Angiopoietin-like protein 4 is an exercise-induced hepatokine in humans, regulated by glucagon and cAMP

Objective: Angiopoietin-like protein-4 (ANGPTL4) is a circulating protein that is highly expressed in liver and implicated in regulation of plasma triglyceride levels. Systemic ANGPTL4 increases during prolonged fasting and is suggested to be secreted from skeletal muscle following exercise. Methods: We investigated the origin of exercise-induced ANGPTL4 in humans by measuring the arterial-to-venous difference over the leg and the hepato-splanchnic bed during an acute bout of exercise. Furthermore, the impact of the glucagon-to-insulin ratio on plasma ANGPTL4 was studied in healthy individuals. The regulation of ANGPTL4 was investigated in both hepatic and muscle cells. Results: The hepato-splanchnic bed, but not the leg, contributed to exercise-induced plasma ANGPTL4. Further studies using hormone infusions revealed that the glucagon-to-insulin ratio is an important regulator of plasma ANGPTL4 as elevated glucagon in the absence of elevated insulin increased plasma ANGPTL4 in resting subjects, whereas infusion of somatostatin during exercise blunted the increase of both glucagon and ANGPTL4. Moreover, activation of the cAMP/PKA signaling cascade let to an increase in ANGPTL4 mRNA levels in hepatic cells, which was prevented by inhibition of PKA. In humans, muscle ANGPTL4 mRNA increased during fasting, with only a marginal further induction by exercise. In human muscle cells, no inhibitory effect of AMPK activation could be demonstrated on ANGPTL4 expression. Conclusions: The data suggest that exercise-induced ANGPTL4 is secreted from the liver and driven by a glucagon-cAMP-PKA pathway in humans. These findings link the liver, insulin/glucagon, and lipid metabolism together, which could implicate a role of ANGPTL4 in metabolic diseases

A novel length back-calculation approach accounting for ontogenetic changes in the fish length – otolith size relationship during the early life of sprat (Sprattus sprattus)

(Sprattus sprattus), accounting for ontogenetic changes in the relationship between fish length and otolith length. In sprat, metamorphosis from larvae to juveniles is characterized by the coincidence of low length growth, strong growth in body height, and maximal otolith growth. Consequently, the method identifies a point of metamorphosis for an individual as the otolith radius at maximum increment widths. By incorporating this information in our back-calculation method, estimated length growth for the early larval stage was more than 60% higher compared with the result of the biological intercept model. After minimal length growth during metamorphosis, we found the highest increase in length during the early juvenile stage. We thus located the strongest growth potential in the early juvenile stage, which is supposed to be critical in determining recruitment strength in Baltic sprat

Association between growth and Pan I genotype within Atlantic cod (Gadus morhua) full sib families

Studies of the pantophysin (Pan I*) locus in Atlantic cod Gadus morhua and other marine gadoids indicate that the locus is under positive selection; in Atlantic cod, genotypic variation at this locus has been linked to differences in growth. Here, we present preliminary data comparing the growth and condition of different Atlantic cod Pan I* genotypes within families held under seminatural mesocosm conditions. Larvae from three full-sibling families carrying Pan I*bb or Pan I*ab genotypes were reared for 10 weeks in two mesocosms. Multivariate analysis of variance indicated that larvae carrying the Pan I*ab genotype exhibited significantly higher standard length, dry weight, and RNA: DNA ratio (condition factor) than did larvae that carried the Pan I*bb genotype, potentially indicating selection. The influence of linked loci cannot be excluded; indeed, the absence of a significant correlation between genotype and growth in one family may substantiate this. The lack of differences in survival among genotypes indicates that moderate selective effects are acting primarily through size-specific mortality and fecundity. The proposed putative fitness effects, together with documented marked geographic differentiation in the wild, have implications for Atlantic cod population structure, effective migration rates, recruitment, and local adaptation, which are of particular relevance in a species threatened by continuing exploitation and rising sea temperatures

Juvenile king scallop, Pecten maximus, is potentially tolerant to low levels of ocean acidification when food is unrestricted.

The decline in ocean water pH and changes in carbonate saturation states through anthropogenically mediated increases in atmospheric CO2 levels may pose a hazard to marine organisms. This may be particularly acute for those species reliant on calcareous structures like shells and exoskeletons. This is of particular concern in the case of valuable commercially exploited species such as the king scallop, Pecten maximus. In this study we investigated the effects on oxygen consumption, clearance rates and cellular turnover in juvenile P. maximus following 3 months laboratory exposure to four pCO2 treatments (290, 380, 750 and 1140 µatm). None of the exposure levels were found to have significant effect on the clearance rates, respiration rates, condition index or cellular turnover (RNA: DNA) of individuals. While it is clear that some life stages of marine bivalves appear susceptible to future levels of ocean acidification, particularly under food limiting conditions, the results from this study suggest that where food is in abundance, bivalves like juvenile P. maximus may display a tolerance to limited changes in seawater chemistry

The influence of temperature on the development of Baltic Sea sprat (Sprattus sprattus) eggs and yolk sac larvae

In spring 2004 and 2005 we performed two sets of experiments with Baltic sprat (Sprattus sprattus balticus Schneider) eggs and larvae from the Bornholm Basin simulating ten different temperature scenarios. The goal of the present study was to analyse and parameterise temperature effects on the duration of developmental stages, on the timing of important ontogenetic transitions, growth during the yolk sac phase as well as on the survival success of eggs and early larval stages. Egg development and hatching showed exponential temperature dependence. No hatching was observed above 14.7°C and hatching success was significantly reduced below 3.4°C. Time to eye pigmentation, as a proxy for mouth gape opening, decreased with increasing temperatures from 17 days post hatch at 3.4°C to 7 days at 13°C whereas the larval yolk sac phase was shortened from 20 to 10 days at 3.8 and 10°C respectively. Maximum survival duration of non-fed larvae was 25 days at 6.8°C. Comparing the experimental results of Baltic sprat with existing information on sprat from the English Channel and North Sea differences were detected in egg development rate, thermal adaptation and in yolk sac depletion rate (YSDR). Sprat eggs from the English Channel showed significantly faster development and the potential to develop at temperatures higher than 14.7°C. North Sea sprat larvae were found to have a lower YSDR compared to larvae from the Baltic Sea. In light of the predictions for global warming, Baltic sprat stocks could experience improved conditions for egg development and surviva

Geographic clustering of testicular cancer incidence in the northern part of The Netherlands

Geographic variations in testicular cancer incidence may be caused by differences in environmental factors, genetic factors, or both. In the present study, geographic patterns of age-adjusted testicular cancer incidence rates (IRs) in 12 provinces in The Netherlands in the period 1989–1995 were analysed. In addition, the age-adjusted IR of testicular cancer by degree of urbanization was evaluated. Cancer incidence data were obtained from the Netherlands Cancer Registry. The overall annual age-adjusted IR of testicular cancer in The Netherlands in the period 1989–1995 was 4.4 per 100 000 men. The province Groningen in the north of the country showed the highest annual IR with 5.8 per 100 000 men, which was higher (P < 0.05) than the overall IR in The Netherlands (incidence rate ratio (IRR) 1.3, 95% confidence interval (CI) 1.1–1.6). The highest IR in Groningen was seen for both seminomas and non-seminomas. In addition, Groningen showed the highest age-specific IRs in all relevant younger age groups (15–29, 30–44 and 45–59 years), illustrating the consistency of data. The province Friesland, also situated in the northern part of the country, showed the second highest IR of testicular cancer with 5.3 cases per 100 000 men per year (IRR 1.2, 95% Cl 1.0–1.5, not significant). This mainly resulted from the high IR of seminoma in Friesland. Analysis of age-adjusted IRs of testicular cancer by degree of urbanization in The Netherlands showed no urban–rural differences at analysis of all histological types combined, or at separate analyses of seminomas and non-seminomas. Geographic clustering of testicular cancer seems to be present in the rural north of The Netherlands with some stable founder populations, which are likely to share a relatively high frequency of genes from common ancestors including genes possibly related to testicular cancer. Although this finding does not exclude the involvement of shared environmental factors in the aetiology of testicular cancer, it may also lend support to a genetic susceptibility to testicular cancer development. Testicular cancer cases in stable founder populations seem particularly suitable for searching for testicular cancer susceptibility genes because such genes are likely to be more frequent among affected men in such populations. © 1999 Cancer Research Campaig

The swimming kinematics of larval Atlantic cod, Gadus morhua L., are resilient to elevated seawater pCO2

Kinematics of swimming behavior of larval Atlantic cod, aged 12 and 27 days post-hatch (dph) and cultured under three pCO2 conditions (control-370, medium-1800, and high-4200 μatm) from March to May 2010, were extracted from swim path recordings obtained using silhouette video photography. The swim paths were analyzed for swim duration, distance and speed, stop duration, and horizontal and vertical turn angles to determine whether elevated seawater pCO2—at beyond near-future ocean acidification levels—affects the swimming kinematics of Atlantic cod larvae. There were no significant differences in most of the variables tested: the swimming kinematics of Atlantic cod larvae at 12 and 27 dph were highly resilient to extremely elevated pCO2 levels. Nonetheless, cod larvae cultured at the highest pCO2 concentration displayed vertical turn angles that were more restricted (median turn angle, 15°) than larvae in the control (19°) and medium (19°) treatments at 12 dph (but not at 27 dph). Significant reduction in the stop duration of cod larvae from the high treatment (median stop duration, 0.28 s) was also observed compared to the larvae from the control group (0.32 s) at 27 dph (but not at 12 dph). The functional and ecological significance of these subtle differences are unclear and, therefore, require further investigation in order to determine whether they are ecologically relevant or spurious

GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans

ObjectiveGrowth differentiation factor (GDF)-15 is implicated in regulation of metabolism and circulating GDF15 increases in response to exercise. The source and regulation of the exercise-induced increase in GDF15 is, however not known.MethodPlasma GDF15 was measured by ELISA under the following conditions: 1) Arterial-to-hepatic venous differences sampled before, during, and after exercise in healthy male subjects (n=10); 2) exogenous glucagon infusion compared to saline infusion in resting healthy subjects (n=10); 3) an acute exercise bout with and without a pancreatic clamp (n=6); 4) healthy subjects for 36 hours (n=17), and 5) patients with anorexia nervosa (n=25) were compared to healthy age-matched subjects (n=25). Tissue GDF15 mRNA content was determined in mice in response to exhaustive exercise (n=16).ResultsThe splanchnic bed released GDF15 to the circulation during exercise and increasing the glucagon-to-insulin ratio in resting humans led to a 2.7-fold (P&lt;0.05) increase in circulating GDF15. Conversely, inhibiting the exercise-induced increase in the glucagon-to-insulin ratio blunted the exercise-induced increase in circulating GDF15. Fasting for 36 hours did not affect circulating GDF15, whereas resting patients with anorexia nervosa displayed elevated plasma concentrations (1.4-fold, P&lt;0.05) compared to controls. In mice, exercise increased GDF15 mRNA contents in liver, muscle, and adipose tissue.ConclusionIn humans, GDF15 is a “hepatokine” which increases during exercise and is at least in part regulated by the glucagon-to-insulin ratio. Moreover, chronic energy deprivation is associated with elevated plasma GDF15, which supports that GDF15 is implicated in metabolic signalling in humans

Phosphodiesterase-5 inhibitors have distinct effects on the hemodynamics of the liver

<p>Abstract</p> <p>Background</p> <p>The NO - cGMP system plays a key role in the regulation of sinusoidal tonus and liver blood flow with phosphodiesterase-5 (PDE-5) terminating the dilatory action of cGMP. We, therefore, investigated the effects of PDE-5 inhibitors on hepatic and systemic hemodynamics in rats.</p> <p>Methods</p> <p>Hemodynamic parameters were monitored for 60 min. after intravenous injection of sildenafil and vardenafil [1, 10 and 100 μg/kg (sil1, sil10, sil100, var1, var10, var100)] in anesthetized rats.</p> <p>Results</p> <p>Cardiac output and heart rate remained constant. After a short dip, mean arterial blood pressure again increased. Systemic vascular resistance transiently decreased slightly. Changes in hepatic hemodynamic parameters started after few minutes and continued for at least 60 min. Portal (var10 -31%, sil10 -34%) and hepatic arterial resistance (var10 -30%, sil10 -32%) decreased significantly (p < 0.05). At the same time portal venous (var10 +29%, sil10 +24%), hepatic arterial (var10 +34%, sil10 +48%), and hepatic parenchymal blood flow (var10 +15%, sil10 +15%) increased significantly (p < 0.05). The fractional liver blood flow (total liver flow/cardiac output) increased significantly (var10 26%, sil10 23%). Portal pressure remained constant or tended to decrease. 10 μg/kg was the most effective dose for both PDE-5 inhibitors.</p> <p>Conclusion</p> <p>Low doses of phosphodiesterase-5 inhibitors have distinct effects on hepatic hemodynamic parameters. Their therapeutic use in portal hypertension should therefore be evaluated.</p