Adipose tissue is essential for whole-body glucose homeostasis, with a primary role in lipid storage. It has been previously observed that lactate production is also an important metabolic feature of ...adipocytes, but its relationship to adipose and whole-body glucose disposal remains unclear. Therefore, using a combination of metabolic labeling techniques, here we closely examined lactate production of cultured and primary mammalian adipocytes. Insulin treatment increased glucose uptake and conversion to lactate, with the latter responding more to insulin than did other metabolic fates of glucose. However, lactate production did not just serve as a mechanism to dispose of excess glucose, because we also observed that lactate production in adipocytes did not solely depend on glucose availability and even occurred independently of glucose metabolism. This suggests that lactate production is prioritized in adipocytes. Furthermore, knocking down lactate dehydrogenase specifically in the fat body of Drosophila flies lowered circulating lactate and improved whole-body glucose disposal. These results emphasize that lactate production is an additional metabolic role of adipose tissue beyond lipid storage and release.
Exercise engages signaling networks to control the release of circulating factors beneficial to health. However, the nature of these networks remains undefined. Using high-throughput ...phosphoproteomics, we quantify 20,249 phosphorylation sites in skeletal muscle-like myotube cells and monitor their responses to a panel of cell stressors targeting aspects of exercise signaling in vivo. Integrating these in-depth phosphoproteomes with the phosphoproteome of acute aerobic exercise in human skeletal muscle suggests that co-administration of β-adrenergic and calcium agonists would activate complementary signaling relevant to this exercise context. The phosphoproteome of cells treated with this combination reveals a surprising divergence in signaling from the individual treatments. Remarkably, only the combination treatment promotes multisite phosphorylation of SERBP1, a regulator of Serpine1 mRNA stability, a pro-fibrotic secreted protein. Secretome analysis reveals that the combined treatments decrease secretion of SERPINE1 and other deleterious factors. This study provides a framework for dissecting phosphorylation-based signaling relevant to acute exercise.
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•Global phosphoproteomes of 9 acute cell stressors integrated with human acute exercise•Comparing AMPK activators reveals potential AMPK substrates and aripiprazole mechanism•Co-administering β-adrenergic and calcium agonists causes extensive interactions•Global secretomes show potential links between exercise benefits and upstream signaling
Needham et al. measure phosphoproteomes of acute cell stressors targeting different aspects of exercise signaling. This reveals treatment actions and creates a resource of treatments that regulate phosphosites regulated in acute aerobic exercise in human skeletal muscle. Combining isoproterenol and thapsigargin causes extensive interactions within the phosphoproteome and secretome.
The failure of metabolic tissues to appropriately respond to insulin ("insulin resistance") is an early marker in the pathogenesis of type 2 diabetes. Protein phosphorylation is central to the ...adipocyte insulin response, but how adipocyte signaling networks are dysregulated upon insulin resistance is unknown. Here we employ phosphoproteomics to delineate insulin signal transduction in adipocyte cells and adipose tissue. Across a range of insults causing insulin resistance, we observe a marked rewiring of the insulin signaling network. This includes both attenuated insulin-responsive phosphorylation, and the emergence of phosphorylation uniquely insulin-regulated in insulin resistance. Identifying dysregulated phosphosites common to multiple insults reveals subnetworks containing non-canonical regulators of insulin action, such as MARK2/3, and causal drivers of insulin resistance. The presence of several bona fide GSK3 substrates among these phosphosites led us to establish a pipeline for identifying context-specific kinase substrates, revealing widespread dysregulation of GSK3 signaling. Pharmacological inhibition of GSK3 partially reverses insulin resistance in cells and tissue explants. These data highlight that insulin resistance is a multi-nodal signaling defect that includes dysregulated MARK2/3 and GSK3 activity.
Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward ...causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in
, encoding mitofusin 2. How the resulting selective form of mitochondrial dysfunction leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this,
knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation measured in isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation selectively perturbs mitochondrial morphology and activates the integrated stress response in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.
Proteins which associate with the surface of lipid droplets are intimately involved in the regulation of the droplets. Several human inherited disorders have now been linked to loss‐ and, in some ...cases, likely gain‐of‐function mutations in the genes encoding these proteins. These are summarised in this Graphical Review.
Abstract
Through the analysis of the types of tasks and flight routes faced by the warning vehicle, this paper proposes the problem of continuous static coverage of the multi-heterogeneous warning ...vehicle (referred to as WV) considering No-fly areas to be solved. By analysing things like detection area, no-fly area, WV patrol strategy form, patrol strategy planning mechanism and detection capability of WV, based on the philosophy of model stratification and time segmentation, a multi-layer multi-stage patrol strategy planning method (referred to as MLMPSPM) for determining the patrol strategies of multiple heterogeneous warning vehicles (WVs) during multi-patrol cycles considering no-fly areas is proposed, including the process of determining the planning stage index. In detail, MLMPSPM mainly introduces the patrol strategy planning method of
EF
and
ER
. Whether
EF
or
ER
includes input section, planning section, stage warning effect of planning stage, and patrol strategy objective planning, etc.
EU
planning processes is the extension of
EF
and
ER
. In the experimental results section, the relevant experimental parameters are designed in detail, the experimental results show that MLMPSPM can not only determine the patrol strategies of all WVs throughout the alert process considering time-varying no-fly areas, but also achieve a large total warning effect.
•Whether sevoflurane postconditioning could ameliorate spatial learning and memory deficit after hemorrhage shock and resuscitation injury via suppressing apoptosis induced by endoplasmic reticulum ...stress (ERS).•We used three concentrations of sevoflurane.•We assessed the spatial learning and memory ability by using Morris water maze.•This study may provide new insights into the neuroprotection of hemorrhage shock and resuscitation.
Hemorrhage shock could initiate endoplasmic reticulum stress (ERS) and then induce neuronal apoptosis. The aim of this study was to investigate whether sevoflurane postconditioning could attenuate brain injury via suppressing apoptosis induced by ERS. Seventy male rats were randomized into five groups: sham, shock, low concentration (sevo1, 1.2%), middle concentration (sevo2, 2.4%) and high concentration (sevo3, 3.6%) of sevoflurane postconditioning. Hemorrhage shock was induced by removing 40% of the total blood volume during an interval of 30 min. 1 h after the completion of bleeding, the animals were reinfused with shed blood during the ensuing 30 min. The spatial learning and memory ability of rats were measured by Morris water maze (MWM) test three days after the operation. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells in the hippocampus CA1 region were assessed after the MWM test. The expression of C/EBP-homologousprotein (CHOP) and glucose-regulated protein 78 (GRP78) in the hippocampus were measured at 24 h after reperfusion. We found that sevoflurane postconditioning with the concentrations of 2.4% and 3.6% significantly ameliorated the spatial learning and memory ability, decreased the TUNEL-positive cells, and reduced the GRP78 and CHOP expression compared with the shock group. These results suggested that sevoflurane postconditioning with the concentrations of 2.4% and 3.6% could ameliorate spatial learning and memory deficit after hemorrhage shock and resuscitation injury via suppressing apoptosis induced by ERS.
In this paper, the methods and results from Tsinghua University and Shanghai Institute of Satellite Engineering for the 11th Global Trajectory Optimization Competition (GTOC11) are presented. To deal ...with the complicated “Dyson Sphere” building problem, a three-stage procedure is conducted. First, the pre-analysis is performed to reduce search space. It is found that two-impulse maneuvers between asteroid flybys are near-optimal, the semi-major axis of the “Dyson Ring” should be better at 1.0–1.5 AU, and the larger arrival mass asteroids tend to be selected. Second, the globally optimal trajectory design problem is further divided into two sub-problems, the mothership trajectory design and the asteroid assignment to the “Dyson Ring” power stations. For the first problem, beam search is used to obtain numerous single mothership trajectories based on a pre-constructed flyby trajectory database of 3–8 asteroids. The overall trajectories and asteroids visited are obtained by selecting 10 mothership trajectories with a genetic algorithm. For the second problem, we build a database of optimal rendezvous times for all the 83,453 asteroids at different phase angles to reach power stations of different radii and phase angles, then a greedy algorithm is proposed to obtain the asteroid arrival schedule based on all the asteroids visited by motherships. Finally, local optimization of asteroid sequence and flyby epochs is conducted. The activation time adjustment in combination with indirect continuous-thrust trajectory optimization is used based on the global optimization result. In the final submission, motherships fly by 388 asteroids, and the minimum mass of twelve power stations reaches 94% of the theoretical upper bound, which is defined using the minimum-time orbital transfers with free initial and target phases.
•The winning result submitted for GTOC 11 is discussed.•Solving the flyby by the rendezvous in combination with geometric corrections.•Optimizing the flyby times in asteroid chains to solve the time-dependent problems.•An exponential form of the heuristic function is used in beam search.•A low-thrust solution database is constructed to obtain accurate flight time.
•Severe hemorrhagic shock and the following resusucitation could induces cognitive dysfunction of rats.•Sevoflurane postconditioning could improve the cognitive function impairments induced by ...hemorrhagic shock and resuscitation.•This neuroprotective effect may be partly by suppressing ER stress through IRE1α–caspase-12 pathway.
Severe hemorrhagic shock induces cognitive dysfunction by promoting cell death mediated by activating endoplasmic reticulum (ER) stress. Sevoflurane postconditioning prevents neuronal apoptosis against cerebral ischemia/reperfusion injury. It is unknown if this protective effect on hemorrhagic shock and resuscitation rats (HSR) is associated with ER stress attenuation. Male adult Sprague-Dawley rats were subjected HSR by removing 40% blood volume within 30 min, and 60 min later the animals were resuscitated with infusion of the removing blood in 30 min. Sevoflurane postconditioning was performed by inhaling sevoflurane at three different concentrations (0.5, 1.0, 1.5 MAC) at the onset of resuscitation for 30 min. Severe hypotension (mean arterial pressure 40–45 mmHg) occurred in the shock session for 60 min accompanying with significantly elevated lactate, decreased BE and pH values in arterial blood gas analysis. There were impaired spatial learning and memory following HSR indicated by persistently longer escape latency and lower correct rate, as well as less duration and crossing in the target quadrant by using Morris water maze and Y-maze tests. In the hippocampal CA1 region, there was significantly higher activity of caspase-3 induced by HSR. HSR also elevated the expression of inositol-requiring enzyme 1α (IRE1α) and caspase-12 in the hippocampus by western blot analysis. Sevoflurane postconditioning at 1.0 and 1.5 MAC significantly reversed these changes. These findings suggested that sevoflurane postconditioning could improve spatial learning and memory deficits induced by severe hemorrhagic shock and subsequent resuscitation. The suppression of endoplasmic reticulum stress provided critical contribution in neural apoptosis mediated by IRE1α-caspase-12 pathway.
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