Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia1,2. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism3–5. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as ‘lipokines’6–8. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin resistance. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.
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.
Hemorrhagic shock (HS) and trauma is currently the leading cause of death in young adults worldwide. Morbidity and mortality after HS and trauma is often the result of multi-organ failure such as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), conditions with few therapeutic options. Bone marrow derived mesenchymal stem cells (MSCs) are a multipotent stem cell population that has shown therapeutic promise in numerous pre-clinical and clinical models of disease. In this paper, in vitro studies with pulmonary endothelial cells (PECs) reveal that conditioned media (CM) from MSCs and MSC-PEC co-cultures inhibits PEC permeability by preserving adherens junctions (VE-cadherin and β-catenin). Leukocyte adhesion and adhesion molecule expression (VCAM-1 and ICAM-1) are inhibited in PECs treated with CM from MSC-PEC co-cultures. Further support for the modulatory effects of MSCs on pulmonary endothelial function and inflammation is demonstrated in our in vivo studies on HS in the rat. In a rat “fixed volume” model of mild HS, we show that MSCs administered IV potently inhibit systemic levels of inflammatory cytokines and chemokines in the serum of treated animals. In vivo MSCs also inhibit pulmonary endothelial permeability and lung edema with concurrent preservation of the vascular endothelial barrier proteins: VE-cadherin, Claudin-1, and Occludin-1. Leukocyte infiltrates (CD68 and MPO positive cells) are also decreased in lungs with MSC treatment. Taken together, these data suggest that MSCs, acting directly and through soluble factors, are potent stabilizers of the vascular endothelium and inflammation. These data are the first to demonstrate the therapeutic potential of MSCs in HS and have implications for the potential use of MSCs as a cellular therapy in HS-induced lung injury.
A syndecan-1 level ≥40 ng/mL identified patients with significantly worse outcomes, despite admission physiology similar to those without the condition.
Objective:Investigate and confirm the association between sympathoadrenal activation, endotheliopathy and poor outcome in trauma patients.Background:The association between sympathoadrenal activation, endotheliopathy, and poor outcome in trauma has only been demonstrated in smaller patient cohorts and animal models but needs confirmation in a large independent patient cohort.Methods:Prospective observational study of 424 trauma patients admitted to a level 1 Trauma Center. Admission plasma levels of catecholamines (adrenaline, noradrenaline) and biomarkers reflecting endothelial damage (syndecan-1, thrombomodulin, and sE-selectin) were measured and demography, injury type and severity, physiology, treatment, and mortality up till 28 days were recorded.Results:Patients had a median ISS of 17 with 72% suffering from blunt injury. Adrenaline and noradrenaline correlated with syndecan-1 (r = 0.38, P < 0.001 and r = 0.23, P < 0.001, respectively) but adrenaline was the only independent predictor of syndecan-1 by multiple linear regression adjusted for age, injury severity score, Glascow Coma Scale, systolic blood pressure, base excess, platelet count, hemoglobin, prehospital plasma, and prehospital fluids (100 pg/mL higher adrenaline predicted 2.75 ng/mL higher syndecan-1, P < 0.001). By Cox analyses adjusted for age, sex, injury severity score, Glascow Coma Scale, base excess, platelet count and hemoglobin, adrenaline, and syndecan-1 were the only independent predictors of both <24-hours, 7-day and 28-day mortality (all P < 0.05). Furthermore, noradrenaline was an independent predictor of <24-hours mortality and thrombomodulin was an independent predictor of 7-day and 28-day mortality (all P < 0.05).Conclusions:We confirmed that sympathoadrenal activation was strongly and independently associated with endothelial glycocalyx and cell damage (ie, endotheliopathy) and furthermore that sympathoadrenal activation and endotheliopathy were independent predictors of mortality in trauma patients.
SummaryExercise 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.
Severe hyperfibrinolysis after trauma is a poorly understood phenomenon associated with profound shock, serious anatomic injuries, increased transfusions, and high mortality rates. Molecular mechanisms driving hyperfibrinolysis in trauma have not been completely delineated. The authors aimed to determine the relationship between severe hyperfibrinolysis and outcomes in trauma patients and characterize the role of the plasminogen activator (PA) system in this condition. A prospective observational study was performed in 163 adult level I trauma patients admitted between April and August 2012. Blood was collected on admission, and fibrinolysis was determined by plasmin-α2 antiplasmin (PAP) levels. Tissue-derived and urokinase PA (tPA and uPA, respectively), PA inhibitor (PAI-1), fibrinogen, and antithrombin levels were also measured. Patient demographics, vital signs, laboratory values, mechanisms and severity of injuries, transfusions, and outcomes were collected at admission or from patient records. Moderate fibrinolysis was defined as PAP level 1,500 to 20,000 μg/L and severe hyperfibrinolysis as PAP level more than 20,000 μg/L. Severe hyperfibrinolysis was observed in 10% of patients and associated with increased injury severity, greater transfusions, fewer ventilator and hospital-free days, and higher mortality. Plasmin-α2 antiplasmin level was directly correlated with tPA level and inversely correlated with PAI-1 level. Patients with both elevated tPA and reduced PAI-1 were more severely injured, received more transfusions, and experienced fewer ventilator and hospital-free days. In conclusion, Severe hyperfibrinolysis is observed in a small percentage of trauma patients and is associated with severe injuries, greater transfusions, and worse outcomes. This condition is mediated, in part, by excessive upregulation of profibrinolytic tPA in the absence of concomitant increases in antifibrinolytic PAI-1.
Summary Exercise improves whole-body metabolic health through adaptations to various tissues including adipose tissue, but the effects of exercise training on the lipidome of white (WAT) and brown (BAT) adipose tissue are unknown. Here, we utilized MS/MSALL shotgun lipidomics to determine the molecular signatures of exercise-induced adaptations to subcutaneous WAT (scWAT) and BAT. Three weeks of exercise-training decreased specific molecular species of phosphatidic acid (PA), phosphatidylcholines (PC), phosphatidylethanolamines (PE), and phosphatidylserines (PS) in scWAT and increased specific molecular species of PC and PE in BAT. Exercise also decreased most triacylglycerols (TAGs) in scWAT and BAT. In summary, exercise-induced changes to the scWAT and BAT lipidome were highly specific to certain molecular lipid species, indicating that changes in tissue lipid content reflects selective remodeling in scWAT and BAT of both phospholipids and glycerol lipids in response to exercise training, thus providing a comprehensive resource for future studies of lipid metabolism pathways.
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