Central Regulator Of Metabolism Research Articles

A nematode-derived, mitochondrial stress signaling-regulated peptide exhibits broad antibacterial activity.

ABSTRACTA dramatic rise of infections with antibiotic-resistant bacterial pathogens continues to challenge the healthcare field due to the lack of effective treatment regimes. As such, there is an urgent need to develop new antimicrobial agents that can combat these multidrug-resistant superbugs. Mitochondria are central regulators of metabolism and other cellular functions, including the regulation of innate immunity pathways involved in the defense against infection. The mitochondrial unfolded protein response (UPRmt) is a stress-activated pathway that mitigates mitochondrial dysfunction through the regulation of genes that promote recovery of the organelle. In the model organism Caenorhabditis elegans, the UPRmt also mediates an antibacterial defense program that combats pathogen infection, which promotes host survival. We sought to identify and characterize antimicrobial effectors that are regulated during the UPRmt. From our search, we discovered that the antimicrobial peptide CNC-4 is upregulated during this stress response. CNC-4 belongs to the caenacin family of antimicrobial peptides, which are predominantly found in nematodes and are known to have anti-fungal properties. Here, we find that CNC-4 also possesses potent antimicrobial activity against a spectrum of bacterial species and report on its characterization.

Promotion of Anti-Tuberculosis Macrophage Activity by L-Arginine in the Absence of Nitric Oxide.

Macrophages are indispensable immune cells tasked at eliminating intracellular pathogens. Mycobacterium tuberculosis (Mtb), one of the most virulent intracellular bacterial pathogens known to man, infects and resides within macrophages. While macrophages can be provoked by extracellular stimuli to inhibit and kill Mtb bacilli, these host defense mechanisms can be blocked by limiting nutritional metabolites, such as amino acids. The amino acid L-arginine has been well described to enhance immune function, especially in the context of driving macrophage nitric oxide (NO) production in mice. In this study, we aimed to establish the necessity of L-arginine on anti-Mtb macrophage function independent of NO. Utilizing an in vitro system, we identified that macrophages relied on NO for only half of their L-arginine-mediated host defenses and this L-arginine-mediated defense in the absence of NO was associated with enhanced macrophage numbers and viability. Additionally, we observed macrophage glycolysis to be driven by both L-arginine and mechanistic target of rapamycin (mTOR), and inhibition of glycolysis or mTOR reduced macrophage control of Mtb as well as macrophage number and viability in the presence of L-arginine. Our data underscore L-arginine as an essential nutrient for macrophage function, not only by fueling anti-mycobacterial NO production, but also as a central regulator of macrophage metabolism and additional host defense mechanisms.

Seasonal Regulation of Metabolism: The Effect of Wintertime Fasting and Autumnal Fattening on Key Central Regulators of Metabolism and the Metabolic Profile of the Raccoon Dog (Nyctereutes Procyonoides).

Investigations into the mechanisms regulating obesity are frantic and novel translational approaches are needed. The raccoon dog (Nyctereutes procyonoides) is a canid species representing a promising model to study metabolic regulation in a species undergoing cycles of seasonal obesity and fasting. To understand the molecular mechanisms of metabolic regulation in seasonal adaptation, we analyzed key central nervous system and peripheral signals regulating food intake and metabolism from raccoon dogs after autumnal fattening and winter fasting. Expressions of neuropeptide Y (NPY), orexin-2 receptor (OX2R), pro-opiomelanocortin (POMC) and leptin receptor (ObRb) were analyzed as examples of orexigenic and anorexigenic signals using qRT-PCR from raccoon dog hypothalamus samples. Plasma metabolic profiles were measured with 1H NMR-spectroscopy and LC-MS. Circulating hormones and cytokines were determined with canine specific antibody assays. Surprisingly, NPY and POMC were not affected by the winter fasting nor autumn fattening and the metabolic profiles showed a remarkable equilibrium, indicating conserved homeostasis. However, OX2R and ObRb expression changes suggested seasonal regulation. Circulating cytokine levels were not increased, demonstrating that the autumn fattening did not induce subacute inflammation. Thus, the raccoon dog developed seasonal regulatory mechanisms to accommodate the autumnal fattening and prolonged fasting making the species unique in coping with the extreme environmental challenges.

MTOR-Mediated Cell Death and Infection

Abstract The battle between pathogens and hosts is an ongoing phenomenon that has been studied for centuries. Although multicellular organisms have developed sophisticated immune systems to defend against pathogens, pathogens are often able to successfully infect their hosts. To enhance their chance of survival, pathogens can hijack the host's metabolism, which serves as a critical control point that can potentially impact infections. Mammalian target of rapamycin (mTOR) is the nutrient sensor and central regulator of metabolism in innate and adaptive immune cells. Rapamycin, a drug targeting the mTOR pathway, has been widely used in clinical practice for decades and is relatively safe. However, some unexpected infections occur after long-term administration of rapamycin, indicating the presence of a close relationship between mTOR signaling and the infection process. In this manuscript, we briefly review the mTOR pathway and the current clinical use of rapamycin; we also summarize the role of the mTOR pathway in immune cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, and its impact on anti-infection immunity. Finally, potential application of mTOR inhibitor in coronavirus disease 2019 clinical therapy is discussed.

Protein Phosphorylation Signaling Cascades in Autism: The Role of mTOR Pathway.

The mammalian target of rapamycin (mTOR) signaling pathway is a central regulator of cell metabolism, growth, and survival in response to hormones, growth factors, nutrients, and stress-induced signals. In this review, we analyzed the studies on the molecular abnormalities of the mTOR-associated signaling cascades in autism spectrum disorders (ASDs) and outlined the prospects for the pathogenicity-targeting pharmacotherapeutic approaches to ASDs, in particular syndromic ASDs. Based on available experimental and clinical data, we suggest that very early detection of molecular abnormalities in the ASD risk groups can be facilitated by using peripheral blood platelets. Also, identification of the time window of critical dysregulations in the described pathways in the ASD risk groups might suggest further research directions leading to more efficacious pharmacotherapeutic interventions in ASDs.

Elaborating the Physiological Role of YAP as a Glucose Metabolism Regulator:A Systematic Review.

Yes-associated protein (YAP) is one of the Hippo pathway's two effectors, a pathway associated with organ size control. Research on YAP has focused on its oncogenic potential. However, in cancer cells, aside from inducing growth, YAP was also found to regulate glucose metabolism. The present review explores YAP's control of glucose metabolism and whether these findings are translatable to physiological conditions. According to current literature, YAP induces the transcriptional activity of most genes associated with glucose metabolism from enzymes to transport proteins. In glycolysis and gluconeogenesis, YAP upregulates all enzymes except for enolase and pyruvate kinase. Multiple research has also shown YAP's ability to regulate the expression of glucose transporter of the GLUT family. Additionally, glucose concentration, hypoxia, and hormones such as insulin and glucagon regulate YAP activity and depend on YAP to exert their biological activity. YAP is thus a central regulator of glucose metabolism, controlling both enzymes and proteins involved in glucose transport. YAP is also situated strategically in several pathways controlling glucose and was found to mediate their effects. If these results were consistent in physiological conditions and across glucose-associated metabolic disturbances, then YAP may become a prospective therapeutic target.

Gut microbiota in obesity and nonalcoholic fatty liver disease

• GM plays a regulatory role in the gut–liver axis by disrupting the integrity of the gut mucosal barrier. • The increasing evidence between human metabolism and gut bacteria suggest the new therapeutic strategies based on gut microbiota to treat or prevent obesity/type 2 diabetes. • The microbiota constitution changes before and after bariatric surgery and varies types of surgery. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide with prevalence estimates ranging from 25% to 45%, increasing in parallel with that of obesity and diabetes. There are inherent links between the liver and the gut, with the two are all budding from the entoderm during development. The gut microbiota is a central regulator of host metabolism. The composition and function of the gut microbiota is dynamic and affected by many factors. The gut microbiota has been shown to affect lipid metabolism and lipid levels in blood and tissues, both in mice and humans. Furthermore, diseases linked to dyslipidemia, such as non-alcoholic liver disease and atherosclerosis, are associated with changes in gut microbiota profile. This review explores the role of the gut microbiota in the pathogenesis of nonalcoholic fatty liver disease, as well as the prospects of microbiota and treatment of the nonalcoholic fatty liver disease.

Hormonal contraceptive use, bone density and biochemical markers of bone metabolism in British Army recruits

IntroductionHormonal contraceptive use might impair bone health and increase the risk of stress fracture by decreasing endogenous oestrogen production, a central regulator of bone metabolism. This cross-sectional study investigated bone...

Metabolic Regulation of Hypoxia-Inducible Factors in Hypothalamus.

The earliest hypoxia-inducible factor (HIF) function was to respond to hypoxia or hypoxic conditions as a transcription factor. Recent studies have expanded our understanding of HIF, and a large amount of evidence indicates that HIF has an essential effect on central regulation of metabolism. The central nervous system’s response to glucose, inflammation, and hormones’ main influence on systemic metabolism are all regulated by HIF to varying degrees. In the hypothalamus, HIF mostly plays a role in inhibiting energy uptake and promoting energy expenditure, which depends not only on the single effect of HIF or a single part of the hypothalamus. In this paper, we summarize the recent progress in the central regulation of metabolism, describe in detail the role of HIF in various functions of the hypothalamus and related molecular mechanisms, and reveal that HIF is deeply involved in hypothalamic-mediated metabolic regulation.

Calm on the surface, dynamic on the inside. Molecular homeostasis of Anabaena sp. PCC 7120 nitrogen metabolism.

Nitrogen sources are all converted into ammonium/ia as a first step of assimilation. It is reasonable to expect that molecular components involved in the transport of ammonium/ia across biological membranes connect with the regulation of both nitrogen and central metabolism. We applied both genetic (i.e., Δamt mutation) and environmental treatments to a target biological system, the cyanobacterium Anabaena sp PCC 7120. The aim was to both perturb nitrogen metabolism and induce multiple inner nitrogen states, respectively, followed by targeted quantification of key proteins, metabolites and enzyme activities. The absence of AMT transporters triggered a substantial whole-system response, affecting enzyme activities and quantity of proteins and metabolites, spanning nitrogen and carbon metabolisms. Moreover, the Δamt strain displayed a molecular fingerprint indicating nitrogen deficiency even under nitrogen replete conditions. Contrasting with such dynamic adaptations was the striking near-complete lack of an externally measurable altered phenotype. We conclude that this species evolved a highly robust and adaptable molecular network to maintain homeostasis, resulting in substantial internal but minimal external perturbations. This analysis provides evidence for a potential role of AMT transporters in the regulatory/signalling network of nitrogen metabolism and the existence of a novel fourth regulatory mechanism controlling glutamine synthetase activity.

Impact of COVID-19 pandemic on STIs in Greece

<h3>Abstract</h3> The AKT-mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However,...

MTORC1-chaperonin CCT signaling regulates m6A RNA methylation to suppress autophagy

Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a central regulator of cell growth and metabolism that senses and integrates nutritional and environmental cues with cellular responses. Recent studies have revealed critical roles of mTORC1 in RNA biogenesis and processing. Here, we find that the m6A methyltransferase complex (MTC) is a downstream effector of mTORC1 during autophagy in Drosophila and human cells. Furthermore, we show that the Chaperonin Containing Tailless complex polypeptide 1 (CCT) complex, which facilitates protein folding, acts as a link between mTORC1 and MTC. The mTORC1 activates the chaperonin CCT complex to stabilize MTC, thereby increasing m6A levels on the messenger RNAs encoding autophagy-related genes, leading to their degradation and suppression of autophagy. Altogether, our study reveals an evolutionarily conserved mechanism linking mTORC1 signaling with m6A RNA methylation and demonstrates their roles in suppressing autophagy.

Thioredoxin-mediated regulation of (photo)respiration and central metabolism.

Thioredoxins (TRXs) are ubiquitous proteins engaged in the redox regulation of plant metabolism. Whilst the light-dependent TRX-mediated activation of Calvin-Benson cycle enzymes is well documented, the role of extraplastidial TRXs in the control of the mitochondrial (photo)respiratory metabolism has been revealed relatively recently. Mitochondrially located TRX o1 has been identified as a regulator of alternative oxidase, enzymes of, or associated with, the tricarboxylic acid (TCA) cycle, and the mitochondrial dihydrolipoamide dehydrogenase (mtLPD) involved in photorespiration, the TCA cycle, and the degradation of branched chain amino acids. TRXs are seemingly a major point of metabolic regulation responsible for activating photosynthesis and adjusting mitochondrial photorespiratory metabolism according to the prevailing cellular redox status. Furthermore, TRX-mediated (de)activation of TCA cycle enzymes contributes to explain the non-cyclic flux mode of operation of this cycle in illuminated leaves. Here we provide an overview on the decisive role of TRXs in the coordination of mitochondrial metabolism in the light and provide in silico evidence for other redox-regulated photorespiratory enzymes. We further discuss the consequences of mtLPD regulation beyond photorespiration and provide outstanding questions that should be addressed in future studies to improve our understanding of the role of TRXs in the regulation of central metabolism.

Central regulation of glucose metabolism in an insulin-dependent and -independent manner.

The central nervous system (CNS) contributes significantly to glucose homeostasis. The available evidence indicates that insulin directly acts on the CNS, in particular the hypothalamus, to regulate hepatic glucose production, thereby controlling whole-body glucose metabolism. Additionally, insulin also acts on the brain to regulate food intake and fat metabolism, which may indirectly regulate glucose metabolism. Studies conducted over the last decade have found that the CNS can regulate glucose metabolism in an insulin-independent manner. Enhancement of central leptin signalling reverses hyperglycaemia in insulin-deficient rodents. Here, I review the mechanisms by which central insulin and leptin actions regulate glucose metabolism. Although clinical studies have shown that insulin treatment is currently indispensable for managing diabetes, unravelling the neuronal mechanisms underlying the central regulation of glucose metabolism will pave the way for the design of novel therapeutic drugs for diabetes.

Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome.

Introduction: Congenital hypopituitarism (CH) is characterized by a deficiency of one or more pituitary hormones. The pituitary gland is a central regulator of growth, metabolism, and reproduction. The anterior pituitary produces and secretes growth hormone (GH), adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin. The posterior pituitary hormone secretes antidiuretic hormone and oxytocin.Epidemiology: The incidence is 1 in 4,000–1 in 10,000. The majority of CH cases are sporadic; however, a small number of familial cases have been identified. In the latter, a molecular basis has frequently been identified. Between 80–90% of CH cases remain unsolved in terms of molecular genetics.Pathogenesis: Several transcription factors and signaling molecules are involved in the development of the pituitary gland. Mutations in any of these genes may result in CH including HESX1, PROP1, POU1F1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, GLI2, and FGF8. Over the last 5 years, several novel genes have been identified in association with CH, but it is likely that many genes remain to be identified, as the majority of patients with CH do not have an identified mutation.Clinical manifestations: Genotype-phenotype correlations are difficult to establish. There is a high phenotypic variability associated with different genetic mutations. The clinical spectrum includes severe midline developmental disorders, hypopituitarism (in isolation or combined with other congenital abnormalities), and isolated hormone deficiencies.Diagnosis and treatment: Key investigations include MRI and baseline and dynamic pituitary function tests. However, dynamic tests of GH secretion cannot be performed in the neonatal period, and a diagnosis of GH deficiency may be based on auxology, MRI findings, and low growth factor concentrations. Once a hormone deficit is confirmed, hormone replacement should be started. If onset is acute with hypoglycaemia, cortisol deficiency should be excluded, and if identified this should be rapidly treated, as should TSH deficiency. This review aims to give an overview of CH including management of this complex condition.

Relationships between metabolic profiles and gene expression in liver and leukocytes of dairy cows in early lactation

Homeorhetic mechanisms assist dairy cows in the transition from pregnancy to lactation. Less successful cows develop severe negative energy balance (NEB), placing them at risk of metabolic and infectious diseases and reduced fertility. We have previously placed multiparous Holstein Friesian cows from 4 herds into metabolic clusters, using as biomarkers measurements of plasma nonesterified fatty acids, β-hydroxybutyrate, glucose and IGF-1 collected at 14 and 35 d in milk (DIM). This study characterized the global transcriptomic profiles of liver and circulating leukocytes from the same animals to determine underlying mechanisms associated with their metabolic and immune function. Liver biopsy and whole-blood samples were collected around 14 DIM for RNA sequencing. All cows with available RNA sequencing data were placed into balanced (BAL, n = 44), intermediate (n = 44), or imbalanced (IMBAL, n = 19) metabolic cluster groups. Differential gene expression was compared between the 3 groups using ANOVA, but only the comparison between BAL and IMBAL cows is reported. Pathway analysis was undertaken using DAVID Bioinformatic Resources (https://david.ncifcrf.gov/). Milk yields did not differ between BAL and IMBAL cows but dry matter intake was less in IMBAL cows and they were in greater energy deficit at 14 DIM (-4.48 v -11.70 MJ/d for BAL and IMBAL cows). Significantly differentially expressed pathways in hepatic tissue included AMPK signaling, glucagon signaling, adipocytokine signaling, and insulin resistance. Genes involved in lipid metabolism and cholesterol transport were more highly expressed in IMBAL cows but IGF1 and IGFALS were downregulated. Leukocytes from BAL cows had greater expression of histones and genes involved in nucleosomes and cell division. Leukocyte expression of heat shock proteins increased in IMBAL cows, suggesting an unfolded protein response, and several key genes involved in immune responses to pathogens were upregulated (e.g., DEFB13, HP, OAS1Z, PTX3, and TLR4). Differentially expressed genes upregulated in IMBAL cows in both tissues included CD36, CPT1, KFL11, and PDK4, all central regulators of energy metabolism. The IMBAL cows therefore had greater difficulty maintaining glucose homeostasis and had dysregulated hepatic lipid metabolism. Their energy deficit was associated with a reduced capacity for cell division and greater evidence of stress responses in the leukocyte population, likely contributing to an increased risk of infectious disease.

Central Regulation of Metabolism by Growth Hormone.

Growth hormone (GH) is secreted by the pituitary gland, and in addition to its classical functions of regulating height, protein synthesis, tissue growth, and cell proliferation, GH exerts profound effects on metabolism. In this regard, GH stimulates lipolysis in white adipose tissue and antagonizes insulin’s effects on glycemic control. During the last decade, a wide distribution of GH-responsive neurons were identified in numerous brain areas, especially in hypothalamic nuclei, that control metabolism. The specific role of GH action in different neuronal populations is now starting to be uncovered, and so far, it indicates that the brain is an important target of GH for the regulation of food intake, energy expenditure, and glycemia and neuroendocrine changes, particularly in response to different forms of metabolic stress such as glucoprivation, food restriction, and physical exercise. The objective of the present review is to summarize the current knowledge about the potential role of GH action in the brain for the regulation of different metabolic aspects. The findings gathered here allow us to suggest that GH represents a hormonal factor that conveys homeostatic information to the brain to produce metabolic adjustments in order to promote energy homeostasis.

Reprogramming of Central Carbon Metabolism in Myeloid Cells upon Innate Immune Receptor Stimulation

Immunometabolism is a relatively new field of research that aims at understanding interconnections between the immune system and cellular metabolism. This is now well-documented for innate immune cells of the myeloid lineage such as macrophages and myeloid dendritic cells (DCs) when they engage their differentiation or activation programs. Several studies have shown that stimulation of DCs or macrophages by the binding of pathogen-associated molecular patterns (PAMPs) to pattern recognition receptors (PRRs) leads to increased glycolytic activity and rewiring of central carbon metabolism. These metabolic modulations are essential to support and settle immunological functions by providing energy and immunoregulatory metabolites. As the understanding of molecular mechanisms progressed, significant differences between cell types and species have also been discovered. Pathways leading to the regulation of central carbon metabolism in macrophages and DCs by PRR signaling and consequences on cellular functions are reviewed here.

MTOR as a senescence manipulation target: A forked road.

Cellular senescence, cancer and aging are highly interconnected. Among many important molecular machines that lie at the intersection of this triad, the mechanistic (formerly mammalian) target of rapamycin (mTOR) is a central regulator of cell metabolism, proliferation, and survival. The mTOR signaling cascade is essential to maintain cellular homeostasis in normal biological processes or in response to stress, and its dysregulation is implicated in the progression of many disorders, including age-associated diseases. Accordingly, the pharmacological implications of mTOR inhibition using rapamycin or others rapalogs span the treatment of various human diseases from immune disorders to cancer. Importantly, rapamycin is one of the only known pan-species drugs that can extend lifespan. The molecular and cellular mechanisms explaining the phenotypic consequences of mTOR are vast and heavily studied. In this review, we will focus on the potential role of mTOR in the context of cellular senescence, a tumor suppressor mechanism and a pillar of aging. We will explore the link between senescence, autophagy and mTOR and discuss the opportunities to exploit senescence-associated mTOR functions to manipulate senescence phenotypes in age-associated diseases and cancer treatment.

Monounsaturated Fatty Acids in Obesity-Related Inflammation.

Obesity is an important aspect of the metabolic syndrome and is often associated with chronic inflammation. In this context, inflammation of organs participating in energy homeostasis (such as liver, adipose tissue, muscle and pancreas) leads to the recruitment and activation of macrophages, which secrete pro-inflammatory cytokines. Interleukin-1β secretion, sustained C-reactive protein plasma levels and activation of the NLRP3 inflammasome characterize this inflammation. The Stearoyl-CoA desaturase-1 (SCD1) enzyme is a central regulator of lipid metabolism and fat storage. This enzyme catalyzes the generation of monounsaturated fatty acids (MUFAs)—major components of triglycerides stored in lipid droplets—from saturated fatty acid (SFA) substrates. In this review, we describe the molecular effects of specific classes of fatty acids (saturated and unsaturated) to better understand the impact of different diets (Western versus Mediterranean) on inflammation in a metabolic context. Given the beneficial effects of a MUFA-rich Mediterranean diet, we also present the most recent data on the role of SCD1 activity in the modulation of SFA-induced chronic inflammation.