lost similar amounts of body weight (–10 ± 1%), fat mass (–24 ± 3%), visceral fat (–27 ± 3%), and had increased insulin sensitivity (CR: 40 ± 20%, CR + EX: 66 ± 22%). Leptin was significantly decreased from baseline (p < 0.001) in both groups however TNF-α and IL-6 were not changed. hsCRP was decreased in CR + EX. There was no change in the expression of genes involved in macrophage infiltration (CD68, MIF MCP-1, PAI-1) or inflammation (IL-6, TNF-α, adiponectin) in either CR or CR + EX. Conclusion: A 10% weight loss with a 25% CR diet alone or with exercise did not impact markers of systemic inflammation or the expression of inflammation-related adipose genes in overweight individuals

Increase in Mitochondrial content after Electrical Pulse Stimulation is dependent on duration of stimulation

Increase in Mitochondrial content after Electrical Pulse Stimulation is dependent on duration of stimulation Daniel Conde B.S.1, Jeffrey D. Covington Ph.D.2, Cecilia Gamboa3 George A. King Ph.D.1, Arild C. Rustan Ph.D.4, Sudip Bajpeyi Ph.D.1. 1 Department of Kinesiology, University of Texas at El Paso, TX; 2Louisiana State University Health Sciences Center, New Orleans, LA; 3Clinical Laboratory Sciences, University of Texas at El Paso; 4Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway. Skeletal Muscle Metabolism Laboratory; Kinesiology; University of Texas at El Paso; El Paso, TX Category: Masters Advisor / Mentor: Bajpeyi, Sudip ([email protected]) ABSTRACT We have previously shown that human skeletal muscle myotubes cultured in vitro, retain in vivo characteristics of the donors. Recent studies indicate that electrical pulse stimulation (EPS) can be used as an exercise mimetic in a cell culture model, and could be beneficial to understand molecular mechanisms underlying exercise training. Purpose: The purpose of this study was to compare acute, moderate and long duration EPS treatments on mitochondrial and lipid content in cultured myotubes. Methods: EPS stimulation was applied to human myotubes cultured from sedentary donors under three conditions: Acute (bipolar pulses of 100 Hz for 200 ms every 5th second; 30V for 60 min) and chronic stimulation (single bipolar pulses of 2 ms; 30V, 1Hz continuously for 24 h or 48 h). Mitochondrial and lipid contents were measured by primary antibody for complex IV and bodipy green dye, respectively, using immunohistochemistry techniques. Fluoroskan ascent microplate reader was used to quantify fluorescence signals. OXPHOS proteins were measured using western immunoblotting. Results: There was no change in lipid or mitochondrial content as assessed by immunohistochemistry after acute EPS stimulation. Chronic stimulation resulted in a significant increase in the mitochondrial content after 24 h (from 0.183 ± 0.02 AU to 0.350 ± 0.03 AU; p=0.008) and 48 h (from 0.290 ± 0.01 AU to 0.337 ± 0.01 AU; p=0.02) of continuous EPS stimulation. OXPHOS proteins increased after 48 h of EPS. There was also a significant increase in lipid content after 48 h of EPS stimulation (from 0.210 ± 0.01 AU to 0.256 ± 0.01 AU; p=0.02). Conclusion: These findings suggest that 48 h of chronic EPS results in an increase in both mitochondrial and lipid contents in human myotubes. The concomitant increase in lipid and mitochondrial content after exercise mimetic EPS stimulation supports the elevated level of intramyocellular lipid and mitochondrial content evident in endurance trained athletes

Eight Weeks of Combined Exercise Training Induced Improvements in Insulin Sensitivity is Associated with Improvement in Aerobic Capacity, but not with Improvement in Strength.

A lifestyle compromised of predominantly sedentary behavior is a risk factor that promotes the development of metabolic syndrome. It has been demonstrated that individuals with blunted insulin sensitivity (IS) and metabolic flexibility (MF) tend to be more prone to develop the disease. An increase in physical activity is recommended in order to prevent cardiovascular disease and type 2 diabetes mellitus. PURPOSE: to determine whether healthy, sedentary, normoglycemic, Mexican American men without a family history of type 2 diabetes are able to improve IS and MF after participating in a combined (aerobic/resistance) exercise intervention. METHODS: Subjects (n=6; 21.83±0.8 years; BMI 28.92 ± 1.6 kg/m2), participated in 8 weeks of combined exercise training three times per week (35 minutes of aerobic training & 45 minutes of resistance training/session). Upper body 1 repetition maximum (1RM) was measured using the flat barbell bench press and lower body 1RM was measured using a back leg strength dynamometer. IS was assessed using the hyperinsulinemic euglycemic clamp (clamp). Insulin dose administered to each subject was set 80mU/m2/min. MF was assessed by determining change in RQ (ΔRQ) at the steady state of the clamp compared to RQ measured at baseline/resting. Participants were provided with standard diet 5 days before pre and post intervention testing in order to control for the effects of diet on insulin sensitivity. Body composition was measured using dual x-ray absorptiometry. RESULTS: IS improved significantly after the 8 weeks of combined exercise training (3.18±0.35 to 3.75±0.34 mg/kg EMBS/min, p=0.05). There was no significant improvement in MF (0.06±0.02 to 0.08±0.02 ∆RER, p=0.19). Body weight significantly increased (3.76%; 81.06±5.38 to 84.11±5.67 kg, p=0.01) with no change in fat mass and a trend to increase in fat free mas (2.8%; 55.92±2.77 to 57.5±2.38 kg, p=0.1). Upper body strength significantly increased (168.3±26.57 to 195±26.04 lb., p=0.001). Lower body strength increased (356.7±46.52 to 428.3±34.51 lb., p=0.02).VO2 max improved significantly (3.90±0.14 to 4.19±0.16 L/min, p=0.037). Improvement in IS was associated with an increase in VO2max (r=0.92, p=0.008) but not with the improvement in strength. Improvement in MF was significantly correlated with fasting glucose (r=-0.83, p=0.04), and an increase in lean mass (r=0.82, p=0.04). CONCLUSION: 8 weeks of combined exercise improves insulin sensitivity in healthy, sedentary, normoglycemic Hispanic men. Improvement in insulin sensitivity is associated with improvement in aerobic fitness but not gain in upper and lower body strength

24 hours of Electrical Pulse Stimulation upregulates GLUT4 and AMPK protein content in human myotubes

Electrical pulse stimulation (EPS), an in vitro exercise mimetic, has been shown to increase mitochondrial and lipid content in cultured human myotubes. We have recently shown that myotubes retain certain in vivo characteristics of the donors. Purpose: We aimed to examine the EPS-induced adaptations in relation to Glucose Transporter Type 4 (GLUT4) and 5’Adenosine Monophosphate-activated Protein Kinase (AMPK) content using human myotubes. Additionally, we examined if the duration of EPS as well as cell harvest times (immediate vs. 24hrs. after the cessation of EPS) plays a role in EPS induced changes in GLUT4 and AMPK content. Methods: EPS was applied to myotubes 24 and 48 hr. (single bipolar pulses of 1 Hz for 2 ms; 30V) and were harvested at two different time points: immediately after (early harvest) and 24hr after (late harvest) the end of stimulation. Total GLUT4 and AMPK content were measured by western immunoblotting. Results: GLUT4 content was ~ 1.7 fold higher after 24 hr. early harvest and ~2.1 fold higher after 48 hr. late harvest stimulation. Total AMPK content was ~3.2 fold higher after 24 hr. early harvest stimulation and ~1.4 fold higher after 48 hr. late harvest stimulation. There was a ~0.6 fold decrease in AMPK after 24 hr. late harvest stimulation. Conclusion: These findings suggest that 24Hr of EPS stimulation upregulates GLUT4 and AMPK protein content. Duration and harvesting time (a reflection of post-exercise recovery) with regards to EPS treatment is a key factor leading to GLUT4 and AMPK content adaptations to exercise in human myotubes

Weight gain reveals dramatic increases in skeletal muscle extracellular matrix remodeling

Context: In animal models of obesity, chronic inflammation and dysregulated extracellular matrix remodeling in adipose tissue leads to insulin resistance. Whether similar pathophysiology occurs in humans is not clear. Objective: The aim of this study was to test whether 10% weight gain induced by overfeeding triggers inflammation and extracellular matrix remodeling (gene expression, protein, histology) in skeletal muscleandsc adipose tissue in humans.Wealso investigated whether such remodelingwas associated with an impaired metabolic response (hyperinsulinemic-euglycemic clamp). Design, Setting, Participants, and Intervention: Twenty-nine free-living males were fed 40% over their baseline energy requirements for 8 weeks. Results: Ten percent body weight gain prompted dramatic up-regulation of a repertoire of extracellular matrix remodeling genes in muscle and to a lesser degree in adipose tissue. The amount of extracellular matrix genes in the muscle were directly associated with the amount of lean tissue deposited during overfeeding. Despite weight gain and impaired insulin sensitivity, there was no change in local adipose tissue or systemic inflammation, but there was a slight increase in skeletal muscle inflammation. Conclusion:Wepropose that skeletal muscle extracellular matrix remodeling is another feature of the pathogenic milieu associated with energy excess and obesity, which, if disrupted, may contribute to the development of metabolic dysfunction. © 2014 by the Endocrine Society

The DEEP2 Galaxy Redshift Survey: Design, Observations, Data Reduction, and Redshifts

We describe the design and data sample from the DEEP2 Galaxy Redshift Survey, the densest and largest precision-redshift survey of galaxies at z ~ 1 completed to date. The survey has conducted a comprehensive census of massive galaxies, their properties, environments, and large-scale structure down to absolute magnitude M_B = -20 at z ~ 1 via ~90 nights of observation on the DEIMOS spectrograph at Keck Observatory. DEEP2 covers an area of 2.8 deg^2 divided into four separate fields, observed to a limiting apparent magnitude of R_AB=24.1. Objects with z < 0.7 are rejected based on BRI photometry in three of the four DEEP2 fields, allowing galaxies with z > 0.7 to be targeted ~2.5 times more efficiently than in a purely magnitude-limited sample. Approximately sixty percent of eligible targets are chosen for spectroscopy, yielding nearly 53,000 spectra and more than 38,000 reliable redshift measurements. Most of the targets which fail to yield secure redshifts are blue objects that lie beyond z ~ 1.45. The DEIMOS 1200-line/mm grating used for the survey delivers high spectral resolution (R~6000), accurate and secure redshifts, and unique internal kinematic information. Extensive ancillary data are available in the DEEP2 fields, particularly in the Extended Groth Strip, which has evolved into one of the richest multiwavelength regions on the sky. DEEP2 surpasses other deep precision-redshift surveys at z ~ 1 in terms of galaxy numbers, redshift accuracy, sample number density, and amount of spectral information. We also provide an overview of the scientific highlights of the DEEP2 survey thus far. This paper is intended as a handbook for users of the DEEP2 Data Release 4, which includes all DEEP2 spectra and redshifts, as well as for the publicly-available DEEP2 DEIMOS data reduction pipelines. [Abridged]Comment: submitted to ApJS; data products available for download at http://deep.berkeley.edu/DR4

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN