Metabolic Cues Research Articles

Tether Me, Tether Me Not-Dynamic Organelle Contact Sites in Metabolic Rewiring.

Membrane contact sites (CSs) are specialized cellular regions where distinct organelles are actively positioned very close to each other, at a distance of just a few nanometers. Structurally, CS formation depends on tether proteins that physically link organellar membranes to each other. Functionally, these structures act as hotspots for communication and material transfer. In recent years, we are starting to understand that the cellular CS landscape is not static but instead responds dynamically to diverse metabolic cues. This review describes the interplay between cellular metabolism and CS-based organelle communication and discusses molecular mechanisms of contact modulation in cellular adaptation to changing metabolic requirements.

Should I Lay or Should I Grow: Photoperiodic Versus Metabolic Cues in Chickens.

While photoperiod has been generally accepted as the primary if not the exclusive cue to stimulate reproduction in photoperiodic breeders such as the laying hen, current knowledge suggests that metabolism, and/or body composition can also play an influential role to control the hypothalamic-pituitary gonadal (HPG)-axis. This review thus intends to first describe how photoperiodic and metabolic cues can impact the HPG axis, then explore and propose potential common pathways and mechanisms through which both cues could be integrated. Photostimulation refers to a perceived increase in day-length resulting in the stimulation of the HPG. While photoreceptors are present in the retina of the eye and the pineal gland, it is the deep brain photoreceptors (DBPs) located in the hypothalamus that have been identified as the potential mediators of photostimulation, including melanopsin (OPN4), neuropsin (OPN5), and vertebrate-ancient opsin (VA-Opsin). Here, we present the current state of knowledge surrounding these DBPs, along with their individual and relative importance and, their possible downstream mechanisms of action to initiate the activation of the HPG axis. On the metabolic side, specific attention is placed on the hypothalamic integration of appetite control with the stimulatory (Gonadotropin Releasing Hormone; GnRH) and inhibitory (Gonadotropin Inhibitory Hormone; GnIH) neuropeptides involved in the control of the HPG axis. Specifically, the impact of orexigenic peptides agouti-related peptide (AgRP), and neuropeptide Y (NPY), as well as the anorexigenic peptides pro-opiomelanocortin (POMC), and cocaine-and amphetamine regulated transcript (CART) is reviewed. Furthermore, beyond hypothalamic control, several metabolic factors involved in the control of body weight and composition are also presented as possible modulators of reproduction at all three levels of the HPG axis. These include peroxisome proliferator-activated receptor gamma (PPAR-γ) for its impact in liver metabolism during the switch from growth to reproduction, adiponectin as a potential modulator of ovarian development and follicular maturation, as well as growth hormone (GH), and leptin (LEP).

Fatty acid β-oxidation is required for the differentiation of larval hematopoietic progenitors in Drosophila.

Cell-intrinsic and extrinsic signals regulate the state and fate of stem and progenitor cells. Recent advances in metabolomics illustrate that various metabolic pathways are also important in regulating stem cell fate. However, our understanding of the metabolic control of the state and fate of progenitor cells is in its infancy. Using Drosophila hematopoietic organ: lymph gland, we demonstrate that Fatty Acid Oxidation (FAO) is essential for the differentiation of blood cell progenitors. In the absence of FAO, the progenitors are unable to differentiate and exhibit altered histone acetylation. Interestingly, acetate supplementation rescues both histone acetylation and the differentiation defects. We further show that the CPT1/whd (withered), the rate-limiting enzyme of FAO, is transcriptionally regulated by Jun-Kinase (JNK), which has been previously implicated in progenitor differentiation. Our study thus reveals how the cellular signaling machinery integrates with the metabolic cue to facilitate the differentiation program.

C. elegans Males Integrate Food Signals and Biological Sex to Modulate State-Dependent Chemosensation and Behavioral Prioritization

Dynamic integration of internal and external cues is essential for flexible, adaptive behavior. In C.elegans, biological sex and feeding state regulate expression of the food-associated chemoreceptor odr-10, contributing to plasticity in food detection and the decision between feeding and exploration. In adult hermaphrodites, odr-10 expression is high, but in well-fed adult males, odr-10 expression is low, promoting exploratory mate-searching behavior. Food-deprivation transiently activates male odr-10 expression, heightening food sensitivity and reducing food leaving. Here, we identify a neuroendocrine feedback loop that sex-specifically regulates odr-10 in response to food deprivation. In well-fed males, insulin-like (insulin/IGF-1 signaling [IIS]) and transforming growth factor β (TGF-β) signaling repress odr-10 expression. Upon food deprivation, odr-10 is directly activated by DAF-16/FoxO, the canonical C.elegans IIS effector. The TGF-β ligand DAF-7 likely acts upstream of IIS and links feeding to odr-10 only in males, due in part to the male-specific expression of daf-7 in ASJ. Surprisingly, these responses to food deprivation are not triggered by internal metabolic cues but rather by the loss of sensory signals associated with food. When males are starved in the presence of inedible food, they become nutritionally stressed, but odr-10 expression remains low and exploratory behavior is suppressed less than in starved control males. Food signals are detected by a small number of sensory neurons whose activity non-autonomously regulates daf-7 expression, IIS, and odr-10. Thus, adult C.elegans males employ a neuroendocrine feedback loop that integrates food detection and genetic sex to dynamically modulate chemoreceptor expression and influence the feeding-versus-exploration decision.

Regulatory Nucleotide Sequence Signals for Expression of the Genes Encoding Ribosomal Proteins.

Ribosomal proteins (RPs) are essential components that translate genetic information from mRNA templates into proteins. Their expressional dysregulation adversely affects the survival and growth of human cells. Nevertheless, little is known about the nucleotide sequences regulating the expression of RPs. Genome-wide associations for expression level of 70 RP genes were conducted across expression stages. Eighteen expression regulatory quantitative trait loci (erQTLs) were identified for protein abundances of 21 RPs (P < 1 × 10–5), but not for their mRNA expression and ribosome occupancy (P > 1 × 10–5). These erQTLs for protein abundance (pQTLs) were all trans-acting. Three of the pQTLs were associated with the expression of long noncoding RNAs (lncRNAs). Target genes of these lncRNAs may produce ribosomal components or may control the metabolic cues for ribosome synthesis. mRNAs of the RP genes extensively interact with miRNAs. The protein-specific erQTLs may become engendered by intensive miRNA controls at the translational stage, which in turn can produce RPs efficient in handling instantaneous cell requirements. This study suggests that the expression levels of RPs may be greatly influenced by trans-acting regulation, presumably via interference of miRNAs and target genes of lncRNAs. Further studies are warranted to examine the molecular functions of pQTLs presented in this study and to understand the underlying regulatory mechanisms of gene expression of RPs.

The Endogenous Metabolite Sphingosine-1-Phosphate (S1P) Activates NOD1/2-Dependent Inflammation Triggered by Cellular Stress

Cellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, known receptors of bacterial peptidoglycans, as general stress sensors detecting perturbations of cellular homeostasis. NOD1/2 activation upon such perturbations required generation of the endogenous metabolite sphingosine-1-phosphate (S1P). Unlike peptidoglycan sensing via the LRR domain, cytosolic S1P directly bound to the NBD domain of NOD1/2, triggering NF-κB activation and inflammatory responses. S1P-NOD1/2 axis was essential for Bleomycin induced inflammation in vivo. In sum, we unveiled a hitherto unknown role of NOD1/2 in surveillance of cellular homeostasis through sensing of cytosolic metabolite S1P. We propose S1P as a novel endogenous stress-associated molecular pattern (SAMP) and NOD1/2 as molecular hubs integrating bacterial and metabolic cues.

SAT-284 Musashi Exerts Translational Control Within Anterior Pituitary Cells of the POU1F1 Lineage

The activation of transcription factor Pou1f1 at embryonic day 13 gives rise to the pituitary populations of somatotropes, lactotropes, and thyrotropes and these populations maintain expression of Pou1f1 throughout life. The Musashi family of RNA regulatory proteins is known to regulate stem cell fate by repressing translation of target mRNAs needed for differentiation. Previously our lab has shown that female Lepr-null somatotropes have reduced POU1F1 protein levels but do not have changes in Pou1f1 mRNA expression. Stimulation with leptin increased the POU1F1 protein levels 3-fold, but did not change Pou1f1 mRNA suggesting a post-transcriptional mechanism for leptin’s regulation of Pou1f1. An in silico analysis indicated the presence a number of potential regulatory elements (MBEs) within the Pou1f1 mRNA 3’ UTR, including 8 consensus Musashi binding elements. Interestingly, we found musashi mRNA and protein levels were increased in Lepr-null somatotropes. This suggested that leptin regulates the expression of musashi in somatotrope populations and may be a candidate translational regulator of the Pou1f1 mRNA. We verified that MSI binds directly to the Pou1f1 mRNA 3’ UTR MBEs by EMSA in vitro and exerts translational repression (using reporter mRNA assays in transfected cell populations). Single cell RNA sequencing of pituitary cells from control male and female mice indicates that MSI and Pou1f1 mRNAs are co-expressed in somatotropes, lactotropes as well as thyrotropes. Immunocytochemical analyses confirmed that Musashi protein is present in mixed and purified somatotrope populations. Furthermore, immunoprecipitation with Musashi1 antibody showed a 5-fold enrichment of Pou1f1 mRNA in control female mouse pituitaries. These findings point to a critical in vivo role for Musashi-mediated mRNA translational regulation within the Pou1f1 lineage and specifically in the control of somatotrope maturation and response to metabolic cues.

Timekeeping in the hindbrain: a multi-oscillatory circadian centre in the mouse dorsal vagal complex

Metabolic and cardiovascular processes controlled by the hindbrain exhibit 24 h rhythms, but the extent to which the hindbrain possesses endogenous circadian timekeeping is unresolved. Here we provide compelling evidence that genetic, neuronal, and vascular activities of the brainstem’s dorsal vagal complex are subject to intrinsic circadian control with a crucial role for the connection between its components in regulating their rhythmic properties. Robust 24 h variation in clock gene expression in vivo and neuronal firing ex vivo were observed in the area postrema (AP) and nucleus of the solitary tract (NTS), together with enhanced nocturnal responsiveness to metabolic cues. Unexpectedly, we also find functional and molecular evidence for increased penetration of blood borne molecules into the NTS at night. Our findings reveal that the hindbrain houses a local network complex of neuronal and non-neuronal autonomous circadian oscillators, with clear implications for understanding local temporal control of physiology in the brainstem.

The Application of 3D Printing and Nutrient/Biomaterial Microhabitats for In Situ Enrichment of Microbial Cultures

The objective of this study was to develop a new tool for selectively capturing new microorganisms from the environment. High‐throughput environmental sequencing has revealed a diversity much greater than that which we have brought into culture. Even so, the microorganisms that have been successfully cultured have yielded a wealth of pharmaceuticals, enzymes and living cultures for medical, agricultural and industrial use. Bringing new microorganisms into culture thus has great value.A MicroCaptureArray for high‐throughput in situ enrichment of new species from the environment using metabolic cues was created using 3D printing. The system is based on repurposing biomaterials developed for medical implants and controlled release devices [1], [2]. The MicroCaptureArray was tested in a terrestrial (soil) and an aquatic (pond) environment for 9 and 7 days, respectively. DNA was then isolated from the array and subjected to 16S sequencing with Qiime2 data analysis.The MicroCaptureArray attracted, captured and enriched different species, many of which were undetectable in the background community using 16S sequencing. The different metabolic cues resulted in the enrichment of different microorganisms. The system also enriched potentially new species, in several samples more then 25% of the captured microorganisms were unassignable beyond the Kingdom of Bacteria or the Phylum of Proteobacteria, in constrast, unassignable bacteria accounted for less than 0.3% of the background samples.In conclusion, the MicroCaptureArray shows that metabolic cues may be used for in situ baiting and enrichment culture of bacteria. The tool may allow researchers to detect rare microorganisms that are present but undetectable in the environment that may nonetheless play a major role when certain nutrients are introduced. It may also allow selective attraction and enrichment of environmental bacteria that are capable of metabolizing particular substances. This may allow targeted discovery of entirely new species with desirable properties.Support or Funding InformationThe project was supported by the Villum Foundation (grant number 17627)

Effects of the Astrocyte Endozepine Octadecaneuropeptide (ODN) on Hypoglycemia Patterns of Ventromedial Hypothalamic Nucleus (VMN) Metabolic‐Sensory Neuron Transmitter Signaling and Energy Sensor Activation in Male and Female Rats

The astrocyte gliotransmitter octadecaneuropeptide (ODN) is a cleavage product of diazepam‐binding inhibitor (DBI) and an endogenous central benzodiazepine receptor ligand. ODN regulation of feeding responses to excess or diminished glucose availability in the brain infers ability to modulate neural metabolic‐sensory function [Lanfray et al., 2013]. The ventromedial hypothalamic nucleus (VMN), a principal component of the neural glucostatic network, integrates nutrient and other cues to shape glucose counter‐regulation. Our studies show that VMN gluco‐stimulatory nitric oxide (NO) and gluco‐inhibitory g‐aminobutyric acid (GABA) neurons express the ultra‐sensitive energy sensor 5′‐AMP‐activated protein kinase (AMPK). This research examined the premise that ODN exerts sex‐specific effects on hypoglycemic patterns of VMN nitrergic and/or GABAergic nerve cell sensor activation and neurotransmitter signaling. Testes‐intact male and ovariectomized, estradiol‐replaced female rats were pretreated by intracerebroventricular administration of the ODN octapeptide (OP) fragment or vehicle prior to insulin injection. VMN NO and GABA cells were identified by immunocytochemistry prior to combinatory laser‐catapult dissection/high‐sensitivity Western blotting. Results identified nitrergic cells exhibiting OP‐reversible effects of hypoglycemia on expression profiles of the NO marker protein neuronal nitric oxide synthase (nNOS), AMPK, and phospho (activated)‐AMPK in distinctive regions of the male and female VMN. In each sex, OP effects on GABA neuron AMPK protein content and activation were also observed at specific levels of the VMN. Outcomes provide novel evidence that ODN may critically impact VMN substrate fuel screening. Further studies are needed to characterize neuroanatomical connectivity of OP‐sensitive nitrergic and GABAergic neurons within central metabolic pathways, and to examine whether metabolic cues that regulate VMN astrocyte ODN release, astrocyte reactivity to ODN‐controlling signals, and metabolic‐sensory nerve cell receptivity to ODN are sex‐dimorphic.Support or Funding InformationNIH DK 109382

Role for NADH‐sensitive Kv channels in the myocardial‐vascular signaling axis.

Voltage‐gated potassium (Kv) channels expressed in the coronary vasculature play a pivotal role in coupling oxygen delivery with myocardial metabolic demand. Despite their importance in maintaining adequate perfusion to support proper cardiac function, the processes by which these channels respond to metabolic cues from the myocardium to elicit smooth muscle hyperpolarization and rapid relaxation are unclear. We tested the hypothesis that the heteromeric auxiliary Kvβ subunit (Kvβ1:Kvβ2) complex facilitates increases in Kv1 channel activity and coronary vasodilation during periods of elevated myocardial oxygen consumption. The Kvβ proteins are functional aldo‐keto reductases, and thus catalyze nicotinamide cofactor‐ (i.e., NAD(P)H) dependent reduction of a range of aldehyde substrates. Intriguingly, these subunits also differentially modify the voltage‐sensitivity of Kv1 channels in a manner that depends upon the redox state of bound cofactor. Imaging mass spectrometry revealed that lactate:pyruvate (used as a surrogate for NADH:NAD+) was significantly increased in intramyocardial arteries in hearts from mice acutely treated with dobutamine to drive elevated cardiac workload versus those from vehicle‐treated mice. Elevation of NADH:NAD+ ratio in coronary arterial myocytes following perfusion of sodium lactate reversibly increased whole cell Kv currents and shifted the voltage‐dependence of activation by ~−15 mV. Moreover, application of 1 mM NADH, but not NAD+, increased single Kv1 channel currents in excised membrane patches from coronary arterial myocytes of wild type mice. In contrast, ablation of Kvβ2 abolished the NADH sensitivity of Kv1 activity, whereas ablation of Kvβ1 had little effect. Consistent with this, we found that vasodilation of coronary arteries to reduced bath oxygen (to ~3%) and the relationship between cardiac work and myocardial blood flow was significantly blunted in Kvβ2−/− arteries/mice when compared with wild type arteries/mice. Together, our results suggest that the Kvβ complex is a functional sensing unit that modulates native coronary Kv1 channel activity upon changes in pyridine nucleotide redox ratio, which may impart a profound influence on the control of myocardial blood flow.Support or Funding InformationThis work is supported by grants from the National Institutes of Health (HL142710, GM103492).

Enhanced fatty acid oxidation provides glioblastoma cells metabolic plasticity to accommodate to its dynamic nutrient microenvironment

Despite advances in molecularly characterizing glioblastoma (GBM), metabolic alterations driving its aggressive phenotype are only beginning to be recognized. Integrative cross-platform analysis coupling global metabolomic and gene expression profiling on patient-derived glioma identified fatty acid β-oxidation (FAO) as a metabolic node in GBM. We determined that the biologic consequence of enhanced FAO is directly dependent upon tumor microenvironment. FAO serves as a metabolic cue to drive proliferation in a β-HB/GPR109A dependent autocrine manner in nutrient favorable conditions, while providing an efficient, alternate source of ATP only in nutrient unfavorable conditions. Rational combinatorial strategies designed to target these dynamic roles FAO plays in gliomagenesis resulted in necroptosis-mediated metabolic synthetic lethality in GBM. In summary, we identified FAO as a dominant metabolic node in GBM that provides metabolic plasticity, allowing these cells to adapt to their dynamic microenvironment. Combinatorial strategies designed to target these diverse roles FAO plays in gliomagenesis offers therapeutic potential in GBM.

Oxygen-releasing nanofibers for breathable bone tissue engineering application.

Oxygen is a vital molecule for cell and tissue processes. Electrospun fibers have been extensively used as drug loading carriers due to possibility of well control over drug release with modulating fiber properties. However, they have not been used as depots for oxygen release. In the present study, an oxygen-releasing nanofibrous scaffold has been developed by electrospinning of polylactic acid/nano-calcium peroxide suspension with different polylactic acid concentrations (6.5 and 13% w/v). The electrospun fibers with calcium peroxide cargo provided oxygen content of 30-94 mmHg in a period of 14 days which lies well within the oxygen level of osseous tissue. The release profile of 13% polylactic acid fibers was different with that of 6.5% fibers with respects to the initial content of released oxygen and the release rate. Not only did 13% fibers supply oxygen with a slower rate, but also they resulted in a lower burst release of oxygen. Cell culture studies in hypoxia corroborated that 13% polylactic acid fibers better preserve cell viability comparing 6.5% counterparts as perceived by MTT assay. Moreover, they endowed more favored milieu for adherence, arrangement and migration of mesenchymal stem cells as confirmed by microscopy images. The oxygen-releasing fibers equally affected alkaline phosphatase, osteocalcin, and calcium deposition by mesenchymal stem cells most likely due to interplay between topographical and metabolic cues offered by 6.5 and 13% formulations.

The interaction of reactive oxygen species and antioxidants at the metabolic interface in salicylic acid-induced adventitious root formation in mung bean [Vigna radiata (L.) R. Wilczek

Implications of the role of antioxidant buffering in reactive oxygen species (ROS)-antioxidant interactions and associated redox regulation during adventitious root formation (ARF) were assessed in redox-manipulated salicylic acid (SA)-treated hypocotyl explants of mung bean [Vigna radiata (L.) R. Wilczek]. Application of pro-oxidant H2O2 (500 μM) followed by SA (600 μM) was shown to stimulate ARF, whereas treatments combining 600 μM SA and 10 × 10−4 M DPI (diphenyleneiodonium, an inhibitor of NADPH-oxidase) and 600 μM and SA 10 × 10−4 M (dimethylthiourea, a free radical scavenger) were found to prevent ARF. The redox status of the experimental explants monitored under such treatment conditions (in terms of accumulation of pro-oxidants, in situ localization of O2- and H2O2, radical scavenging property and total thiol content) revealed significant changes in ROS-antioxidant interactions at the metabolic interface, causing alterations in the pattern of ARF. Further, the assessment of activities and transcript abundance of the enzymes of the H2O2 turnover pathway (mainly the ascorbate-glutathione system) supported the transcriptional regulation of genes such as vrrboh, vrAPX, vrGR, vrSOD, and vrCAT and the activities of the relevant enzymes necessary for the generation of endogenous redox cues during ARF. The present work provides an inventory in support of the importance of antioxidant buffering associated with redox regulation for the origin of the metabolic redox cue (redox signal) necessary for SA-induced ARF in mung bean.

The metabolic signature of T cells in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a prototypic autoimmune disease manifesting as chronic inflammation of the synovium and leading to acceleration of cardiovascular disease and shortening of life expectancy. The basic defect causing autoimmunity has remained elusive, but recent insights have challenged the notion that autoantigen is the core driver. Emerging data have added metabolic cues involved in the proper maintenance and activation of immune cells as pathogenic regulators. Specifically, studies have unveiled metabolic pathways that enforce T cell fate decisions promoting tissue inflammation; including T cell tissue invasiveness, T cell cytokine release, T cell-dependent macrophage activation and inflammatory T cell death. At the center of the metabolic abnormalities lies the mitochondria, which is consistently underperforming in RA T cells. The mitochondrial defect results at least partially from insufficient DNA repair and leads to lipid droplet accumulation, formation of invasive membrane ruffles, inflammasome activation and pyroptotic T cell death. T cells in patients with RA, even naïve T cells never having been involved in inflammatory lesions, have a unique metabolic signature and the changes in intracellular metabolites drive pathogenic T cell behavior. Recognizing the role of metabolic signals in cell fate decisions opens the possibility for immunomodulation long before the end stage synovial inflammation encountered in clinical practice.

Fission and fusion machineries converge at ER contact sites to regulate mitochondrial morphology.

The steady-state morphology of the mitochondrial network is maintained by a balance of constitutive fission and fusion reactions. Disruption of this steady-state morphology results in either a fragmented or elongated network, both of which are associated with altered metabolic states and disease. How the processes of fission and fusion are balanced by the cell is unclear. Here we show that mitochondrial fission and fusion are spatially coordinated at ER membrane contact sites (MCSs). Multiple measures indicate that the mitochondrial fusion machinery, Mitofusins, accumulate at ER MCSs where fusion occurs. Furthermore, fission and fusion machineries colocalize to form hotspots for membrane dynamics at ER MCSs that can persist through sequential events. Because these hotspots can undergo fission and fusion, they have the potential to quickly respond to metabolic cues. Indeed, we discover that ER MCSs define the interface between polarized and depolarized segments of mitochondria and can rescue the membrane potential of damaged mitochondria by ER-associated fusion.

The Interplay Between Tissue Niche and Macrophage Cellular Metabolism in Obesity.

Obesity is associated with the development of metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. The presence of chronic, low-grade inflammation appears to be an important mechanistic link between excess nutrients and clinical disease. The onset of these metabolic disorders coincides with changes in the number and phenotype of macrophages in peripheral organs, particularly in the liver and adipose tissue. Macrophage accumulation in these tissues has been implicated in tissue inflammation and fibrosis, contributing to metabolic disease progression. Recently, the concept has emerged that changes in macrophage metabolism affects their functional phenotype, possibly triggered by distinct environmental metabolic cues. This may be of particular importance in the setting of obesity, where both liver and adipose tissue are faced with a high metabolic burden. In the first part of this review we will discuss current knowledge regarding macrophage dynamics in both adipose tissue and liver in obesity. Then in the second part, we will highlight data linking macrophage metabolism to functional phenotype with an emphasis on macrophage activation in metabolic disease. The importance of understanding how tissue niche influences macrophage function in obesity will be highlighted. In addition, we will identify important knowledge gaps and outstanding questions that are relevant for future research in this area and will facilitate the identification of novel targets for therapeutic intervention in associated metabolic diseases.

Circadian rhythms in innate immunity and stress responses.

Circadian clocks are a common feature of life on our planet, allowing physiology and behaviour to be adapted to recurrent environmental fluctuation. There is now compelling evidence that disturbance of circadian coherence can severely undermine mental and physical health, as well as exacerbate pre-existing pathology. Common molecular design principles underpin the generation of cellular circadian rhythms across the kingdoms, and in animals, the genetic components are extremely well conserved. In mammals, the circadian timing mechanism is present in most cell types and establishes local cycles of gene expression and metabolic activity. These distributed tissue clocks are normally synchronized by a central pacemaker, the suprachiasmatic nuclei (SCN), located in the hypothalamus. Nevertheless, most clocks of the body remain responsive to non-SCN-derived hormonal and metabolic cues (for example, re-alignment of liver clocks to altered meal patterning). It has been demonstrated that the clock is an influential regulator of energy metabolism, allowing key pathways to be tuned across the 24-hr cycle as metabolic requirements fluctuate. Furthermore, clock components, including Cryptochrome and Rev-Erb proteins, have been identified as essential modulators of the innate immune system and inflammatory responses. Studies have also revealed that these proteins regulate glucocorticoid receptor function, a major drug target and crucial regulator of inflammation and metabolism.

Escherichia coli Metabolite Profiling Leads to the Development of an RNA Interference Strain for Caenorhabditis elegans.

The relationship of genotypes to phenotypes can be modified by environmental inputs. Such crucial environmental inputs include metabolic cues derived from microbes living together with animals. Thus, the analysis of genetic effects on animals’ physiology can be confounded by variations in the metabolic profile of microbes. Caenorhabditis elegans exposed to distinct bacterial strains and species exhibit phenotypes different at cellular, developmental, and behavioral levels. Here we reported metabolomic profiles of three Escherichia coli strains, B strain OP50, K-12 strain MG1655, and B-K-12 hybrid strain HB101, as well as different mitochondrial and fat storage phenotypes of C. elegans exposed to MG1655 and HB101 vs. OP50. We found that these metabolic phenotypes of C. elegans are not correlated with overall metabolic patterning of bacterial strains, but their specific metabolites. In particular, the fat storage phenotype is traced to the betaine level in different bacterial strains. HT115 is another K-12 E. coli strain that is commonly utilized to elicit an RNA interference response, and we showed that C. elegans exposed to OP50 and HT115 exhibit differences in mitochondrial morphology and fat storage levels. We thus generated an RNA interference competent OP50 (iOP50) strain that can robustly and consistently knockdown endogenous C. elegans genes in different tissues. Together, these studies suggest the importance of specific bacterial metabolites in regulating the host’s physiology and provide a tool to prevent confounding effects when analyzing genotype-phenotype interactions under different bacterial backgrounds.

Myeloid Cell Diversity and Impact of Metabolic Cues during Atherosclerosis

Abstract Myeloid cells are key contributors to tissue, immune and metabolic homeostasis and their alteration fuels inflammation and associated disorders such as atherosclerosis. Conversely, in a classical chicken-and-egg situation, systemic and local metabolism, together with receptor-mediated activation, regulate intracellular metabolism and reprogram myeloid cell functions. Those regulatory loops are notable during the development of atherosclerotic lesions. Therefore, understanding the intricate metabolic mechanisms regulating myeloid cell biology could lead to innovative approaches to prevent and treat cardiovascular diseases. In this review, we will attempt to summarize the different metabolic factors regulating myeloid cell homeostasis and contribution to atherosclerosis, the most frequent cardiovascular disease.