Effect of chitinase- 3- like protein 1 on glucose metabolism: In vitro skeletal muscle and human genetic association study

We investigated the effect of chitinase- 3- like protein 1 (CHI3L1) on glucose metabolism and its underlying mechanisms in skeletal muscle cells, and evaluated whether the observed effects are relevant in humans. CHI3L1 was associated with increased glucose uptake in skeletal muscles in an AMP- activated protein kinase (AMPK)- dependent manner, and with increased intracellular calcium levels via PAR2. The improvement in glucose metabolism observed in an intraperitoneal glucose tolerance test on male C57BL/6J mice supported this association. Inhibition of the CaMKK was associated with suppression of CHI3L1- mediated glucose uptake. Additionally, CHI3L1 was found to influence glucose uptake through the PI3K/AKT pathway. Results suggested that CHI3L1 stimulated the phosphorylation of AS160 and p38 MAPK downstream of AMPK and AKT, and the resultant GLUT4 translocation. In primary myoblast cells, stimulation of AMPK and AKT was observed in response to CHI3L1, underscoring the biological relevance of CHI3L1. CHI3L1 levels were elevated in cells under conditions that mimic exercise in vitro and in exercised mice in vivo, indicating that CHI3L1 is secreted during muscle contraction. Finally, similar associations between CHI3L1 and metabolic parameters were observed in humans alongside genotype associations between CHI3L1 and diabetes at the population level. CHI3L1 may be a potential therapeutic target for the treatment of diabetes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162777/2/fsb220907.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162777/1/fsb220907_am.pd

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Sex specific effect of ATPase inhibitory factor 1 on body weight: studies in high fat diet induced obese mice and genetic association studies in humans

Background: Based on the metabolic effect of exogenous ATPase inhibitory factor 1 (IF1) on glucose metabolism, we tested whether IF1 treatment is effective in ameliorating weight gain and whether its effects are sex specific. Methods: HFD-fed C57BL/6 mice were treated with IF1 (5 mg/kg body weight, injected intraperitoneally). The underlying mechanisms of effect of IF1 on body weight were investigated in vitro and in vivo. Associations between genotypes of IF1 and obesity and relevant phenotype were further tested at the population level. Results: Chronic treatment with IF1 significantly decreased body weight gain by regulating food intake of HFD-fed male mice. IF1 activated the AKT/mTORC pathway and modulated the expression of appetite genes in the hypothalamus of HFD-fed male mice and its effect was confirmed in hypothalamic cell lines as well as hypothalamic primary cells. This required the interaction of IF1 with β-F1-ATPase on the plasma membrane of hypothalamic cells, which led to an increase in extracellular ATP production. In addition, IF1 treatment showed sympathetic nerve activation as measured by serum norepinephrine levels and UCP-1 expression in the subcutaneous fat of HFD-fed male mice. Notably, administration of recombinant IF1 to HFD-fed ovariectomized female mice showed remarkable reductions in food intake as well as body weight, which was not observed in wild-type 5-week female mice. Lastly, sex-specific genotype associations of IF1 with obesity prevalence and metabolic traits were demonstrated at the population level in humans. IF1 genetic variant (rs3767303) was significantly associated with lower prevalence of obesity and lower levels of body mass index, waist circumference, hemoglobin A1c, and glucose response area only in male participants. Conclusion: IF1 is involved in weight regulation by controlling food intake and potentially sympathetic nerve activation in a sex-specific manner. © 2020 Elsevier Inc.1

Biglycan reduces body weight by regulating food intake in mice and improves glucose metabolism through AMPK/AKT dual pathways in skeletal muscle

While biglycan (BGN) is suggested to direct diverse signaling cascades, the effects of soluble BGN as a ligand on metabolic traits have not been studied. Herein, we tested the effects of BGN on obesity in high- fat diet (HFD)- induced obese animals and glucose metabolism, with the underlying mechanism responsible for observed effects in vitro. Our results showed that BGN administration (1 mg/kg body weight, intraperitoneally) significantly prevented HFD- induced obesity, and this was mainly attributed to reduced food intake. Also, intracerebroventricular injection of BGN reduced food intake and body weight. The underlying mechanism includes modulation of neuropeptides gene expression involved in appetite in the hypothalamus in vitro and in vivo. In addition, BGN regulates glucose metabolism as shown by improved glucose tolerance in mice as well as AMPK/AKT dual pathway- driven enhanced glucose uptake and GLUT4 translocation in L6 myoblast cells. In conclusion, our results suggest BGN as a potential therapeutic target to treat risk factors for metabolic diseases.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168488/1/fsb221794_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168488/2/fsb221794.pd

ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways

ATPase inhibitory factor 1 (IF1) is an ATP synthase–interacting protein that suppresses the hydrolysis activity of ATP synthase. In this study, we observed that the expression of IF1 was up-regulated in response to electrical pulse stimulation of skeletalmuscle cells and in exercized mice and healthy men. IF1 stimulates glucose uptake viaAMPKin skeletalmuscle cells and primary culturedmyoblasts.Reactive oxygen species and Rac family small GTPase 1 (Rac1) function in the upstream and downstream of AMPK, respectively, in IF1-mediated glucose uptake. In diabetic animal models, the administration of recombinant IF1 improved glucose tolerance and down-regulated blood glucose level. In addition, IF1 inhibitsATPhydrolysis byb-F1-ATPase inplasmamembrane, thereby increasing extracellular ATP and activating the protein kinase B (Akt) pathway, ultimately leading to glucose uptake. Thus, we suggest that IF1 is a novel myokine and propose amechanismby which AMPK and Akt contribute independently to IF1-mediated improvement of glucose tolerance impairment. These results demonstrate the importance of IF1 as a potential antidiabetic agent

The Current Status and Future Prospects of KAGRA, the Large-Scale Cryogenic Gravitational Wave Telescope Built in the Kamioka Underground

International audienceKAGRA is a gravitational-wave (GW) detector constructed in Japan with two unique key features: It was constructed underground, and the test-mass mirrors are cooled to cryogenic temperatures. These features are not included in other kilometer-scale detectors but will be adopted in future detectors such as the Einstein Telescope. KAGRA performed its first joint observation run with GEO600 in 2020. In this observation, the sensitivity of KAGRA to GWs was inferior to that of other kilometer-scale detectors such as LIGO and Virgo. However, further upgrades to the detector are ongoing to reach the sensitivity for detecting GWs in the next observation run, which is scheduled for 2022. In this article, the current situation, sensitivity, and future perspectives are reviewed.</jats:p