scholarly journals Elevated plasma levels of the appetite-stimulator ACBP/DBI in fasting and obese subjects

Cell Stress ◽  
2021 ◽  
Vol 5 (7) ◽  
pp. 89-98
Author(s):  
Sijing Li ◽  
Adrien Joseph ◽  
Isabelle Martins ◽  
Guido Kroemer
Keyword(s):  
Weight Control ◽  
Bioinformatics Analysis ◽  
Tissue Type ◽  
Eukaryotic Cells ◽  
Obese Mice ◽  
Elevated Plasma ◽  
Protein Levels ◽  
Obese Subjects ◽  
Acyl Coenzyme A ◽  
Post Transcriptional Regulation

Eukaryotic cells release the phylogenetically ancient protein acyl coenzyme A binding protein (ACBP, which in humans is encoded by the gene DBI, diazepam binding inhibitor) upon nutrient deprivation. Accordingly, mice that are starved for one to two days and humans that undergo voluntary fasting for one to three weeks manifest an increase in the plasma concentration of ACBP/DBI. Paradoxically, ACBP/DBI levels also increase in obese mice and humans. Since ACBP/DBI stimulates appetite, this latter finding may explain why obesity constitutes a self-perpetuating state. Here, we present a theoretical framework to embed these findings in the mechanisms of weight control, as well as a bioinformatics analysis showing that, irrespective of the human cell or tissue type, one single isoform of ACBP/DBI (ACBP1) is preponderant (~90% of all DBI transcripts, with the sole exception of the testis, where it is ~70%). Based on our knowledge, we conclude that ACBP1 is subjected to a biphasic transcriptional and post-transcriptional regulation, explaining why obesity and fasting both are associated with increased circulating ACBP1 protein levels.

scholarly journals Post-transcriptional regulation across human tissues

2015 ◽  
Author(s):  
Alexander Franks ◽  
Edoardo Airoldi ◽  
Nikolai Slavov
Keyword(s):  
Transcriptional Regulation ◽  
Cell Types ◽  
Tissue Type ◽  
Mrna Levels ◽  
Human Tissues ◽  
Protein Levels ◽  
Physiological Variability ◽  
Reliable Quantification ◽  
Post Transcriptional Regulation ◽  
Different Cell Types

AbstractTranscriptional and post-transcriptional regulation shape tissue-type-specific proteomes, but their relative contributions remain contested. Estimates of the factors determining protein levels in human tissues do not distinguish between (i) the factors determining the variability between the abundances of different proteins, i.e., mean-level-variability and, (ii) the factors determining the physiological variability of the same protein across different tissue types, i.e., across-tissues variability. We sought to estimate the contribution of transcript levels to these two orthogonal sources of variability, and found that scaled mRNA levels can account for most of the mean-level-variability but not necessarily for across-tissues variability. The reliable quantification of the latter estimate is limited by substantial measurement noise. However, protein-to-mRNA ratios exhibit substantial across-tissues variability that is functionally concerted and reproducible across different datasets, suggesting extensive post-transcriptional regulation. These results caution against estimating protein fold-changes from mRNA fold-changes between different cell-types, and highlight the contribution of post-transcriptional regulation to shaping tissue-type-specific proteomes.

Detection of coronary disease patients at high risk for recurrent myocardial infarction by elevated plasma inactive creatine kinase B protein levels

1981 ◽  
Vol 101 (5) ◽  
pp. 561-569 ◽  
Author(s):  
Michael H. Burnam ◽  
Marisa A. Crouch ◽  
Christopher Y.C. Chew ◽  
Winifred Carnegie ◽  
Harvey Hecht ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Creatine Kinase ◽  
High Risk ◽  
Coronary Disease ◽  
Elevated Plasma ◽  
Protein Levels ◽  
Recurrent Myocardial Infarction ◽  
Creatine Kinase B

Abstract 203: Role of Glucagon Receptor Signalling in PCSK9 Regulation

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Stefano Spolitu ◽  
Lale Ozcan
Keyword(s):  
Lipid Metabolism ◽  
Blood Glucose ◽  
Ldl Cholesterol ◽  
Cholesterol Metabolism ◽  
Ldl Receptor ◽  
Receptor Protein ◽  
Obese Mice ◽  
Glucagon Receptor ◽  
Protein Levels ◽  
New Findings

Excessive glucagon receptor action in hepatocytes is a major contributing factor to type 2 diabetes (T2D). Accordingly, there has been great interest in developing glucagon receptor antagonists (GRAs) as a treatment for T2D. Although phase 2 clinical trials have shown that GRAs effectively lower blood glucose in T2D subjects, they increase plasma low density lipoprotein (LDL) cholesterol levels, which has presented a significant block to their development. In this context, recent studies have suggested that cholesterol and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels can be regulated by fasting and perhaps glucagon, but in-depth mechanistic insight is lacking. In order to test the functional importance of hepatic glucagon action on lipid metabolism, we silenced glucagon receptor (GcgR) in obese mice using AAV8-H1-shGcgr to silence the receptor in hepatocytes. Consistent with previous reports, this treatment effectively lowered blood glucose in obese mice without a change in body weight. Moreover, GcgR silencing, like GRAs in humans, significantly increased plasma LDL cholesterol. In search for the mechanism, we found that inhibition of GcgR significantly lowered hepatic LDL-receptor protein levels and increased both hepatic PCSK9 and circulating PCSK9. To determine causation, we treated GcgR-silenced mice with a neutralizing monoclonal antibody against PCSK9 and found that this intervention restored hepatic LDL-receptor protein levels and prevented the increase in LDL cholesterol. Further mechanistic work revealed that GcgR silencing in hepatocytes did not increase Pcsk9 mRNA. Rather, blocking GcgR increased the half-life of PCSK9 protein by suppressing signalling through exchange protein activated by cAMP 1 (Epac1). In particular, the ability of GcgR silencing to increase PCSK9 and suppress LDL receptor protein levels was mimicked by hepatocytes lacking Epac1. Thus, GcgR signalling through Epac1 appears to have critical effects on processes that regulate cholesterol metabolism through PCSK9. These new findings have important implications for the lipid metabolism effects of hepatic glucagon signalling in both normal physiology and metabolic disease, and for the development of safer GRA-like drugs to treat T2D.

MiR-664-2 impacts pubertal development in a precocious-puberty rat model through targeting the NMDA receptor-1†

2019 ◽  
Vol 100 (6) ◽  
pp. 1536-1548 ◽  
Author(s):  
Minda Ju ◽  
Liu Yang ◽  
Jing Zhu ◽  
Zhejun Chen ◽  
Mizhen Zhang ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Bioinformatics Analysis ◽  
Pubertal Development ◽  
Follicle Stimulating Hormone ◽  
Gonadotropin Releasing Hormone ◽  
Untranslated Regions ◽  
Vaginal Opening ◽  
Protein Levels ◽  
Pulsatile Gnrh ◽  
Puberty Onset

Abstract Precocious puberty (PP) commonly results from premature activation of the hypothalamic–pituitary–gonadal axis (HPGA). Gonadotropin-releasing hormone (GnRH) is the initial trigger for HPGA activation and plays an important role in puberty onset. N-methyl-D-aspartate (NMDA) can promote pulsatile GnRH secretion and accelerates puberty onset. However, the mechanism of N-methyl-D-aspartate receptors (NMDARs) in PP pathogenesis remains obscure. We found that serum GnRH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen (E2) levels, hypothalamic NMDAR1, and GnRH mRNA expression peaked at the vaginal opening (VO) day. Next, the hypothalamic NMDAR1 mRNA and protein levels in rats treated with danazol, a chemical commonly effecting on the reproductive system, were significantly increased at the VO day (postnatal day 24) compared to controls, accompanied by enhanced serum GnRH, LH, FSH, and E2 levels. Further, microRNA-664-2 (miR-664-2) was selected after bioinformatics analysis and approved in primary hypothalamic neurons, which binds to the 3′-untranslated regions of NMDAR1. Consistently, the miR-664-2 expression in hypothalamus of the Danazol group was decreased compared to Vehicle. Our results suggested that attenuated miR-664-2 might participate in PP pathogenesis through enhancing the NMDAR1 signaling.

scholarly journals Plasminogen Activator Inhibitor-1 Induction after Experimental Intracerebral Hemorrhage

2002 ◽  
Vol 22 (1) ◽  
pp. 55-61 ◽  
Author(s):  
Ya Hua ◽  
Guohua Xi ◽  
Richard F. Keep ◽  
Jimin Wu ◽  
Yajun Jiang ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Plasminogen Activator ◽  
Serine Proteases ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tissue Type Plasminogen Activator ◽  
Protein Levels ◽  
Type Plasminogen Activator ◽  
Activator Inhibitor

Serine proteases, such as thrombin and tissue-type plasminogen activator, play an important role in brain injury after intracerebral hemorrhage and other neurologic disorders. Plasminogen activator inhibitor-1 is one of the serine protease inhibitors, or serpins. The balance between serine proteases and serpins may affect the outcome of intracerebral hemorrhage. The purpose of this study was to determine whether plasminogen activator inhibitor-1 and tissue-type plasminogen activator are upregulated after intracerebral hemorrhage and the role that thrombin plays in that induction. Plasminogen activator inhibitor-1 protein levels were upregulated after intracerebral hemorrhage. Brain plasminogen activator inhibitor-1 content also increased after thrombin infusion in a dose-dependent manner. Hirudin, a specific thrombin inhibitor, blocked the upregulation of plasminogen activator inhibitor-1 after intracerebral hemorrhage. Time courses showed that plasminogen activator inhibitor-1 levels around the hematoma peaked at the first day. Plasminogen activator inhibitor-1–positive cells were detected in the perihematomal area and the ipsilateral basal ganglia after thrombin infusion, but not in the contralateral hemisphere. Plasminogen activator inhibitor-1 messenger RNA levels were increased at 24 hours after intracerebral hemorrhage and after thrombin infusion. However, tissue-type plasminogen activator protein levels were the same in the control, whole-blood, and thrombin-infusion groups. In conclusion, intracerebral hemorrhage and thrombin infusion stimulate plasminogen activator inhibitor-1 but not tissue-type plasminogen activator production in the brain. The upregulation of plasminogen activator inhibitor-1 may be neuroprotective by limiting thrombin or other serine protease-induced toxicity.

Electroacupuncture and Exercise in Body Weight Reduction and their Application in Rehabilitating Patients with Knee Osteoarthritis

1995 ◽  
Vol 23 (01) ◽  
pp. 15-25 ◽  
Author(s):  
Tarek S. Shafshak
Keyword(s):  
Knee Osteoarthritis ◽  
Weight Reduction ◽  
Weight Control ◽  
Exercise Program ◽  
Appetite Control ◽  
Body Weight Reduction ◽  
Low Calorie Diet ◽  
Diet And Exercise ◽  
Calorie Diet ◽  
Obese Subjects

The efficacy of ear electroacupuncture on appetite and weight control was investigated in 3 separate studies. Part I: The Stomach, Hunger, or placebo ear points were stimulated in three different groups. Stimulating the Stomach, or Hunger, points was significantly more effective in appetite control than stimulating the placebo points. Part II: Stimulation of 3 pairs of ear points (Stomach, Hunger, and Shen Men) was performed on 61 obese subjects for 8 weeks. Only 43 subjects engaged, in addition, in an exercise program. 79% of the subjects succeeded to follow a low calorie diet for 8 weeks with subsequent weight reduction. Active exercises significantly increased weight loss. Part III: 19 obese patients with knee osteoarthritis participated in electroacupuncture, diet, and exercise program and 89% of them lost 5-10 kg in 8 weeks.

Pax5 Activates Oncogenic Transcription Factors of the Ets Family by Repressing the mir-15a/16-1 microRNA Cluster.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 346-346
Author(s):  
Elaine Y. Chung ◽  
Diana Cozma ◽  
Duonan Yu ◽  
Michael Dews ◽  
Erik A. Wentzel ◽  
...  
Keyword(s):  
Transcription Factors ◽  
B Cell ◽  
Western Blotting ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Mrna Levels ◽  
Down Regulation ◽  
Protein Levels ◽  
Ets Family ◽  
Post Transcriptional Regulation

Abstract We have recently demonstrated that Pax5 promotes B-lymphomagenesis by upregulating key components of B-cell receptor signaling [Cozma et al, J Clin Inv, 117 (8), 2007]. Gene regulation by Pax5 often involves complex formation with other oncogenic transcription factors of the Ets family, namely Myb and Ets1. We determined that expression of these proteins themselves depends on the presence of Pax5, as seen in human diffuse large B-cell lymphomas with Pax5 knockdown and murine lymphomas with epigenetic silencing of Pax5 [Yu et al, Blood, 101:1950–1955, 2003; Johnson et al, Nat Immunol, 5:853–861, 2004]. Upon reconstitution with the Pax5 gene, Myb and Ets1 levels increase sharply. This occurs with little increase in steady-state mRNA levels, suggesting post-transcriptional regulation, possibly by microRNAs. To test this hypothesis, we compared miRNA profiles of Pax5-deficieint and sufficient cells and discovered that several miRNAs are indeed repressed by Pax5. Among them is the miR-15a/16-1 cluster whose predicted targets include both Myb and Ets1. Consistent with this prediction, forced expression of miR-15a/16 brings down Myb and Ets1 protein levels. This is accompanied by impaired Pax5 function and overall suppression of B-lymphomagenesis. Thus, Ets family members (along with previously identified bcl-2) are key targets of the miR-15a/16 locus, a tumor suppressor in chronic lymphocytic leukemia. Interplay between Pax5, Myb/Ets1, and miR-15a/16-1. (A) Upregulation of Myb and Ets 1 in tumors over-expressing Pax5ER fusion, as compared to control GFP-only neoplasms. (B) Down-regulation of Myb and Ets1 in Pax5 tumors engineered to over-express the miR-15a/16-1 cluster. All panels depict Western blotting. Interplay between Pax5, Myb/Ets1, and miR-15a/16-1. (A) Upregulation of Myb and Ets 1 in tumors over-expressing Pax5ER fusion, as compared to control GFP-only neoplasms. (B) Down-regulation of Myb and Ets1 in Pax5 tumors engineered to over-express the miR-15a/16-1 cluster. All panels depict Western blotting.

scholarly journals In vivo activation of ROCK1 by insulin is impaired in skeletal muscle of humans with type 2 diabetes

2011 ◽  
Vol 300 (3) ◽  
pp. E536-E542 ◽  
Author(s):  
Kwang-Hoon Chun ◽  
Kang-Duk Choi ◽  
Dae-Ho Lee ◽  
YoonShin Jung ◽  
Robert R. Henry ◽  
...  
Keyword(s):  
Vastus Lateralis ◽  
Kinase Domain ◽  
Glucose Disposal ◽  
Vastus Lateralis Muscle ◽  
Protein Levels ◽  
Resistance To Insulin ◽  
Obese Subjects ◽  
Type 2 Diabetic

To determine whether serine/threonine ROCK1 is activated by insulin in vivo in humans and whether impaired activation of ROCK1 could play a role in the pathogenesis of insulin resistance, we measured the activity of ROCK1 and the protein content of the Rho family in vastus lateralis muscle of lean, obese nondiabetic, and obese type 2 diabetic subjects. Biopsies were taken after an overnight fast and after a 3-h hyperinsulinemic euglycemic clamp. Insulin-stimulated GDR was reduced 38% in obese nondiabetic subjects compared with lean, 62% in obese diabetic subjects compared with lean, and 39% in obese diabetic compared with obese nondiabetic subjects (all comparisons P < 0.001). Insulin-stimulated IRS-1 tyrosine phosphorylation is impaired 41–48% in diabetic subjects compared with lean or obese subjects. Basal activity of ROCK1 was similar in all groups. Insulin increased ROCK1 activity 2.1-fold in lean and 1.7-fold in obese nondiabetic subjects in muscle. However, ROCK1 activity did not increase in response to insulin in muscle of obese type 2 diabetic subjects without change in ROCK1 protein levels. Importantly, insulin-stimulated ROCK1 activity was positively correlated with insulin-mediated GDR in lean subjects ( P < 0.01) but not in obese or type 2 diabetic subjects. Moreover, RhoE GTPase that inhibits the catalytic activity of ROCK1 by binding to the kinase domain of the enzyme is notably increased in obese type 2 diabetic subjects, accounting for defective ROCK1 activity. Thus, these data suggest that ROCK1 may play an important role in the pathogenesis of resistance to insulin action on glucose disposal in muscle of obese type 2 diabetic subjects.

scholarly journals Differential regulation of lipid and protein metabolism in obese vs. lean subjects before and after a 72-h fast

2016 ◽  
Vol 311 (1) ◽  
pp. E224-E235 ◽  
Author(s):  
Ann Mosegaard Bak ◽  
Andreas Buch Møller ◽  
Mikkel Holm Vendelbo ◽  
Thomas Svava Nielsen ◽  
Rikke Viggers ◽  
...  
Keyword(s):  
Amino Acid ◽  
Fat Mass ◽  
Muscle Protein ◽  
Whole Body ◽  
Mrna Levels ◽  
Mass Unit ◽  
Body Protein ◽  
Protein Levels ◽  
Tracer Techniques ◽  
Obese Subjects

Increased availability of lipids may conserve muscle protein during catabolic stress. Our study was designed to define 1) intracellular mechanisms leading to increased lipolysis and 2) whether this scenario is associated with decreased amino acid and urea fluxes, and decreased muscle amino acid release in obese subjects under basal and fasting conditions. We therefore studied nine lean and nine obese subjects twice, after 12 and 72 h of fasting, using measurements of mRNA and protein expression and phosphorylation of lipolytic and protein metabolic signaling molecules in fat and muscle together with whole body and forearm tracer techniques. Obese subjects displayed increased whole body lipolysis, decreased urea production rates, and decreased forearm muscle protein breakdown per 100 ml of forearm tissue, differences that persisted after 72 h of fasting. Lipolysis per fat mass unit was reduced in obese subjects and, correspondingly, adipose tissue hormone-sensitive lipase (HSL) phosphorylation and mRNA and protein levels of the adipose triglyceride lipase (ATGL) coactivator CGI58 were decreased. Fasting resulted in higher HSL phosphorylations and lower protein levels of the ATGL inhibitor G0S2. Muscle protein expressions of mammalian target of rapamycin (mTOR) and 4EBP1 were lower in obese subjects, and MuRf1 mRNA was higher with fasting in lean but not obese subjects. Phosphorylation and signaling of mTOR decreased with fasting in both groups, whereas ULK1 protein and mRNA levels increased. In summary, obese subjects exhibit increased lipolysis due to a large fat mass with blunted prolipolytic signaling, together with decreased urea and amino acid fluxes both in the basal and 72-h fasted state; this is compatible with preservation of muscle and whole body protein.

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