The Effects of Physical Activity on Hepatic Lipid Metabolism During Weight-Loss

Non-alcoholic fatty liver disease (NAFLD) develops as a result of physical inactivity and overnutrition. Changing dietary behaviors and increasing physical activity are common strategies used for weight-loss; however, it remains unclear what additional benefits are provided by incorporating physical activity in a weight-loss program for the treatment of NAFLD. The purpose of this study was to determine how physical activity reduces hepatic steatosis and changes the expression of hepatic lipogenic genes during weight-loss. Male C57BL/6 mice were fed either a low-fat (LFD; 10% kcal fat) or high-fat (HFD; 60% kcal fat) diet for 10-weeks. Following 10-weeks, the HFD group was randomly assigned to either a LFD (Diet) or LFD with physical activity (Diet+PA) to induce weight-loss for 8-weeks. After 8-weeks of weight-loss, reductions in body and liver mass were observed in both Diet and Diet+PA groups (see Table 1.). Interestingly, the Diet+PA group lost significantly (P\u3c0.05) more body mass than the Diet group. Reductions in body mass and HOMA-IR in the Diet and Diet+PA groups were matched by reductions in hepatic triglyceride levels. In the Diet+PA group, liver triglyceride and cholesterol levels were significantly (P\u3c0.05) lower than all other groups. The greater reduction in hepatic triglyceride levels from physical activity was due to significant (P\u3c0.05) reductions in the expression of lipogenic FASN and SCD-1 mRNA. Interestingly, physical activity did not alter fatty acid uptake or fatty acid oxidation as observed with CD36 and CPT-1a mRNA levels, respectively. Based on these findings, the addition of physical activity to a diet-induced weight-loss intervention provides a more effective approach for the treatment of NAFLD than dieting alone. Table 1. Whole body and hepatic metabolic characteristics following weight-loss. Variables LFD (n=12) HFD (n=12) Diet (n=12) Diet+PA (n=12) Body mass (g) 30.2 ± 1.1 48.8 ± 0.5* 30.3 ± 0.7† 26.1 ± 0.3*,†,‡ Liver mass (g) 1.2 ± 0.1 2.9 ± 0.2* 1.2 ± 0.1† 1.2 ± 0.1† Triglyceride (mg/dL) 99.4 ± 8.7 96.7 ± 5.5 88.3 ± 6.1 88.4 ± 4.8 Cholesterol (mg/dL) 153.5 ± 10.1 246.0 ± 8.7* 148.2 ± 15.5† 127.6 ± 4.7*,† HOMA-IR 22.9 ± 1.2 187.3 ± 7.5* 19.4 ± 8.8† 25.3 ± 10.5† Liver Tg (mg/mg tissue) 1.18 ± 0.14 2.53 ± 0.05* 0.96 ± 0.15† 0.58 ± 0.07*,†,‡ Liver Chol (μg/mg tissue) 437.0 ± 43.0 585.2 ± 54.4* 527.0 ± 56.5 324.0 ± 27.3*,†,‡ FASN mRNA 1.00 ± 0.20 1.90 ± 0.34* 2.10 ± 0.54* 0.46 ± 0.11*,†,‡ CD36/FAT mRNA 1.00 ± 0.22 0.19 ± 0.20* 0.97 ± 0.10† 0.80 ± 0.04† SCD-1 mRNA 1.00 ± 0.28 1.94 ± 0.83* 0.76 ± 0.13† 0.44 ± 0.05*,†,‡ CPT-1a mRNA 1.00 ± 0.18 0.74 ± 0.04* 0.62 ± 0.08* 0.73 ± 0.05* Note. Data are presented as mean ± SEM.*Significantly (P\u3c0.05) different than LFD; †significantly (P\u3c0.05) different than HFD; ‡significantly (P\u3c0.05) different than Diet

The Effects of Physical Activity on Markers of Hepatic Inflammation During Weight-Loss

Non-alcoholic fatty liver disease (NAFLD) represents a continuum that begins with accumulation of lipid in hepatic cells progressing to hepatic steatosis with inflammation (steatohepatitis), fibrosis, and cirrhosis. Weight-loss using dietary modification and physical activity are common strategies used for the treatment of NAFLD; however, it remains to be determined the effects of physical activity on hepatic inflammation during weight-loss. The purpose of this study was to determine the therapeutic role of physical activity on plasma and hepatic inflammatory markers during weight-loss. Male C57BL/6 mice were fed either a low-fat (LFD; 10% kcal fat) or high-fat (HFD; 60% kcal fat) diet for 10-weeks. Following 10-weeks, the HFD group was randomly assigned to either a LFD (Diet) or LFD with physical activity (Diet+PA) to induce weight loss for 8-weeks. After 8-weeks, reductions in body mass were observed in both Diet and Diet+PA groups (see Table 1.). Interestingly, the Diet+PA group lost significantly (P\u3c0.05) more body mass than the Diet group. Despite significant (P\u3c0.05) reductions in body mass and HOMA-IR, plasma TNF-α remained elevated in the Diet and Diet+PA groups. Moreover, Diet+PA plasma TNF-α was significantly (P\u3c0.05) greater than the HFD obese controls. Elevated plasma TNF-α in the Diet+PA was matched by a greater hepatic expression of IL-1β and IL-6 mRNA when compared to all groups. Interestingly, the expression of TGF-β1 mRNA was significantly (P\u3c0.05) reduced in the Diet+PA when compared to all groups. The elevated plasma TNF-α and expression of IL-1β and IL-6 mRNA are likely due to physical activity. It remains unclear as to the pro-inflammatory effects of physical activity during weight-loss; however, this may be part of a protective adaption to regular exercise. Furthermore, the reduced hepatic TGF-β1 mRNA levels suggest a protective strategy against fibrogenesis in the spectrum of liver disease. Table 1. Whole body and hepatic metabolic characteristics following weight-loss. Variables LFD (n=12) HFD (n=12) Diet (n=12) Diet+PA (n=12) Body mass (g) 30.2 ± 1.1 48.8 ± 0.5* 30.3 ± 0.7† 26.1 ± 0.3*,†,‡ HOMA-IR 22.9 ± 1.2 187.3 ± 7.5* 19.4 ± 8.8† 25.3 ± 10.5† IL-6 (pg/mL) 6.4 ± 0.7 6.2 ± 1.0 5.9 ± 0.9 6.4 ± 0.9 TNF-α (pg/mL) 30.8 ± 6.7 60.6 ± 5.3* 74.0 ± 8.1* 82.5 ± 7.7*,† IL-1β mRNA 1.00 ± 0.51 0.97 ± 0.34 1.20 ± 0.59 2.83 ± 0.62*,†,‡ IL-6 mRNA 1.00 ± 0.45 1.53 ± 0.50 1.16 ± 0.72 2.36 ± 0.55*,†,‡ TNF-α mRNA 1.00 ± 0.09 0.89 ± 0.08 0.94 ± 0.14 0.83 ± 0.06 TGF-β1 mRNA 1.00 ± 0.06 1.02 ± 0.06 1.02 ± 0.10 0.84 ± 0.05† Note. Data are presented as mean ± SEM. *Significantly (P\u3c0.05) different than LFD; †significantly (P\u3c0.05) different than HFD; ‡significantly (P\u3c0.05) different than Diet

The Effects of Physical Activity on Markers of Hepatic Lipid Metabolism during Weight Cycling

Non-alcoholic fatty liver disease (NAFLD) has emerged as the leading cause of liver disease and develops when the rate of hepatic triglyceride formation exceeds the rate of disposal. Weight loss is often prescribed to treat NAFLD; however, only one in six obese or overweight individuals who lose weight through diet are successful at maintaining weight loss resulting in weight regain (i.e., weight cycling). Purpose: To determine the effect of physical activity on the prevention of hepatic steatosis and expression of lipogenic genes during weight cycling. Methods: To induce obesity, male C57BL/6 mice were fed a 60% fat diet for 10-weeks. Following weight gain, mice were randomly assigned to a 10% fat diet either with (Diet+PA) or without (Diet) physical activity to induce weight loss for 8 weeks. Physical activity consisted of unrestricted access to running wheels. Following weight loss, the Diet and Diet+PA groups were switched back to a 60% fat diet for 10 weeks to cause weight regain. The Diet+PA had continued access to physical activity during weight regain. Age-matched lean and obese control mice were fed either a 10% fat diet (LF) or 60% fat diet (HF) for the entire 28 weeks of the study. Significant differences (P\u3c0.05) between groups were identified by one-way ANOVA. Results: Following weight regain, body mass of the Diet+PA was significantly lower than the HF (47.8 vs. 55.3 g) and Diet (47.8 vs. 53.9 g). No significant difference in body mass was observed between Diet and HF groups. The Diet+PA had significantly lower plasma cholesterol levels compared to HF (230.5 vs. 254.5 mg/dL) and Diet (230.5 vs. 271.9 mg/dL). In addition, the Diet+PA group had significantly lower total hepatic lipid (23.2 vs. 26.5%) when compared with Diet, which was associated with 60%, 50%, and 40% lower expression of lipogenic genes Fasn, Srebp1c, and Chrebp, respectively. No difference was noted between Diet and Diet+PA for the expression of lipogenic genes Scd1 and Acc1. Conclusions: These data suggests that the continued physical activity during weight cycling resulted in lower weight regain and reduced the accumulation of hepatic lipid by decreased de novo lipogenesis. Overall, the reduced expression of lipogenic related genes might point to a potential protective mechanism that physical activity has on the development of NAFLD during weight cycling

The Effects of Physical Activity on Markers of Adipose Inflammation during Weight Cycling

Weight loss using diet and exercise are the main treatment strategies for obesity; however, weight loss is rarely maintained resulting in weight regain or weight cycling. Obesity is associated with chronic low-grade inflammation resulting in the release of adipokines and activation of macrophages (M1) accelerating the development of insulin resistance. In contrast, the M2 macrophage phenotype is characterized by blocking inflammatory responses and promoting tissue repair. Despite the effectiveness of exercise on preventing comorbidities of obesity during weight-loss, the influence of physical activity during weight cycling on markers of adipose inflammation remains unclear. Purpose: The purpose of this study was to determine the role of physical activity on the expression of inflammatory markers in adipose tissue during weight cycling. Methods: Male C57BL/6 mice were randomly assigned to one of three groups for 28 weeks: a high-fat diet obese control (HFD; 60% kcal from fat), an alternating high-low-high fat diet group (Diet; 60%/10%/60% kcal from fat) to simulate weight cycling, or a diet-matched weight cycling group that had unrestricted access to running wheels (Diet+PA). After weight regain, MCP-1, CD11c, CD163, F4/80, TLR4, and TNFα mRNA levels were quantified in perigonadal adipose tissue using qRT-PCR. A one-way ANOVA was used to identify significant differences between groups with significance set at PWeight cycling without physical activity resulted in obesity and insulin resistance when compared to HFD obese controls. Interestingly, compared to the HFD control group, the Diet group demonstrated significantly greater expression of F4/80 (+50%), CD11c (+113%), TLR4 (+77%), and TNFα (+72%) mRNA, which may represent greater macrophage infiltration and M1 macrophage polarization. Physical activity during weight cycling resulted in lower weight regain compared to both HFD and Diet groups; however, mice still developed insulin resistance and increased expression of TLR4 (+76%), TNFα (+94%), and CD11c (+58%) suggesting increased M1 macrophage activation when compared to the HFD group. Conclusions: The data presented suggests weight cycling may accelerate the development of adipose dysfunction, and unrestricted physical activity appears to have minimal effects on the negative inflammatory effects of weight cycling

Exploring extensions to the standard cosmological model and the impact of baryons on small scales

It has been claimed that the standard model of cosmology (ΛCDM) cannot easily account for a number of observations on relatively small scales, motivating extensions to the standard model. Here, we introduce a new suite of cosmological simulations that systematically explores three plausible extensions: warm dark matter, self-interacting dark matter, and a running of the scalar spectral index of density fluctuations. Current observational constraints are used to specify the additional parameters that come with these extensions. We examine a large range of observable metrics on small scales, including the halo mass function, density, and circular velocity profiles, the abundance of satellite subhaloes, and halo concentrations. For any given metric, significant degeneracies can be present between the extensions. In detail, however, the different extensions have quantitatively distinct mass and radial dependencies, suggesting that a multiprobe approach over a range of scales can be used to break the degeneracies. We also demonstrate that the relative effects on the radial density profiles in the different extensions (compared to the standard model) are converged down to significantly smaller radii than are the absolute profiles. We compare the derived cosmological trends with the impact of baryonic physics using the EAGLE and ARTEMIS simulations. Significant degeneracies are also present between baryonic physics and cosmological variations (with both having similar magnitude effects on some observables). Given the inherent uncertainties both in the modelling of galaxy formation physics and extensions to ΛCDM, a systematic and simultaneous exploration of both is strongly warranted

Comparison of characteristics and function of translation termination signals between and within prokaryotic and eukaryotic organisms

Six diverse prokaryotic and five eukaryotic genomes were compared to deduce whether the protein synthesis termination signal has common determinants within and across both kingdoms. Four of the six prokaryotic and all of the eukaryotic genomes investigated demonstrated a similar pattern of nucleotide bias both 5′ and 3′ of the stop codon. A preferred core signal of 4 nt was evident, encompassing the stop codon and the following nucleotide. Codons decoded by hyper-modified tRNAs were over-represented in the region 5′ to the stop codon in genes from both kingdoms. The origin of the 3′ bias was more variable particularly among the prokaryotic organisms. In both kingdoms, genes with the highest expression index exhibited a strong bias but genes with the lowest expression showed none. Absence of bias in parasitic prokaryotes may reflect an absence of pressure to evolve more efficient translation. Experiments were undertaken to determine if a correlation existed between bias in signal abundance and termination efficiency. In Escherichia coli signal abundance correlated with termination efficiency for UAA and UGA stop codons, but not in mammalian cells. Termination signals that were highly inefficient could be made more efficient by increasing the concentration of the cognate decoding release factor

Preliminary observations on soluble programmed cell death protein-1 as a prognostic and predictive biomarker in patients with metastatic melanoma treated with patient-specific autologous vaccines.

Because of its role as an immune checkpoint, levels of soluble programmed cell death protein-1 (sPD-1) could be useful as a prognostic biomarker or predictive biomarker in cancer patients treated with vaccines. Very low levels of sPD-1 may indicate lack of an existing anti-cancer immune response; very high levels may indicate an active immune response that is suppressed. In between these extremes, a decrease in PD-1 following injections of an anti-cancer vaccine may indicate an enhanced immune response that has not been suppressed. Blood samples obtained during a randomized trial in patients with metastatic melanoma were tested from 22 patients treated with a tumor cell vaccine (TCV) and 17 treated with a dendritic cell vaccine (DCV). Survival was better in DCV-treated patients. sPD-1 was measured at week-0, one week before the first of three weekly subcutaneous injections, and at week-4, one week after the third injection. The combination of a very low baseline sPD-1, or absence of a very high PD-1 at baseline followed by a decline in sPD-1 at week-4, was predictive of surviving three or more years in DCV-treated patients, but not TCV-treated. Among DCV-treated patients, these sPD-1 criteria appropriately classified 8/10 (80%) of 3-year survivors, and 6/7 (86%) of patients who did not survive three years. These preliminary observations suggest that sPD-1 might be a useful biomarker for melanoma patients being considered for treatment with this DCV vaccine, and/or to predict efficacy after only three injections, but this would have to be confirmed in larger studies

XMM-Newton observations of the Narrow-Line Seyfert 1 galaxy Mrk 335 in an historical low X-ray flux state

We report the discovery of strong soft X-ray emission lines and a hard continuum above 2 keV in the Narrow-Line Seyfert 1 galaxy Mrk 335 during an extremely low X-ray flux state. Mrk 335 was observed for 22 ks by XMM-Newton in July 2007 as a Target of Opportunity to examine it in its X-ray low-flux state, which was discovered with Swift. Long-term light curves suggest that this is the lowest flux state this AGN has ever been seen in. However, Mrk 335 is still sufficiently bright that its X-ray properties can be studied in detail. The X-ray continuum spectrum is very complex and requires several components to model. Statistically, partial covering and blurred reflection models work well. We confirm the presence of a strong narrow Fe line at 6.4 keV. High-resolution spectroscopy with the XMM-RGS reveals strong, soft X-ray emission lines not detected in previous, higher signal-to-noise, XMM-Newton observations, such as: highly ionized Fe lines, O VII, Ne IX and Mg XI lines. The optical/UV fluxes are similar to those previously measured with Swift. Optical spectroscopy taken in 2007 September do not show any changes to optical spectra obtained 8 years earlier.Comment: Accepted for publication in ApJ; 26 pages, 10 figues, in press, ApJ 681 (July 01, 2008); Updated version with corrections made by the edito

The role of charged residues in the transmembrane helices of monocarboxylate transporter 1 and its ancillary protein basigin in determining plasma membrane expression and catalytic activity

Monocarboxylate transporters MCT1-MCT4 require basigin (CD147) or embigin (gp70), ancillary proteins with a glutamate residue in their single transmembrane (TM) domain, for plasma membrane (PM) expression and activity. Here we use site-directed mutagenesis and expression in COS cells or Xenopus oocytes to investigate whether this glutamate (Glu218 in basigin) may charge-pair with a positively charged TM-residue of MCT1. Such residues were predicted using a new molecular model of MCT1 based upon the published structure of the E. coli glycerol-3-phosphate transporter. No evidence was obtained for Arg306 (TM 8) of MCT1 and Glu218 of basigin forming a charge-pair; indeed E218Q-basigin could replace WT-basigin, although E218R-basigin was inactive. No PM expression of R306E-MCT1 or D302R-MCT1 was observed but D302R/R306D-MCT1 reached the PM, as did R306K-MCT1. However, both were catalytically inactive suggesting that Arg306 and Asp302 form a charge-pair in either orientation, but their precise geometry is essential for catalytic activity. Mutation of Arg86 to Glu or Gln within TM3 of MCT1 had no effect on plasma membrane expression or activity of MCT1. However, unlike WT-MCT1, these mutants enabled expression of E218R-basigin at the plasma membrane of COS cells. We propose that TM3 of MCT1 lies alongside the TM of basigin with Arg86 adjacent to Glu218 of basigin. Only when both these residues are positively charged (E218R-basigin with WT-MCT1) is this interaction prevented; all other residue pairings at these positions may be accommodated by charge-pairing or stabilization of unionized residues through hydrogen bonding or local distortion of the helical structure