scholarly journals Regulation of diurnal energy balance by mitokines

2021 ◽  
Author(s):  
Susanne Klaus ◽  
Carla Igual Gil ◽  
Mario Ost
Keyword(s):  
Energy Balance ◽  
Molecular Mechanisms ◽  
Circadian System ◽  
Fibroblast Growth Factor 21 ◽  
Mitochondrial Stress ◽  
Diurnal Patterns ◽  
Skeletal Muscle Mitochondria ◽  
Metabolic Remodeling ◽  
Feeding Rhythms ◽  
Health And Disease

AbstractThe mammalian system of energy balance regulation is intrinsically rhythmic with diurnal oscillations of behavioral and metabolic traits according to the 24 h day/night cycle, driven by cellular circadian clocks and synchronized by environmental or internal cues such as metabolites and hormones associated with feeding rhythms. Mitochondria are crucial organelles for cellular energy generation and their biology is largely under the control of the circadian system. Whether mitochondrial status might also feed-back on the circadian system, possibly via mitokines that are induced by mitochondrial stress as endocrine-acting molecules, remains poorly understood. Here, we describe our current understanding of the diurnal regulation of systemic energy balance, with focus on fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), two well-known endocrine-acting metabolic mediators. FGF21 shows a diurnal oscillation and directly affects the output of the brain master clock. Moreover, recent data demonstrated that mitochondrial stress-induced GDF15 promotes a day-time restricted anorexia and systemic metabolic remodeling as shown in UCP1-transgenic mice, where both FGF21 and GDF15 are induced as myomitokines. In this mouse model of slightly uncoupled skeletal muscle mitochondria GDF15 proved responsible for an increased metabolic flexibility and a number of beneficial metabolic adaptations. However, the molecular mechanisms underlying energy balance regulation by mitokines are just starting to emerge, and more data on diurnal patterns in mouse and man are required. This will open new perspectives into the diurnal nature of mitokines and action both in health and disease.

scholarly journals Srebp-1c/Fgf21/Pgc-1α Axis Regulated by Leptin Signaling in Adipocytes—Possible Mechanism of Caloric Restriction-Associated Metabolic Remodeling of White Adipose Tissue

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2054
Author(s):  
Masaki Kobayashi ◽  
Seira Uta ◽  
Minami Otsubo ◽  
Yusuke Deguchi ◽  
Ryoma Tagawa ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Caloric Restriction ◽  
White Adipose Tissue ◽  
Mitochondrial Biogenesis ◽  
Molecular Mechanisms ◽  
Whole Body ◽  
Fibroblast Growth Factor 21 ◽  
Leptin Signaling ◽  
Age Related ◽  
Metabolic Remodeling

Caloric restriction (CR) improves whole body metabolism, suppresses age-related pathophysiology, and extends lifespan in rodents. Metabolic remodeling, including fatty acid (FA) biosynthesis and mitochondrial biogenesis, in white adipose tissue (WAT) plays an important role in the beneficial effects of CR. We have proposed that CR-induced mitochondrial biogenesis in WAT is mediated by peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is transcriptionally regulated by sterol regulatory element-binding protein 1c (SREBP-1c), a master regulator of FA biosynthesis. We have also proposed that the CR-associated upregulation of SREBP-1 and PGC-1α might result from the attenuation of leptin signaling and the upregulation of fibroblast growth factor 21 (FGF21) in WAT. However, the detailed molecular mechanisms remain unclear. Here, we interrogate the regulatory mechanisms involving leptin signaling, SREBP-1c, FGF21, and PGC-1α using Srebp-1c knockout (KO) mice, mouse embryonic fibroblasts, and 3T3-L1 adipocytes, by altering the expression of SREBP-1c or FGF21. We show that a reduction in leptin signaling induces the expression of proteins involved in FA biosynthesis and mitochondrial biogenesis via SREBP-1c in adipocytes. The upregulation of SREBP-1c activates PGC-1α transcription via FGF21, but it is unlikely that the FGF21-associated upregulation of PGC-1α expression is a predominant contributor to mitochondrial biogenesis in adipocytes.

Astrocytes in health and disease

2007 ◽  
Vol 148 (15) ◽  
pp. 697-702 ◽  
Author(s):  
Marianna Murányi ◽  
Zsombor Lacza
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Free Radicals ◽  
Molecular Mechanisms ◽  
Neuronal Dysfunction ◽  
Supporting Cells ◽  
Neuronal Synapses ◽  
Health And Disease ◽  
Novel Targets ◽  
Therapeutic Tools

It is now known that astrocytes are not merely supporting cells but they also play an important role in neuronal funcions. Astrocytes tightly ensheat neuronal synapses and regulate the excitation of neurons by uptaking neurotransmitters; reglulate the cerebral blood flow, cerebral fluid volume and extracellular concentrations of ions. They also supply fuel in the form of lactate and provide free radical scavangers such as glutathione for active neurons. These facts indicate that impaired function of astrocytes may lead to neuronal dysfunction. After brain injury (stroke, trauma or tumors) astrocytes are swollen and release active molecules such as glutamate or free radicals resulting in neuronal dysfunction. Thus, investigation of the molecular mechanisms of astrocyte function may reveal novel targets for the development of therapeutic tools in neuronal diseases.

scholarly journals DNA Methylation Profiles of Tph1A and BDNF in Gut and Brain of L. Rhamnosus-Treated Zebrafish

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 142
Author(s):  
Mariella Cuomo ◽  
Luca Borrelli ◽  
Rosa Della Monica ◽  
Lorena Coretti ◽  
Giulia De Riso ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
The Past ◽  
Targeted Analysis ◽  
Lack Of Information ◽  
High Resolution Power ◽  
Resolution Level ◽  
Health And Disease ◽  
High Doses ◽  
The Brain

The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

scholarly journals Circadian Blood Pressure Rhythm in Cardiovascular and Renal Health and Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 868
Author(s):  
Jiayang Zhang ◽  
Ruoyu Sun ◽  
Tingting Jiang ◽  
Guangrui Yang ◽  
Lihong Chen
Keyword(s):  
Blood Pressure ◽  
Circadian Rhythm ◽  
Molecular Mechanisms ◽  
Current Understanding ◽  
Renal Outcomes ◽  
Circadian Blood Pressure ◽  
Health And Disease ◽  
The Relationship

Blood pressure (BP) follows a circadian rhythm, it increases on waking in the morning and decreases during sleeping at night. Disruption of the circadian BP rhythm has been reported to be associated with worsened cardiovascular and renal outcomes, however the underlying molecular mechanisms are still not clear. In this review, we briefly summarized the current understanding of the circadian BP regulation and provided therapeutic overview of the relationship between circadian BP rhythm and cardiovascular and renal health and disease.

scholarly journals Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1564
Author(s):  
Viraj P. Ichhaporia ◽  
Linda M. Hendershot
Keyword(s):  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Dependent Manner ◽  
Nucleotide Exchange ◽  
Multisystem Disorder ◽  
Nucleotide Exchange Factors ◽  
Precise Understanding ◽  
Health And Disease ◽  
Client Proteins ◽  
Er Homeostasis

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.

scholarly journals The Glycine Lipids ofBacteroides thetaiotaomicronAre Important for Fitness during GrowthIn VivoandIn Vitro

2018 ◽  
Vol 85 (10) ◽  
Author(s):  
Alli Lynch ◽  
Seshu R. Tammireddy ◽  
Mary K. Doherty ◽  
Phillip D. Whitfield ◽  
David J. Clarke
Keyword(s):  
Amino Acid ◽  
Gut Microbiome ◽  
Molecular Mechanisms ◽  
Cellular Membrane ◽  
Bacteroides Thetaiotaomicron ◽  
Human Gut ◽  
Acyltransferase Activity ◽  
Content Type ◽  
Health And Disease ◽  
And Function

ABSTRACTAcylated amino acids function as important components of the cellular membrane in some bacteria. Biosynthesis is initiated by theN-acylation of the amino acid, and this is followed by subsequentO-acylation of the acylated molecule, resulting in the production of the mature diacylated amino acid lipid. In this study, we use both genetics and liquid chromatography-mass spectrometry (LC-MS) to characterize the biosynthesis and function of a diacylated glycine lipid (GL) species produced inBacteroides thetaiotaomicron. We, and others, have previously reported the identification of a gene, namedglsBin this study, that encodes anN-acyltransferase activity responsible for the production of a monoacylated glycine calledN-acyl-3-hydroxy-palmitoyl glycine (or commendamide). In all of theBacteroidalesgenomes sequenced so far, theglsBgene is located immediately downstream from a gene, namedglsA, that is also predicted to encode a protein with acyltransferase activity. We use LC-MS to show that the coexpression ofglsBandglsAresults in the production of GL inEscherichia coli. We constructed a deletion mutant of theglsBgene inB. thetaiotaomicron, and we confirm thatglsBis required for the production of GL inB. thetaiotaomicron. Moreover, we show thatglsBis important for the ability ofB. thetaiotaomicronto adapt to stress and colonize the mammalian gut. Therefore, this report describes the genetic requirements for the biosynthesis of GL, a diacylated amino acid species that contributes to fitness in the human gut bacteriumB. thetaiotaomicron.IMPORTANCEThe gut microbiome has an important role in both health and disease of the host. The mammalian gut microbiome is often dominated by bacteria from theBacteroidales, an order that includesBacteroidesandPrevotella. In this study, we have identified an acylated amino acid, called glycine lipid, produced byBacteroides thetaiotaomicron, a beneficial bacterium originally isolated from the human gut. In addition to identifying the genes required for the production of glycine lipids, we show that glycine lipids have an important role during the adaptation ofB. thetaiotaomicronto a number of environmental stresses, including exposure to either bile or air. We also show that glycine lipids are important for the normal colonization of the murine gut byB. thetaiotaomicron. This work identifies glycine lipids as an important fitness determinant inB. thetaiotaomicronand therefore increases our understanding of the molecular mechanisms underpinning colonization of the mammalian gut by beneficial bacteria.

scholarly journals Vascular Dysfunction in Preeclampsia

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3055
Author(s):  
Megan A. Opichka ◽  
Matthew W. Rappelt ◽  
David D. Gutterman ◽  
Justin L. Grobe ◽  
Jennifer J. McIntosh
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Treatment Options ◽  
Cardiovascular Disorder ◽  
Endothelial Damage ◽  
Spiral Artery ◽  
Mitochondrial Stress ◽  
Inflammatory State ◽  
Life Threatening

Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.

scholarly journals Changes in selected biochemical parameters during subclinical and clinical ketosis in dairy cows

2019 ◽  
Vol 74 (10) ◽  
pp. 6133-2019
Author(s):  
YUANYUAN CHEN ◽  
ZHIHAO DONG ◽  
RUIRUI LI ◽  
CHUANG XU
Keyword(s):  
Lipid Metabolism ◽  
Energy Balance ◽  
Dairy Cows ◽  
Perinatal Period ◽  
Oxidative Capacity ◽  
Negative Energy ◽  
Negative Energy Balance ◽  
Fibroblast Growth Factor 21 ◽  
Acid Oxidation ◽  
Subclinical Ketosis

Negative energy balance (NEB) is a common pathological cause of ketosis. As the major organs of lipid metabolism, the liver and fat tissue take part in regulating lipid oxidative capacity and energy demands, which is also a key metabolic pathway that regulates NEB development during the perinatal period. Fibroblast Growth Factor 21 (FGF21) is a novel metabolic regulator involved in the control of fatty acid oxidation and lipid metabolism during a prolonged negative energy balance. Our study determined a correlation between serum FGF21 and β-hydroxybutyric acid (BHBA) levels in dairy cows with ketosis. We used sixty cows with low milk yield, abnormal glucose metabolism, and ketosis. Serum FGF21 and BHBA levels were measured using commercial kits. Serum FGF21 increased with increasing BHBA levels up to 1.6 mmol/L. At BHBA levels > 1.6 mmol/L, FGF21 decreased. Serum FGF21 levels were positively associated with BHBA levels, particularly in dairy cows with subclinical ketosis (r = 0.647, P < 0.01). At BHBA levels between 1.2 mmol/L and 1.6 mmol/L, FGF21 was more closely correlated with BHBA than with other metabolic parameters. At BHBA levels > 1.6 mmol/L, the association between FGF21 and BHBA was not significant. In conclusion, our results show that FGF21 was closely related with SK in cows. FGF21 may be a promising regulator in the prevention of subclinical ketosis.

scholarly journals Translational Control of Secretory Proteins in Health and Disease

2020 ◽  
Vol 21 (7) ◽  
pp. 2538 ◽  
Author(s):  
Andrey L. Karamyshev ◽  
Elena B. Tikhonova ◽  
Zemfira N. Karamysheva
Keyword(s):  
Translational Control ◽  
Molecular Mechanisms ◽  
Signal Recognition Particle ◽  
Secretory Protein ◽  
Human Diseases ◽  
Secretory Proteins ◽  
Signal Peptides ◽  
Protein Biogenesis ◽  
Health And Disease

Secretory proteins are synthesized in a form of precursors with additional sequences at their N-terminal ends called signal peptides. The signal peptides are recognized co-translationally by signal recognition particle (SRP). This interaction leads to targeting to the endoplasmic reticulum (ER) membrane and translocation of the nascent chains into the ER lumen. It was demonstrated recently that in addition to a targeting function, SRP has a novel role in protection of secretory protein mRNAs from degradation. It was also found that the quality of secretory proteins is controlled by the recently discovered Regulation of Aberrant Protein Production (RAPP) pathway. RAPP monitors interactions of polypeptide nascent chains during their synthesis on the ribosomes and specifically degrades their mRNAs if these interactions are abolished due to mutations in the nascent chains or defects in the targeting factor. It was demonstrated that pathological RAPP activation is one of the molecular mechanisms of human diseases associated with defects in the secretory proteins. In this review, we discuss recent progress in understanding of translational control of secretory protein biogenesis on the ribosome and pathological consequences of its dysregulation in human diseases.

scholarly journals Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1869 ◽  
Author(s):  
Can Huang ◽  
Wenjun Lan ◽  
Nicolas Fraunhoffer ◽  
Analía Meilerman ◽  
Juan Iovanna ◽  
...  
Keyword(s):  
Cell Death ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Proteasome Inhibitors ◽  
Ductal Adenocarcinoma ◽  
Mitochondrial Stress ◽  
Anticancer Mechanism ◽  
Chemotherapeutic Treatment ◽  
Approved Drugs ◽  
Protein Response

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with almost no curative chemotherapeutic treatment. Besides the development of new compounds, repurposing of approved drugs to treat cancer, alone or in combination, has become an attractive strategy, showing many therapeutic and economic advantages. However, it is necessary to improve our knowledge about the mechanism of cell death elicited by approved drugs itself, but also to rationally develop more powerful multidrug treatments. In this work, we focus our attention on determining the mechanism promoting cell death following trifluoperazine (TFP) treatment, which is an antipsychotic drug with strong anticancer activity in PDAC. We demonstrate that TFP induces cell death by apoptosis and necroptosis, which can be partially inhibited by Z-VAD-FMK as well as necrostatin-1, respectively. This cell death promotion is triggered by a poor ATP content, observed in TFP-treated cells as a consequence of a dramatic decrease in OXPHOS metabolism due to mitochondrial stress. Remarkably, mitochondrial homeostasis was seriously affected, and a loss of mitochondrial membrane potential and ROS overproduction was observed. Moreover, this mitochondrial stress was coupled with an ER stress and the activation of the endoplasmic-reticulum-associated protein degradation (ERAD) and the unf olded protein response (UPR) pathways. We took advantage of this information and inhibited this process by using the proteasome inhibitors MG-132 or bortezomib compounds in combination with TFP and found a significant improvement of the anticancer effect of the TFP on primary PDAC-derived cells. In conclusion, this study not only uncovers the molecular mechanisms that are triggered upon TFP-treatment but also its possible combination with bortezomib for the future development of therapies for pancreatic cancer.

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