Circulating factors released from tissues during exercise have been hypothesized to mediate some of the health benefits of regular physical activity. Lipokines are circulating lipid species that have ...recently been reported to affect metabolism in response to cold. Here, lipidomics analysis revealed that a bout of moderate-intensity exercise causes a pronounced increase in the circulating lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) in male, female, young, old, sedentary, and active human subjects. In mice, both a single bout of exercise and exercise training increased circulating 12,13-diHOME and surgical removal of brown adipose tissue (BAT) negated the increase in 12,13-diHOME, suggesting that BAT is the tissue source for exercise-stimulated 12,13-diHOME. Acute 12,13-diHOME treatment of mice in vivo increased skeletal muscle fatty acid uptake and oxidation, but not glucose uptake. These data reveal that lipokines are novel exercise-stimulated circulating factors that may contribute to the metabolic changes that occur with physical exercise.
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•Exercise increases circulating levels of the lipokine 12,13-diHOME in humans and mice•iBAT is the tissue source for the exercise-stimulated increase in 12,13-diHOME in mice•12,13-diHOME increases fatty acid uptake and oxidation in skeletal muscle of mice
Using an MS/MSALL lipidomics platform, Stanford et al. identify 12,13-diHOME as an exercised-induced lipokine in male, female, young, and old human subjects. Murine experiments show that BAT is the tissue source of exercise-induced increases in circulating 12,13-diHOME, and that this lipokine increases fatty acid uptake in skeletal muscle in vivo.
Exercise affects whole-body metabolism through adaptations to various tissues, including adipose tissue (AT). Recent studies investigated exercise-induced adaptations to AT, focusing on inguinal ...white adipose tissue (WAT), perigonadal WAT, and interscapular brown adipose tissue (iBAT). Although these AT depots play important roles in metabolism, they account for only ∼50% of the AT mass in a mouse. Here, we investigated the effects of 3 weeks of exercise training on all 14 AT depots. Exercise induced depot-specific effects in genes involved in mitochondrial activity, glucose metabolism, and fatty acid uptake and oxidation in each adipose tissue (AT) depot. These data demonstrate that exercise training results in unique responses in each AT depot; identifying the depot-specific adaptations to AT in response to exercise is essential to determine how AT contributes to the overall beneficial effect of exercise.
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•This study investigates the effects of exercise on all adipose tissue (AT) depots•Exercise training induces unique metabolic changes to BAT, scWAT, and vWAT•Exercise training differentially affects each AT depot within BAT, scWAT, and vWAT
Molecular Biology; Molecular Mechanism of Behavior; Cell Biology; Specialized Functions of Cells
Brown adipose tissue (BAT) is an important tissue for thermogenesis, making it a potential target to decrease the risks of obesity, type 2 diabetes, and cardiovascular disease, and recent studies ...have also identified BAT as an endocrine organ. Although BAT has been implicated to be protective in cardiovascular disease, to this point there are no studies that identify a direct role for BAT to mediate cardiac function.
To determine the role of BAT on cardiac function, we utilized a model of BAT transplantation. We then performed lipidomics and identified an increase in the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). We utilized a mouse model with sustained overexpression of 12,13-diHOME and investigated the role of 12,13-diHOME in a nitric oxide synthase type 1 deficient (NOS1
) mouse and in isolated cardiomyocytes to determine effects on function and respiration. We also investigated 12,13-diHOME in a cohort of human patients with heart disease.
Here, we determined that transplantation of BAT (+BAT) improves cardiac function via the release of the lipokine 12,13-diHOME. Sustained overexpression of 12,13-diHOME using tissue nanotransfection negated the deleterious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13-diHOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13-diHOME increased mitochondrial respiration. The effects of 12,13-diHOME were absent in
mice and cardiomyocytes. We also provide the first evidence that 12,13-diHOME is decreased in human patients with heart disease.
Our results identify an endocrine role for BAT to enhance cardiac function that is mediated by regulation of calcium cycling via 12,13-diHOME and NOS1.
Poor maternal environments, such as under- or overnutrition, can increase the risk for the development of obesity, type 2 diabetes and cardiovascular disease in offspring
. Recent studies in animal ...models have shown that maternal exercise before and during pregnancy abolishes the age-related development of impaired glucose metabolism
, decreased cardiovascular function
and increased adiposity
; however, the underlying mechanisms for maternal exercise to improve offspring's health have not been identified. In the present study, we identify an exercise-induced increase in the oligosaccharide 3'-sialyllactose (3'-SL) in milk in humans and mice, and show that the beneficial effects of maternal exercise on mouse offspring's metabolic health and cardiac function are mediated by 3'-SL. In global 3'-SL knockout mice (3'-SL
), maternal exercise training failed to improve offspring metabolic health or cardiac function in mice. There was no beneficial effect of maternal exercise on wild-type offspring who consumed milk from exercise-trained 3'-SL
dams, whereas supplementing 3'-SL during lactation to wild-type mice improved metabolic health and cardiac function in offspring during adulthood. Importantly, supplementation of 3'-SL negated the detrimental effects of a high-fat diet on body composition and metabolism. The present study reveals a critical role for the oligosaccharide 3'-SL in milk to mediate the effects of maternal exercise on offspring's health. 3'-SL supplementation is a potential therapeutic approach to combat the development of obesity, type 2 diabetes and cardiovascular disease.
Psoriasis and atopic dermatitis are two inflammatory skin diseases with a high prevalence and a significant burden on the patients. Underlying molecular mechanisms include chronic inflammation and ...abnormal proliferation. However, the cell types contributing to these molecular mechanisms are much less understood. Recently, deconvolution methodologies have allowed the digital quantification of cell types in bulk tissue based on mRNA expression data from biopsies. Using these methods to study the cellular composition of the skin enables the rapid enumeration of multiple cell types, providing insight into the numerical changes of cell types associated with chronic inflammatory skin conditions. Here, we use deconvolution to enumerate the cellular composition of the skin and estimate changes related to onset, progress, and treatment of these skin diseases.
A novel signature matrix, i.e. DerM22, containing expression data from 22 reference cell types, is used, in combination with the CIBERSORT algorithm, to identify and quantify the cellular subsets within whole skin biopsy samples. We apply the approach to public microarray mRNA expression data from the skin layers and 648 samples from healthy subjects and patients with psoriasis or atopic dermatitis. The methodology is validated by comparison to experimental results from flow cytometry and immunohistochemistry studies, and the deconvolution of independent data from isolated cell types.
We derived the relative abundance of cell types from healthy, lesional, and non-lesional skin and observed a marked increase in the abundance of keratinocytes and leukocytes in the lesions of both inflammatory dermatological conditions. The relative fraction of these cells varied from healthy to diseased skin and from non-lesional to lesional skin. We show that changes in the relative abundance of skin-related cell types can be used to distinguish between mild and severe cases of psoriasis and atopic dermatitis, and trace the effect of treatment.
Our analysis demonstrates the value of this new resource in interpreting skin-derived transcriptomics data by enabling the direct quantification of cell types in a skin sample and the characterization of pathological changes in tissue composition.
Both the range of motion (ROM) technique and the tibial tubercle landmark (TTL) technique are frequently used to align the tibial component into proper rotational position during total knee ...arthroplasty (TKA). The aim of the study was to assess the intra-operative differences in tibial rotation position during computer-navigated primary TKA using either the TTL or ROM techniques. The ROM technique was hypothesized to be a repeatable method and to produce different tibial rotation positions compared to the TTL technique.
A prospective, observational study was performed to evaluate the antero-posterior axis of the cut proximal tibia using both the ROM and the TTL technique during primary TKA without postoperative clinical assessment. Computer navigation was used to measure this difference in 20 consecutive knees of 20 patients who underwent a posterior stabilized total knee arthroplasty with a fixed-bearing polyethylene insert and a patella resurfacing.
The ROM technique is a repeatable method with an interclass correlation coefficient (ICC2) of 0.84 (p < 0.001). The trial tibial baseplate was on average 4.56 degrees externally rotated compared to the tubercle landmark. This difference was statistically significant (p = 0.028). The amount of maximum intra-operative flexion and the pre-operative mechanical axis were positively correlated with the magnitude of difference between the two methods.
It is important for the orthopaedic surgeon to realise that there is a significant difference between the TTL technique and ROM technique when positioning the tibial component in a rotational position. This difference is correlated with high maximum flexion and mechanical axis deviations.
Wastewater-based epidemiology (WBE) emerged during the coronavirus disease 2019 (COVID-19) pandemic as a scalable and broadly applicable method for community-level monitoring of infectious disease ...burden. The lack of high-resolution fecal shedding data for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) limits our ability to link WBE measurements to disease burden. In this study, we present longitudinal, quantitative fecal shedding data for SARS-CoV-2 RNA, as well as for the commonly used fecal indicators pepper mild mottle virus (PMMoV) RNA and crAss-like phage (crAssphage) DNA. The shedding trajectories from 48 SARS-CoV-2-infected individuals suggest a highly individualized, dynamic course of SARS-CoV-2 RNA fecal shedding. Of the individuals that provided at least three stool samples spanning more than 14 days, 77% had one or more samples that tested positive for SARS-CoV-2 RNA. We detected PMMoV RNA in at least one sample from all individuals and in 96% (352/367) of samples overall. CrAssphage DNA was detected in at least one sample from 80% (38/48) of individuals and was detected in 48% (179/371) of all samples. The geometric mean concentrations of PMMoV and crAssphage in stool across all individuals were 8.7 × 10
and 1.4 × 10
gene copies/milligram-dry weight, respectively, and crAssphage shedding was more consistent for individuals than PMMoV shedding. These results provide us with a missing link needed to connect laboratory WBE results with mechanistic models, and this will aid in more accurate estimates of COVID-19 burden in sewersheds. Additionally, the PMMoV and crAssphage data are critical for evaluating their utility as fecal strength normalizing measures and for source-tracking applications. IMPORTANCE This research represents a critical step in the advancement of wastewater monitoring for public health. To date, mechanistic materials balance modeling of wastewater-based epidemiology has relied on SARS-CoV-2 fecal shedding estimates from small-scale clinical reports or meta-analyses of research using a wide range of analytical methodologies. Additionally, previous SARS-CoV-2 fecal shedding data have not contained sufficient methodological information for building accurate materials balance models. Like SARS-CoV-2, fecal shedding of PMMoV and crAssphage has been understudied to date. The data presented here provide externally valid and longitudinal fecal shedding data for SARS-CoV-2, PMMoV, and crAssphage which can be directly applied to WBE models and ultimately increase the utility of WBE.
For shorebirds, long distance migration is an energy-demanding activity, and lipids (largely comprised of fatty acids) with their high energy density are an ideal fuel. Diatoms in intertidal biofilms ...provide a rich source of fatty acids for fuel and for critical physiological functions. We compared the composition of intertidal biofilm on mudflats at Roberts Bank, a major stopover site for shorebirds in the Fraser River estuary, between two seasons: spring, during the northward breeding migration of Western Sandpipers (Calidris mauri), and winter, when no migrating shorebirds are present. Mass fractions of fatty acids in biofilm (μg fatty acids/g sample in the upper 2 mm of biofilm-containing sediment) in April were 3–7 × higher than in winter (January and February). This difference included total saturated, monounsaturated, polyunsaturated, omega-3 (n-3), and omega-6 (n-6) fatty acids, as well as individual fatty acids such as palmitoleic acid (16:1n-7), eicosapentaenoic acid (EPA; 20:5n-3), and docosahexaenoic acid (DHA; 22:6n-3). In addition, organic content was ∼25% higher in spring compared to winter. The microphytobenthos in spring biofilm was dominated by marine-influenced diatoms (primarily from the genera Nitzschia and Navicula) which made up >50% (μg/ml) of total biofilm biomass. Higher fatty acid and organic content in biofilm during spring provide shorebirds with both energy and physiologically important fatty acids to support their migration. These findings are consistent with the ‘green wave’ hypothesis, whereby bird migration broadly coincides temporally with the availability of energy and essential nutrients. The role of diatoms as purveyors of important fatty acids to shorebirds underscores the need for new conservation policies that protect the abundance of organic and fatty acid content of intertidal biofilm at estuarine stopover sites.
Emerging evidence has shown the potential risks of arterial hyperoxia, but the lack of a clinical definition and methodologic limitations hamper the interpretation and clinical relevance of previous ...studies. Our purpose was to evaluate previously used and newly constructed metrics of arterial hyperoxia and systematically assess their association with clinical outcomes in different subgroups in the ICU.
Observational cohort study.
Three large tertiary care ICUs in the Netherlands.
A total of 14,441 eligible ICU patients.
None.
In total, 295,079 arterial blood gas analyses, including the PaO2, between July 2011 and July 2014 were extracted from the patient data management system database. Data from all admissions with more than one PaO2 measurement were supplemented with anonymous demographic and admission and discharge data from the Dutch National Intensive Care Evaluation registry. Mild hyperoxia was defined as PaO2 between 120 and 200 mm Hg; severe hyperoxia as PaO2 greater than 200 mm Hg. Characteristics of existing and newly constructed metrics for arterial hyperoxia were examined, and the associations with hospital mortality (primary outcome), ICU mortality, and ventilator-free days and alive at day 28 were retrospectively analyzed using regression models in different subgroups of patients. Severe hyperoxia was associated with higher mortality rates and fewer ventilator-free days in comparison to both mild hyperoxia and normoxia for all metrics except for the worst PaO2. Adjusted effect estimates for conditional mortality were larger for severe hyperoxia than for mild hyperoxia. This association was found both within and beyond the first 24 hours of admission and was consistent for large subgroups. The largest point estimates were found for the exposure identified by the average PaO2, closely followed by the median PaO2, and these estimates differed substantially between subsets. Time spent in hyperoxia showed a linear and positive relationship with hospital mortality.
Our results suggest that we should limit the PaO2 levels of critically ill patients within a safe range, as we do with other physiologic variables. Analytical metrics of arterial hyperoxia should be judiciously considered when interpreting and comparing study results and future studies are needed to validate our findings in a randomized fashion design.
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