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Excessive adipose tissue mass underlies much of the metabolic health complications in obesity. Although exercise training is known to improve metabolic health in individuals with obesity, the effects of exercise training without weight loss on adipose tissue structure and metabolic function remain unclear. Thirty-six adults with obesity (body mass index = 33 ± 3 kg · m

Primary ectopic meningiomas of the nasal cavity are rare tumours and thus, often not diagnosed and treated properly. In this case report we are going to discuss about our experience with a primary nasal meningioma involving bilateral nasal cavity with its diagnosis, management and histopathological features. A 28 year old female presented with nasal obstruction and nasal discharge for the past 1 year and swelling over right side of face for the past 8 months. Patient underwent surgical resection by a combined endoscopic and external approach under general anaesthesia. Histopathological evaluation confirmed the diagnosis of Transitional meningioma WHO grade 1. A repeat nasal endoscopy done one week after surgery, showed no evidence of any residual tumour. Due to ectopic meningiomas being relatively less common one must always exclude the presence of a central meningioma, which makes radiological investigations a must in such cases. As primary extra-cranial meningiomas have an unpredictable behaviour, this study should further aid in diagnosis and management of these tumours.

Although the health benefits of exercise in adults with obesity are well described, the direct effects of exercise on adipose tissue that may lead to improved metabolic health are poorly understood. The primary aims of this study were to perform an unbiased analysis of the subcutaneous abdominal adipose tissue transcriptomic response to acute exercise in adults with obesity, and to compare the effects of moderate-intensity continuous exercise versus high-intensity interval exercise on this response. Twenty-nine adults with obesity performed a session of either high-intensity interval exercise (HI; 10 × 1 min at 90%HRpeak, 1 min recovery between intervals; n = 14) or moderate-intensity continuous exercise (MI; 45 min at 70%HRpeak; n = 15). Groups were well matched for BMI (HI 33 ± 3 vs. MI 33 ± 4 kg/m(2)), sex (HI: 9 women vs. MI: 10 women), and age (HI: 32 ± 6 vs. MI: 29 ± 5). Subcutaneous adipose tissue was collected before and 1 h after the session of HI or MI, and samples were processed for RNA sequencing. Gene set enrichment analysis revealed 7 of 21 gene sets enriched postexercise overlapped between HI and MI. Interestingly, both HI and MI upregulated gene sets involved in inflammation (IL6-JAK-STAT3 signaling, allograft rejection, TNFα signaling via NFκB, and inflammatory response; FDR q value < 0.25). Exercise also downregulated adipogenic and oxidative metabolism gene sets in both groups. Overall, these data suggest genes involved in subcutaneous adipose tissue metabolism and inflammation may be an important part of the initial response after a session of exercise. NEW & NOTEWORTHY This study compared the effects of a single session of high-intensity interval exercise versus moderate-intensity continuous exercise on transcriptional changes in subcutaneous abdominal adipose tissue collected from adults with obesity. Our novel findings indicate exercise upregulated inflammation-related gene sets, while it downregulated metabolism-related gene sets – after both high-intensity and moderate-intensity exercise. These data suggest exercise can alter the adipose tissue transcriptome 1 h after exercise in ways that may impact inflammation and metabolism.

Calorie restriction (CR) and the resultant weight-loss are known to improve metabolic health, but the effects of CR on factors regulating white adipose tissue (WAT) metabolic function and remodeling remain unclear. The purpose of this study was to examine the effects of 8 weeks of CR on markers of lipid storage/release, endoplasmic reticulum (ER) stress, and apoptosis in inguinal and epididymal WAT collected from aged rats. We harvested inguinal and epididymal adipose tissue from 24-month-old male Fischer-344 x Brown Norway rats that were either fed an ad libitum chow diet (AL, n=6) or subjected to CR (consuming 35% below AL intake) of the same diet (n=6) for 8 weeks. Using standard immunoblotting methods, inguinal WAT from CR had a greater abundance of phosphorylated hormone sensitive lipase (pHSL) than AL (11.1±6.6 vs. 4.5±3.3 arbitrary units (AU); P=0.05) indicative of elevated lipase activity in CR, and a lower protein abundance of the esterification marker, diacylglycerol acyltransferase (DGAT; 1.0±0.2 vs. 2.4±0.6 AU; P In summary, CR-mediated responses in WAT of aged rats appeared to be depot-specific and CR may contribute to important metabolic modifications and may impact cellular remodeling of inguinal adipose tissue. Disclosure P. Varshney: None. M. W. Schleh: None. C. Ahn: None. A. Zheng: None. E. B. Arias: None. G. D. Cartee: None. J. F. Horowitz: None. Funding National Institutes of Health (R01DK077966, P30DK089503, R01AG010026)

Low sensitivity to the antilipolytic effects of insulin in adipose tissue has been linked with impaired insulin-mediated glucose uptake in skeletal muscle. The aims of this study were: 1) to compare adipose tissue morphology in obese adults with high- (HIGH) vs. low-sensitivity (LOW) to the antilipolytic effects of insulin, and 2) compare the effects of exercise training on adipose tissue from HIGH vs. LOW subjects. Using isotopic dilution methods before and during a hyperinsulinemic-euglycemic clamp, we measured the antilipolytic response to insulin in a total of 36 obese adults - and we identified sub-cohorts of 13 LOW (64±7% lipolytic suppression by insulin; BMI: 34±4kg/m2) and 13 HIGH (82±3% lipolytic suppression by insulin; BMI:33±3kg/m2). Abdominal subcutaneous adipose tissue (aSAT) samples were collected before the clamp (non-insulin stimulated). Measurements were made before and after a 12-week endurance exercise training program (4 days/week). Before training, capillary density (# of capillaries/mm2) in aSAT samples for LOW was significantly lower than HIGH (p=0.004). Collagen abundance in aSAT extracellular matrix (ECM) was lower in LOW (p=0.013). In response to training, the antilipolytic response to insulin was significantly improved in LOW (72±5% lipolytic suppression by insulin; p In summary, aSAT from obese adults with low antilipolytic sensitivity to insulin displayed lower capillarization and ECM collagen abundance compared with obese adults with high sensitivity to the antilipolytic effects of insulin. Importantly, morphological adaptations to exercise training accompanied an increased antilipolytic sensitivity to insulin in subjects with low antilipolytic sensitivity before training. Disclosure C. Ahn: None. M. W. Schleh: None. B. J. Ryan: None. A. Ludzki: None. P. Varshney: None. J. B. Gillen: None. S. Chen: None. J. F. Horowitz: None. Funding National Institutes of Health (R01DK077966, P30DK089503, T32DK007245, F32DK117522); Canadian Institutes of Health Research (DFS146190, 338735)

New findings What is the central question of this study? Does exercise training modify tissue iron storage in adults with obesity? What is the main finding and its importance? Twelve weeks of moderate-intensity exercise or high-intensity interval training lowered whole-body iron stores, decreased the abundance of the key iron storage protein in skeletal muscle (ferritin) and tended to lower hepatic iron content. These findings show that exercise training can reduce tissue iron storage in adults with obesity and might have important implications for obese individuals with dysregulated iron homeostasis. Abstract The regulation of iron storage is crucial to human health, because both excess and deficient iron storage have adverse consequences. Recent studies suggest altered iron storage in adults with obesity, with increased iron accumulation in their liver and skeletal muscle. Exercise training increases iron use for processes such as red blood cell production and can lower whole-body iron stores in humans. However, the effects of exercise training on liver and muscle iron stores in adults with obesity have not been assessed. The aim of this study was to determine the effects of 12 weeks of exercise training on whole-body iron stores, liver iron content and the abundance of ferritin (the key iron storage protein) in skeletal muscle in adults with obesity. Twenty-two inactive adults (11 women and 11 men; age, 31 ± 6 years; body mass index, 33 ± 3 kg/m2 ) completed 12 weeks (four sessions/week) of either moderate-intensity continuous training (MICT; 45 min at 70% of maximal heart rate; n = 11) or high-intensity interval training (HIIT; 10 × 1 min at 90% of maximal heart rate, interspersed with 1 min active recovery; n = 11). Whole-body iron stores were lower after training, as indicated by decreased plasma concentrations of ferritin (P = 3 × 10-5 ) and hepcidin (P = 0.02), without any change in C-reactive protein. Hepatic R2*, an index of liver iron content, was 6% lower after training (P = 0.06). Training reduced the skeletal muscle abundance of ferritin by 10% (P = 0.03), suggesting lower muscle iron storage. Interestingly, these adaptations were similar in MICT and HIIT groups. Our findings indicate that exercise training decreased iron storage in adults with obesity, which might have important implications for obese individuals with dysregulated iron homeostasis.

Mechanisms underlying the direct effects of exercise on metabolic health (independently of weight loss) are poorly understood, and very little is known about the effects of exercise on adipose tissue. The purpose of this study was to examine the effects of exercise training on the key extracellular matrix (ECM) modifiers, matrix metalloproteinase 2 (MMP2) and MMP9, in abdominal subcutaneous adipose tissue (aSAT) of obese adults. Seven obese adults (BMI=33±4 kg/m2; age=32±6) completed 12 weeks of exercise training (either 45min of steady-state exercise at 70% HRmax or 10x1min intervals at 90% HRmax with 1min recovery between intervals), and they were required to maintain body weight throughout. aSAT biopsies were collected before training (Pre) and twice after training - 1 day post exercise (1d PEX) and again 4 days post exercise (4d PEX; to wash out the acute effects of exercise). Using standard immunoblotting methods, we found no evidence for effects of training on either MMP2 or MMP9. However, using gelatin zymography (a technique with more than 100-fold higher sensitivity than immunoblotting) we found a strong trend for an increased MMP9 abundance 1d PEX (3.7±1.0 vs. 3.0±1.4 arbitrary units (AU), for 1d PEX vs. Pre; P=0.08). Interestingly, however, MMP9 returned to Pre training levels by 4d PEX (1.9±1.3 AU; P In summary, because increased abundance and activity of MMPs may alter the fibrotic content and composition of the ECM, exercise-induced increases in MMP2 and MMP9 within aSAT may contribute to favorable modifications within adipose tissue ECM of obese adults. Disclosure P. Varshney: None. B.J. Ryan: None. C. Ahn: None. M.W. Schleh: None. J.F. Horowitz: None. Funding National Institutes of Health (R01DK077966, P30DK089503, F32DK117522, UL1TR002240)

Objective We compared the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on insulin sensitivity and other important metabolic adaptations in adults with obesity. Methods Thirty-one inactive adults with obesity (age: 31 ± 6 years; body mass index: 33 ± 3 kg/m2) completed 12 weeks (4 sessions/week) of either HIIT (10 × 1-minute at 90%HRmax, 1-minute active recovery; n = 16) or MICT (45 minutes at 70%HRmax; n = 15). To assess the direct effects of exercise independent of weight/fat loss, participants were required to maintain body mass. Results Training increased peak oxygen uptake by ~10% in both HIIT and MICT (P Conclusion Despite large differences in training intensity and exercise time, 12 weeks of HIIT and MICT induce similar acute improvements in peripheral insulin sensitivity the day after exercise, and similar longer term metabolic adaptations in skeletal muscle in adults with obesity. These findings support the notion that the insulin-sensitizing effects of both HIIT and MICT are mediated by factors stemming from the most recent exercise session(s) rather than adaptations that accrue with training.

We have recently reported P21-activated kinase 2 (PAK2), a serine/threonine kinase as a negative regulator of neuronal glucose uptake and insulin sensitivity. Resveratrol (RSV), a natural polyphenol with anti-oxidative, anti-inflammatory and anti-diabetic properties, regulates PAK2 activity in HepG2 and ESC-B5 cell apoptosis. However, regulation of PAK2 by RSV in neuronal insulin signaling pathway, if any, is still unknown. In the present study, RSV treatment significantly increased PAK2 activity under insulin-sensitive and insulin-resistant condition, along with a marked decrease in glucose uptake in differentiated N2A cells. Pretreatment with AMPK inhibitor, followed by RSV treatment resulted in reduction in PAK2 activity whereas glucose uptake showed an increase. However, pretreatment with Akt inhibitor and then RSV exposure significantly increased PAK2 activity, with a corresponding decrease in glucose uptake. RSV treatment increased AMPK activity and decreased Akt activity. In conclusion, RSV negatively regulates neuronal glucose uptake and insulin sensitivity via PAK2.

Abnormalities in muscle lipid metabolism in obesity have been linked to insulin resistance. Exercise training alters skeletal muscle lipid abundance and localization, but the direct effects of exercise training (independent of weight loss) on skeletal muscle lipolytic proteins are not clearly understood, and data are lacking regarding influence of training intensity on factors regulating muscle lipid metabolism in obesity. Our aim was to examine the effects of high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT) on skeletal muscle lipolytic proteins in obese humans. Eighteen sedentary, obese adults completed 12 weeks (4 sessions weekly) of either HIIT (10 x 1 min at 90% HRmax, 1 min recovery; n=8) or MICT (45 min at 70% HRmax; n=10). Muscle biopsies (vastus lateralis) were collected before and after training. Subjects maintained body weight and fat mass and the post-training biopsy occurred 3 days after the final exercise session. Both exercise training programs increased aerobic capacity (VO2max) by ~10% (p=0.003), with no significant difference between HIIT and MICT. In muscle samples, hormone-sensitive lipase (HSL) protein abundance increased ~2-fold after training in HIIT (P In summary, HIIT and MICT result in similar modifications to lipolytic proteins in skeletal muscle, although our findings suggest that HIIT may be a more potent stimulus for increasing HSL abundance. Future work is needed to determine if the concomitant increases in protein abundance of CGI-58 and G0S2 with training may improve lipid handling in obesity. Disclosure B.J. Ryan: None. M.W. Schleh: None. P. Varshney: None. A. Ludzki: None. J.B. Gillen: None. K. Foug: None. B.D. Carr: None. J.F. Horowitz: Research Support; Self; American Diabetes Association. Funding National Institutes of Health (R01DK077966, P30DK089503, T32DK007245); Canadian Institutes of Health Research (DFS146190)

Excessive fatty acid (FA) mobilization from subcutaneous adipose tissue into systemic circulation underlies many metabolic health complications associated with obesity, such as insulin resistance. Exercise is often used to help treat and/or prevent insulin resistance, but the direct effects of exercise training (without weight loss) on systemic FA mobilization are unclear. The aim of this study was to determine the effect of both high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on FA rate of appearance (FA Ra) into systemic circulation and factors regulating FA mobilization from subcutaneous adipose tissue. 18 obese adults (33±3 kg•m-2) were randomized to 12 weeks (4 d/week) of either HIIT (10 x 1 min at 90% HRmax with 1 min recovery; n=8) or MICT (45 min at 70% HRmax; n=10), and were required to maintain bodyweight throughout. Resting FA Ra (13C palmitate dilution) and abdominal subcutaneous adipose tissue samples were collected in the overnight fasted state before and after training (72h following their final exercise session). The abundance of key lipolytic and lipid storage proteins in adipose tissue were measured via immunoblot. Aerobic fitness (VO2peak) increased ∼10% after training (P = 0.002), with no difference between HIIT and MICT. Body weight remained unchanged after training (HIIT: 98±12 vs. 98±13 kg, MICT: 101±12 vs. 100±13), as did fat mass (HIIT: 40±5 vs. 39±5 kg, MICT: 42±8 vs. 41±9). Training did not affect resting FA Ra in either HIIT (16.5±3.2 vs. 15.3±1.8 μmol•kg FM-1•min-1) or MICT (16.5±2.6 vs. 15.8±1.4 μmol•kg FM-1•min-1). In line with this finding, neither HIIT nor MICT altered adipose tissue abundance or phosphorylation-state of the lipolytic enzymes ATGL and HSL, or other factors involved in FA mobilization and storage in adipose tissue (e.g., GPAT, DGAT, CGI-58, G0S2, CD36). In summary, in the absence of weight loss, 12 weeks HIIT or MICT did not alter the regulation of resting FA mobilization from subcutaneous adipose tissue. Disclosure M.W. Schleh: None. B.J. Ryan: None. J.B. Gillen: None. P. Varshney: None. K. Foug: None. A. Ludzki: None. J.F. Horowitz: Research Support; Self; American Diabetes Association. Funding National Institutes of Health (R01DK077966, P30DK089503, T32DK007245); Canadian Institutes of Health Research (DFS146190)

The direct effects of exercise on white adipose tissue morphology and metabolic function remain unclear, due in large part to confounding effects of the reduction in fat mass that often accompanies exercise training. The purpose of this study was to determine if a session of endurance exercise could impact the rate of adipogenesis. Eight lean, healthy human subjects performed a single session of exercise (1 hour of endurance exercise at 65% of their maximal aerobic capacity; VO2max). Blood samples were collected without prior exercise (No-EX) and immediately after exercise (EX). Serum was extracted, and human adipocyte precursor cells were incubated for 72 hours in vitro in either the No-EX or EX serum. This serum preincubation was immediately followed by a standard 14-day differentiation protocol. On both days 3 and 9 of differentiation, mRNA expression levels of differentiation markers, PPARG and FABP4, were significantly greater (P In summary, factors released into the circulation during and/or immediately after a session of endurance exercise can accelerate the rate of differentiation in human adipocyte precursor cells. Enhanced adipogenic signaling in response to exercise may have metabolic health benefits by priming adipose tissue for a more effective energy storage during periods of weight gain. Disclosure P. Varshney: None. L.M. Guth: None. C.M. Anderson: None. A. Raajendiran: None. M.J. Watt: None. J.F. Horowitz: Research Support; Self; American Diabetes Association. Funding National Institutes of Health (R01DK077966, T32DK101357)

Lipid rafts are dynamic assemblies of proteins and lipids that harbour many receptors and regulatory molecules and so act as a platform for signal transduction. They float freely within the liquid‐disordered bilayer of cellular membranes and can cluster to form larger ordered domains. Alterations in lipid rafts are commonly found to be associated with the pathogenesis of several human diseases and recent reports have shown that the raft domains can also be perturbed by targeting raft proteins through microRNAs. Over the last few years, the importance of lipid rafts in modulating both innate and acquired immune responses has been elucidated. Various receptors present on immune cells like B cells, T cells, basophils and mast cells associate with lipid rafts on ligand binding and initiate signalling cascades leading to inflammation. Furthermore, disrupting lipid raft integrity alters lipopolysaccharide‐induced cytokine secretion, IgE signalling, and B‐cell and T‐cell activation. The objective of this review is to summarize the recent progress in understanding the role of lipid rafts in the modulation of immune signalling and its related therapeutic potential for autoimmune diseases and inflammatory disorders.

Psoriasis is an immune-mediated inflammatory disease of the skin. Previous studies including ours have shown that IL-17A plays a major role in its pathogenesis; however, its precise molecular mechanism of action is not well understood. Cytokines like TNF α and IL-23 are also important in mediating the disease and some studies have also reported autophagy as a novel mechanism by which cytokines controls the immune response. Herein, we investigated the effect of IL-17A on autophagy and reveal crosstalk between autophagy and cholesterol signaling in keratinocytes. Our results suggest that IL-17A stimulated keratinocytes activated PI3K/AKT/mTOR signaling and inhibited autophagy by simultaneously inhibiting autophagosome formation and enhancing autophagic flux. Western blotting was utilized to detect the expression of autophagic markers (LC3 and p62), PI3K, mTOR and AKT. Induction of autophagy by mTOR inhibitor rapamycin and/or starvation also inhibited the levels of IL-17A secreted IL-8, CCL20 and S100A7 in keratinocytes. Herein, we also observed that inhibition of autophagy by IL-17A was accompanied by enhanced cellular cholesterol levels which in turn regulated the autophagic flux. To investigate crosstalk between autophagy and cellular cholesterol, we used methyl-β-cyclodextrin (MβCD), which disrupts detergent-insoluble microdomains (DIMs) by depleting cells of cholesterol and checked autophagy. Decreased expression of LC3-II in psoriatic lesional skin compared to non-lesional skin and induction of autophagy by anti-psoriatic drug methotrexate in keratinocytes further confirms the role of autophagy in psoriasis. Our findings suggest that modulators of autophagy and/or cholesterol levels may be developed, and also may lead to new therapeutic agents for psoriasis treatment.

Psoriasis is a chronic inflammatory skin disease characterized by altered proliferation and differentiation of keratinocytes as well as infiltration of immune cells. Increased expression of Th17 cells and cytokines secreted by them provides evidence for its central role in the pathogenesis of psoriasis. IL-17A, signature cytokine of Th17 cells was found to be highly differentially expressed in psoriatic lesional skin. However, cellular and molecular mechanism by which IL-17A exerts its function on keratinocyte is incompletely understood. To understand IL-17A mediated signal transduction pathways, gene expression profiling was done and differentially expressed genes were analysed by IPA software. Here, we demonstrate that during IL-17A signaling total cholesterol levels were elevated, which in turn resulted in the suppression of genes of cholesterol and fatty acid biosynthesis. We found that accumulation of cholesterol was essential for IL-17A signaling as reduced total cholesterol levels by methyl β cyclodextrin (MBCD), significantly decreased IL-17A induced secretion of CCL20, IL-8 and S100A7 from the keratinocytes. To our knowledge this study for the first time unveils that high level of intracellular cholesterol plays a crucial role in IL-17A signaling in keratinocytes and may explain the strong association between psoriasis and dyslipidemia.

P21-activated kinases (PAKs) are recently reported as important players of insulin signaling and glucose homeostasis in tissues like muscle, pancreas and liver. However, their role in neuronal insulin signaling is still unknown. Present study reports the involvement of PAK2 in neuronal insulin signaling, glucose uptake and insulin resistance. Irrespective of insulin sensitivity, insulin stimulation decreased PAK2 activity. PAK2 downregulation displayed marked enhancement of GLUT4 translocation with increase in glucose uptake whereas PAK2 over-expression showed its reduction. Treatment with Akti-1/2 and wortmannin suggested that Akt and PI3K are mediators of insulin effect on PAK2 and glucose uptake. Rac1 inhibition demonstrated decreased PAK2 activity while inhibition of PP2A resulted in increased PAK2 activity, with corresponding changes in glucose uptake. Taken together, present study demonstrates an inhibitory role of insulin signaling (via PI3K-Akt) and PP2A on PAK2 activity and establishes PAK2 as a Rac1-dependent negative regulator of neuronal glucose uptake and insulin sensitivity.

Background Pancreatic cancer, one of the most dreadful gastrointestinal tract malignancies, with the current chemotherapeutic drugs has posed a major impediment owing to poor prognosis and chemo-resistance thereby suggesting critical need for additional drugs as therapeutics in combating the situation. Fluoroquinolones have shown promising and significant anti-tumor effects on several carcinoma cell lines. Methods Previously, we reported growth inhibitory effects of fourth generation fluoroquinolone Gatifloxacin, while in the current study we have investigated the anti-proliferative and apoptosis-inducing mechanism of older generation fluoroquinolones Moxifloxacin and Ciprofloxacin on the pancreatic cancer cell-lines MIA PaCa-2 and Panc-1. Cytotoxicity was measured by MTT assay. Apoptosis induction was evaluated using annexin assay, cell cycle assay and activation of caspase-3, 8, 9 were measured by western blotting and enzyme activity assay. Results Herein, we found that both the fluoroquinolones suppressed the proliferation of pancreatic cancer cells by causing S-phase arrest and apoptosis. Blockade in S-phase of cell cycle was associated with decrease in the levels of p27, p21, CDK2, cyclin-A and cyclin-E. Herein we also observed triggering of extrinsic as well as intrinsic mitochondrial apoptotic pathway as suggested by the activation of caspase-8, 9, 3, and Bid respectively. All this was accompanied by downregulation of antiapoptotic protein Bcl-xL and upregulation of proapoptotic protein Bak. Our results strongly suggest the role of extracellular-signal-regulated kinases (ERK1/2), but not p53, p38 and c-JUN N-terminal kinase (JNK) in fluoroquinolone induced growth inhibitory effects in both the cell lines. Additionally, we also found both the fluoroquinolones to augment the apoptotic effects of broad spectrum anticancer drug Cisplatin via ERK. Conclusion The fact that these fluoroquinolones synergize the effect of cisplatin opens new insight into therapeutic index in treatment of pancreatic cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1560-y) contains supplementary material, which is available to authorized users.