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Cover Story Current Issue

Non-alcoholic fatty liver disease (NAFLD) encompasses a set of pathologies associated with ectopic lipid accumulationin hepatocytes. NAFLD can progress to non-alcoholic steatohepatitis (NASH), an inflammatory condition which is increasing in prevalence in parallel with other diseases connected to lipid metabolism, such as type 2 diabetes and cardiovascular disease. NASH is characterized by hepatic necrosis, increased inflammatory signaling, immune cell infiltration, and the potential to progress to fibrosis, cirrhosis, hepatocellular carcinoma, and ultimately liver failure.
David Montefusco, Maryam Jamil, Melissa A. Maczis, William Schroeder, ... L. Ashley Cowart
Current Issue
Background
It has been reported that diabetes mellitus affects 435 million people globally as a primary health care problem. Despite many therapies available, many diabetes remains uncontrolled, giving rise to irreversible diabetic complications that pose significant risks to patients’ wellbeing and survival.
Scope of Review
In recent years, as much effort is put into elucidating the posttranscriptional gene regulation network of diabetes and diabetic complications; RNA binding proteins (RBPs) are found to be vital. RBPs regulate gene expression through various post-transcriptional mechanisms, including alternative splicing, RNA export, messenger RNA translation, RNA degradation, and RNA stabilization.
Major Conclusions
Here, we summarized recent studies on the roles and mechanisms of RBPs in mediating abnormal gene expression in diabetes and its complications. Moreover, we discussed the potential and theoretical basis of RBPs to treat diabetes and its complications.
Objective
The prostate is metabolically unique: it produces high levels of citrate for secretion via a truncated tricarboxylic acid (TCA) cycle to maintain male fertility. In prostate cancer (PCa), this phenotype is reprogrammed, making it an interesting therapeutic target. However, how the truncated prostate TCA cycle works is still not completely understood.
Methods
We optimized targeted metabolomics in mouse and human organoid models in ex vivo primary culture. We then used stable isotope tracer analyses to identify the pathways that fuel citrate synthesis.
Results
First, mouse and human organoids were shown to recapitulate the unique citrate-secretory program of the prostate, thus representing a novel model that reproduces this unusual metabolic profile. Using stable isotope tracer analysis, several key nutrients were shown to allow the completion of the prostate TCA cycle, revealing a much more complex metabolic profile than originally anticipated. Indeed, along with the known pathway of aspartate replenishing oxaloacetate, glutamine was shown to fuel citrate synthesis through both glutaminolysis and reductive carboxylation in a GLS1-dependent manner. In human organoids, aspartate entered the TCA cycle at the malate entry point, upstream of oxaloacetate. Our results demonstrate that the citrate-secretory phenotype of prostate organoids is supported by the known aspartate–oxaloacetate–citrate pathway, but also by at least three additional pathways: glutaminolysis, reductive carboxylation, and aspartate–malate conversion.
Conclusions
Our results add a significant new dimension to the prostate citrate-secretory phenotype, with at least four distinct pathways being involved in citrate synthesis. Better understanding this distinctive citrate metabolic program will have applications in both male fertility as well as in the development of novel targeted anti-metabolic therapies for PCa.
Objective
Ultra-rapid insulin formulations control postprandial hyperglycemia; however, inadequate understanding of injection siteabsorption mechanisms is limiting further advancement. We used photoacoustic imaging to investigate the injection site dynamics of dye-labeled insulin lispro in the Humalog® and Lyumjev® formulations using the murine ear cutaneous model and correlated it with results from unlabeled insulin lispro in pig subcutaneous injection model.
Methods
We employed dual-wavelength optical-resolution photoacoustic microscopy to study the absorption and diffusion of the near-infrared dye-labeled insulin lispro in the Humalog and Lyumjev formulations in mouse ears. We mathematically modeled the experimental data to calculate the absorption rate constants and diffusion coefficients. We studied the pharmacokinetics of the unlabeled insulin lispro in both the Humalog and Lyumjev formulations as well as a formulation lacking both the zinc and phenolic preservative in pigs. The association state of insulin lispro in each of the formulations was characterized using SV-AUC and NMR spectroscopy.
Results
Through experiments using murine and swine models, we show that the hexamer dissociation rate of insulin lispro is not the absorption rate-limiting step. We demonstrated that the excipients in the Lyumjev formulation produce local tissue expansion and speed both insulin diffusion and microvascular absorption. We also show that the diffusion of insulin lispro at the injection site drives its initial absorption; however, the rate at which the insulin lispro crosses the blood vessels is its overall absorption rate-limiting step.
Conclusions
This study provides insights into injection site dynamics of insulin lispro and the impact of formulation excipients. It also demonstrates photoacoustic microscopy as a promising tool for studying protein therapeutics. The results from this study address critical questions around the subcutaneous behavior of insulin lispro and the formulation excipients, which could be useful to make faster and better controlled insulin formulations in the future.
Objective
Type 1 Diabetes (T1D) is characterized by progressive loss of insulin-producing pancreatic β cells as a result of autoimmune destruction. In addition to β cell death, recent work has shown that subpopulations of β cells acquire dysfunction during T1D. We previously reported that β cells undergoing a DNA damage response (DDR) and senescence accumulate during the pathogenesis of T1D. However, the question of how senescence develops in β cells has not been investigated.
Methods
Here, we tested the hypothesis that unrepaired DNA damage in the context of genetic susceptibility triggers β cell senescence using culture models including the mouse NIT1 β cell line derived from the T1D-susceptible nonobese diabetic (NOD) strain, human donor islets and EndoC β cells. DNA damage was chemically induced using etoposide or bleomycin and cells or islets were analyzed by a combination of molecular assays for senescence phenotypes including Western blotting, qRT-PCR, Luminex assays, flow cytometry and histochemical staining. RNA-seq was carried out to profile global transcriptomic changes in human islets undergoing DDR and senescence. Insulin ELISAs were used to quantify glucose-stimulated insulin secretion from chemically-induced senescent human islets, EndoC β cells and mouse β cell lines in culture.
Results
Sub-lethal DNA damage in NIT1 cells led to several classical hallmarks of senescence including sustained DDR activation, growth arrest, enlarged flattened morphology and a senescence-associated secretory phenotype (SASP) resembling what occurs in primary β cells during T1D in NOD mice. These phenotypes differed between NIT1 cells and the MIN6 β cell line derived from a non-T1D susceptible mouse strain. RNA-seq analysis of DNA damage-induced senescence in human islets from two different donors revealed a p53 transcriptional program and upregulation of prosurvival and SASP genes, with inter-donor variability in this response. Inter-donor variability in human islets was also apparent in the extent of persistent DDR activation and SASP at the protein level. Notably, chemically induced DNA damage also led to DDR activation and senescent phenotypes in EndoC-βH5 human β cells, confirming that this response can occur directly in a human β cell line. Finally, DNA damage led to different effects on glucose-stimulated insulin secretion in mouse β cell lines as compared with human islets and EndoC β cells.
Conclusions
Taken together, these findings suggest that some of the phenotypes of senescent β cells that accumulate during the development of T1D in the NOD mouse and humans can be modeled by chemically induced DNA damage to mouse β cell lines, human islets and EndoC β cells in culture. The differences between β cells from different mouse strains and different human islet donors and EndoC β cells highlights species differences and the role for genetic background in modifying the β cell response to DNA damage and its effects on insulin secretion. These culture models will be useful tools to understand some of the mechanisms of β cell senescence in T1D.
Objective
Metabolic syndrome (MetS) is defined as a complex of interrelated risk factors for type 2 diabetes and cardiovascular disease, including glucose intolerance, abdominal obesity, hypertension, and dyslipidemia. Studies using diffusion tensor imaging (DTI) have reported white matter (WM) microstructural abnormalities in MetS. However, interpretation of DTI metrics is limited primarily due to the challenges of modeling complex WM structures. The present study used fixel-based analysis (FBA) to assess the effect of MetS on the fiber tract-specific WM microstructure in older adults and its relationship with MetS-related measurements and cognitive and locomotor functions to better understand the pathophysiology of MetS.
Methods
Fixel-based metrics, including microstructural fiber density (FD), macrostructural fiber-bundle cross-section (FC), and a combination of FD and FC (FDC), were evaluated in 16 healthy controls (no components of MetS; four men; mean age, 71.31 ± 5.06 years), 57 individuals with premetabolic syndrome (preMetS; one or two components of MetS; 29 men; mean age, 72.44 ± 5.82 years), and 46 individuals with MetS (three to five components of MetS; 27 men; mean age, 72.15 ± 4.97 years) using whole-brain exploratory FBA. Tract of interest (TOI) analysis was then performed using TractSeg across 14 selected WM tracts previously associated with MetS. The associations between fixel-based metrics and MetS-related measurements, neuropsychological, and locomotor function tests were also analyzed in individuals with preMetS and MetS combined. In addition, tensor-based metrics (i.e., fractional anisotropy [FA] and mean diffusivity [MD]) were compared among the groups using tract-based spatial statistics (TBSS) analysis.
Results
In whole-brain FBA, individuals with MetS showed significantly lower FD, FC, and FDC compared with healthy controls in WM areas, such as the splenium of the corpus callosum (CC), corticospinal tract (CST), middle cerebellar peduncle (MCP), and superior cerebellar peduncle (SCP). Meanwhile, in fixel-based TOI, significantly reduced FD was observed in individuals with preMetS and MetS in the anterior thalamic radiation, CST, SCP, and splenium of the CC compared with healthy controls, with relatively greater effect sizes observed in individuals with MetS. Compared with healthy controls, significantly reduced FC and FDC were only demonstrated in individuals with MetS, including regions with loss of FD, inferior cerebellar peduncle, inferior fronto-occipital fasciculus, MCP, and superior longitudinal fasciculus part I. Furthermore, negative correlations were observed between FD and Brinkman index of cigarette consumption cumulative amount and between FC or FDC and the Trail Making Test (parts B–A), which is a measure of executive function, waist circumference, or low-density lipoprotein cholesterol. Finally, TBSS analysis revealed that FA and MD were not significantly different among all groups.
Conclusions
The FBA results demonstrate that substantial axonal loss and atrophy in individuals with MetS and early axonal loss without fiber-bundle morphological changes in those with preMetS within the WM tracts are crucial to cognitive and motor function. FBA also clarified the association between executive dysfunction, abdominal obesity, hyper-low-density lipoprotein cholesterolemia, smoking habit, and compromised WM neural tissue microstructure in MetS.
Objective
Mitochondrial capacity is critical to adapt the high energy demand of the heart to circadian oscillations and diseased states. Glucocorticoids regulate the circadian cycle of energy metabolism, but little is known about how circadian timing of exogenous glucocorticoid dosing directly regulates heart metabolism through cardiomyocyte-autonomous mechanisms. While chronic once-daily intake of glucocorticoids promotes metabolic stress and heart failure, we recently discovered that intermittent once-weekly dosing of exogenous glucocorticoids promoted muscle metabolism in normal and obese skeletal muscle. However, the effects of glucocorticoid intermittence on heart metabolism and heart failure remain unknown. Here we investigated the extent to which circadian time of dosing regulates the effects of the glucocorticoid prednisone in heart metabolism and function in conditions of single pulse or chronic intermittent dosing.
Methods and Results
In WT mice, we found that prednisone improved cardiac content of NAD+ and ATP with light-phase dosing (ZT0), while the effects were blocked by dark-phase dosing (ZT12). The drug effects on mitochondrial function were cardiomyocyte-autonomous, as shown by inducible cardiomyocyte-restricted glucocorticoid receptor (GR) ablation, and depended on an intact cardiomyocyte clock, as shown by inducible cardiomyocyte-restricted ablation of Brain and Muscle ARNT-like 1 (BMAL1). Conjugating time-of-dosing with chronic intermittence, we found that once-weekly prednisone improved metabolism and function in heart after myocardial injury dependent on circadian time of intake, i.e. with light-phase but not dark-phase dosing.
Conclusions
Our study identifies cardiac-autonomous mechanisms through which circadian-specific intermittent dosing reconverts glucocorticoid drugs to metabolic boosters for the heart.
Objective
Uncoupling protein 1 (UCP1) catalyses mitochondrial proton leak in brown adipose tissue to facilitate nutrient oxidation for heat production, and may combat metabolic disease if activated in humans. During the adrenergic stimulation of brown adipocytes, free fatty acids generated from lipolysis activate UCP1 via an unclear interaction. Here, we set out to characterise activator binding to purified UCP1 to clarify the activation process, discern novel activators and the potential to target UCP1.
Methods
We assessed ligand binding to purified UCP1 by protein thermostability shift analysis, which unlike many conventional approaches can inform on the binding of hydrophobic ligands to membrane proteins. A detailed activator interaction analysis and screening approach was carried out, supported by investigations of UCP1 activity in liposomes, isolated brown fat mitochondria and UCP1 expression-controlled cell lines.
Results
We reveal that fatty acids and other activators influence UCP1 through a specific destabilising interaction, behaving as transport substrates that shift the protein to a less stable conformation of a transport cycle. Through the detection of specific stability shifts in screens, we identify novel activators, including the over-the-counter drug ibuprofen, where ligand analysis indicates that UCP1 has a relatively wide structural specificity for interacting molecules. Ibuprofen successfully induced UCP1 activity in liposomes, isolated brown fat mitochondria and UCP1-expressing HEK293 cells but not in cultured brown adipocytes, suggesting drug delivery differs in each cell type.
Conclusions
These findings clarify the nature of the activator-UCP1 interaction and demonstrate that the targeting of UCP1 in cells by approved drugs is in principle achievable as a therapeutic avenue, but requires variants with more effective delivery in brown adipocytes.
Objective
The liver is the primary internal metabolic organ that coordinates whole body energy homeostasis in response to feeding and fasting. Genetic ablation or pharmacological inhibition of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) has been shown to significantly improve hepatic health and peripheral insulin sensitivity upon overnutrition with high fat diet. However, the precise molecular underpinnings that explain this metabolic protection have remained largely undefined.
Methods
To characterize the role of CaMKK2 in hepatic metabolism, we developed and challenged liver-specific CaMKK2 knockout (CaMKK2LKO) mice with high fat diet and performed glucose and insulin tolerance tests to evaluate peripheral insulin sensitivity. We used a combination of RNA-Sequencing, glucose and fatty acid istotopic tracer studies, a newly developed Seahorse assay for measuring the oxidative capacity of purified peroxisomes, and a degenerate peptide libarary to identify putative CaMKK2 substrates that mechanistically explain the protective effects of hepatic CaMKK2 ablation.
Results
Consistent with previous findings, we show that hepatic CaMKK2 ablation significantly improves indices of peripheral insulin sensitivity. Mechanistically, we found that CaMKK2 phosphorylates and regulates GAPDH to promote glucose metabolism and PEX3 to blunt peroxisomal fatty acid catabolism in the liver.
Conclusion
CaMKK2 is a central metabolic fuel sensor in the liver that significantly contributes to whole body systems metabolism.
Objective
Regulation of proteasomal activity is an essential component of cellular proteostasis and function. This is evident in patients with mutations in proteasome subunits and associated regulators, who suffer from proteasome-associated autoinflammatory syndromes (PRAAS). These patients display lipodystrophy and fevers, which may be partly related to adipocyte malfunction and abnormal thermogenesis in adipose tissue. However, the cell–intrinsic pathways that could underlie these symptoms are unclear. Here, we investigate the impact of two proteasome subunits implicated in PRAAS, Psmb4 and Psmb8, on differentiation, function and proteostasis of brown adipocytes.
Methods
In immortalized mouse brown pre-adipocytes, levels of Psmb4, Psmb8, and downstream effectors genes were downregulated through reverse transfection with siRNA. Adipocytes were differentiated and analyzed with various assays of adipogenesis, lipogenesis, lipolysis, inflammation, and respiration.
Results
Loss of Psmb4, but not Psmb8, disrupted proteostasis and adipogenesis. Proteasome function was reduced upon Psmb4 loss, but partly recovered by the activation of Nuclear factor, erythroid-2, like-1 (Nfe2l1). In addition, cells displayed higher levels of surrogate inflammation and stress markers, including Activating transcription factor-3 (Atf3). Simultaneous silencing of Psmb4 and Atf3 lowered inflammation and restored adipogenesis.
Conclusions
Our study shows that Psmb4 is required for adipocyte development and function in cultured adipocytes. These results imply that in humans with PSMB4 mutations, PRAAS-associated lipodystrophy is partly caused by disturbed adipogenesis. While we uncover a role for Nfe2l1 in the maintenance of proteostasis under these conditions, Atf3 is a key effector of inflammation and blocking adipogenesis. In conclusion, our work highlights how proteasome dysfunction is sensed and mitigated by the integrated stress response in adipocytes with potential relevance for PRAAS patients and beyond.
Objective
Men with non-alcoholic fatty liver disease (NAFLD) are more likely to progress to non-alcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of this dimorphism is unclear. We have previously shown that mice with global deletion of SphK1, the enzyme that produces the bioactive sphingolipid metabolite sphingosine 1-phosphate (S1P), were protected from development of NASH. The aim of this study was to elucidate the role of hepatocyte-specific SphK1 in development of NASH and to compare its contribution to hepatosteatosis in male and female mice.
Methods
We assessed mouse livers in early-stage fibrosis induced by high fat feeding, using single harmonic generation microscopy, LC-MS/MS analysis of hydroxyproline levels, and expression of fibrosis markers. We identified an antifibrotic intercellular signaling mechanism by culturing primary mouse hepatocytes alongside, and in co-culture with, LX2 hepatic stellate cells.
Results
We generated hepatocyte-specific SphK1 knockout mice (SphK1-hKO). Unlike the global knockout, SphK1-hKO male mice were not protected from diet-induced steatosis, inflammation, or fibrogenesis. In contrast, female SphK1-hKO mice were protected from inflammation. Surprisingly, however, in these female mice, there was a ∼10-fold increase in the fibrosis markers Col1α1 and 2–3 fold induction of alpha smooth muscle actin and the pro-fibrotic chemokine CCL5. Because increased fibrosis in female SphK1-hKO mice occurred despite an attenuated inflammatory response, we investigated the crosstalk between hepatocytes and hepatic stellate cells, central players in fibrosis. We found that estrogen stimulated release of S1P from female hepatocytes preventing TGFβ-induced expression of Col1α1 in HSCs via S1PR3.
Conclusions
The results revealed a novel pathway of estrogen-mediated cross-talk between hepatocytes and HSCs that may contribute to sex differences in NAFLD through an anti-fibrogenic function of the S1P/S1PR3 axis. This pathway is susceptible to pharmacologic manipulation, which may lead to novel therapeutic strategies.
Objective
Neuropeptide FF (NPFF) group peptides belong to the evolutionary conserved RF-amide peptide family. While they have been assigned a role as pain modulators, their roles in other aspects of physiology have received much less attention. NPFF peptides and their receptor NPFFR2 have strong and localized expression within the dorsal vagal complex that has emerged as the key centre for regulating glucose homeostasis. Therefore, we investigated the role of the NPFF system in the control of glucose metabolism and the histochemical and molecular identities of NPFF and NPFFR2 neurons.
Methods
We examined glucose metabolism in Npff−/− and wild type (WT) mice using intraperitoneal (i.p.) glucose tolerance and insulin tolerance tests. Body composition and glucose tolerance was further examined in mice after 1-week and 3-week of high-fat diet (HFD). Using RNAScope double ISH, we investigated the neurochemical identity of NPFF and NPFFR2 neurons in the caudal brainstem, and the expression of receptors for peripheral factors in NPFF neurons.
Results
Lack of NPFF signalling in mice leads to improved glucose tolerance without significant impact on insulin excursion after the i.p. glucose challenge. In response to an i.p. bolus of insulin, Npff−/− mice have lower glucose excursions than WT mice, indicating an enhanced insulin action. Moreover, while HFD has rapid and potent detrimental effects on glucose tolerance, this diet-induced glucose intolerance is ameliorated in mice lacking NPFF signalling. This occurs in the absence of any significant impact of NPFF deletion on lean or fat masses, suggesting a direct effect of NPFF signalling on glucose metabolism. We further reveal that NPFF neurons in the subpostrema area (SubP) co-express receptors for peripheral factors involved in glucose homeostasis regulation such as insulin and GLP1. Furthermore, Npffr2 is expressed in the glutamatergic NPFF neurons in the SubP, and in cholinergic neurons of the dorsal motor nucleus of the vagus (DMV), indicating that central NPFF signalling is likely modulating vagal output to innervated peripheral tissues including those important for glucose metabolic control.
Conclusions
NPFF signalling plays an important role in the regulation of glucose metabolism. NPFF neurons in the SubP are likely to receive peripheral signals and mediate the control of whole-body glucose homeostasis via centrally vagal pathways. Targeting NPFF and NPFFR2 signalling may provide a new avenue for treating type 2 diabetes and obesity.
Objective
Aberrant ketogenesis is correlated with the degree of steatosis in non-alcoholic fatty liver disease (NAFLD) patients, and an inborn error of ketogenesis (mitochondrial HMG-CoA synthase deficiency) is commonly associated with the development of the fatty liver. Here we aimed to determine the impact of Hmgcs2-mediated ketogenesis and its modulations on the development and treatment of fatty liver disease.
Methods
Loss- and gain-of-ketogenic function models, achieved by Hmgcs2 knockout and overexpression, respectively, were utilized to investigate the role of ketogenesis in the hepatic lipid accumulation during postnatal development and in a high-fat diet-induced NAFLD mouse model.
Results
Ketogenic function was decreased in NAFLD mice with a reduction in Hmgcs2 expression. Mice lacking Hmgcs2developed spontaneous fatty liver phenotype during postnatal development, which was rescued by a shift to a low-fat dietary composition via early weaning. Hmgcs2 heterozygous adult mice, which exhibited lower ketogenic activity, were more susceptible to diet-induced NAFLD development, whereas HMGCS2 overexpression in NAFLD mice improved hepatosteatosis and glucose homeostasis.
Conclusions
Our study adds new knowledge to the field of ketone body metabolism and shows that Hmgcs2-mediated ketogenesis modulates hepatic lipid regulation under a fat-enriched nutritional environment. The regulation of hepatic ketogenesis may be a viable therapeutic strategy in the prevention and treatment of hepatosteatosis.
Objectives
Glucagon secretion to stimulate hepatic glucose production is the first line of defense against hypoglycemia. This response is triggered by so far incompletely characterized central hypoglycemia-sensing mechanisms, which control autonomous nervous activity and hormone secretion. The objective of this study was to identify novel hypothalamic genes controlling insulin-induced glucagon secretion.
Methods
To obtain new information on the mechanisms of hypothalamic hypoglycemia sensing, we combined genetic and transcriptomic analysis of glucagon response to insulin-induced hypoglycemia in a panel of BXD recombinant inbred mice.
Results
We identified two QTLs on chromosome 8 and chromosome 15. We further investigated the role of Irak4 and Cpne8, both located in the QTL on chromosome 15, in C57BL/6J and DBA/2J mice, the BXD mouse parental strains. We found that the poor glucagon response of DBA/2J mice was associated with higher hypothalamic expression of Irak4, which encodes a kinase acting downstream of the interleukin-1 receptor (Il-1R), and of Il-ß when compared with C57BL/6J mice. We showed that intracerebroventricular administration of an Il-1R antagonist in DBA/2J mice restored insulin-induced glucagon secretion; this was associated with increased c-fos expression in the arcuate and paraventricular nuclei of the hypothalamus and with higher activation of both branches of the autonomous nervous system. Whole body inactivation of Cpne8, which encodes a Ca++-dependent regulator of membrane trafficking and exocytosis, however, had no impact on insulin-induced glucagon secretion.
Conclusions
Collectively, our data identify Irak4 as a genetically controlled regulator of hypoglycemia-activated hypothalamic neurons and glucagon secretion.
Objective
The mechanisms by which glucose stimulates insulin secretion from β-cells are well established and involve inhibition of ATP-sensitive K+ (KATP) channels, followed by a rise in [Ca2+]c that triggers exocytosis. However, the mechanisms by which glucose controls glucagon release from α-cells are much less known. In particular, it is debated whether the sugar controls glucagon secretion by changing α-cell [Ca2+]c, and whether KATP channels or paracrine factors are involved. The present study addresses these issues.
Methods
We tested the effect of a decrease or an increase of glucose concentration (Gx, with x = concentration in mM) on α-cell [Ca2+]c and glucagon secretion. α-cell [Ca2+]c was monitored using GluCreGCaMP6f mice expressing the Ca2+-sensitive fluorescent protein, GCaMP6f, specifically in α-cells. [Ca2+]c was compared between dispersed α-cells and α-cells within islets to evaluate the potential contribution of an indirect effect of glucose. The same protocols were used for experiments of glucagon secretion from whole islets and [Ca2+]c measurements to test if changes in glucagon release mirror those in α-cell [Ca2+]c.
Results
Blockade of KATP channels by sulfonylureas (tolbutamide 100 μM or gliclazide 25 μM) strongly increased [Ca2+]c in both dispersed α-cells and α-cells within islets. By contrast, glucose had no effect on [Ca2+]c in dispersed α-cells, whereas it affected it in α-cells within islets. The effect of glucose was however different in islets expressing (Sst+/+) or not somatostatin (SST) (Sst−/−). Decreasing glucose concentration from G7 to G1 modestly increased α-cell [Ca2+]c, but to a slightly larger extent in Sst+/+ islets than in Sst−/− islets. This G1-induced [Ca2+]c rise was also observed in the continuous presence of sulfonylureas in both Sst+/+ and Sst−/− islets. Increasing glucose concentration from G7 to G20 did not affect α-cell [Ca2+]c in Sst+/+ islets which remained low, whereas it strongly increased it in Sst−/− islets. The observations that this increase was seen only in α-cells within islets but never in dispersed α-cells and that it was abrogated by the gap junction inhibitor, carbenoxolone, point to an indirect effect of G20 and suggest that, in Sst−/− islets, G20-stimulated β-cells entrain α-cells whereas, in Sst+/+ islets, the concomitant release of SST keeps α-cell [Ca2+]c at low levels. The [Ca2+]c lowering effect of endogenous SST is also supported by the observation that SST receptor antagonists (SSTR2/3) increased [Ca2+]c in α-cells from Sst+/+ islets. All these [Ca2+]c changes induced parallel changes in glucagon release. To test if glucose also controls glucagon release independently of [Ca2+]c changes, additional experiments were performed in the continuous presence of 30 mM K+ and the KATP channel opener diazoxide (250 μM). In these conditions, α-cell [Ca2+]c within islets was elevated and its steady-state level was unaffected by glucose. However, decreasing the glucose concentration from G7 to G1 stimulated glucagon release whereas increasing it from G1 to G15 inhibited it. These effects were also evident in Sst−/− islets, and opposite to those on insulin secretion.
Conclusions
We propose a model according to which glucose controls α-cell [Ca2+]c and glucagon secretion through multiple mechanisms. Increasing the glucose concentration modestly decreases [Ca2+]c in α-cells independently of their KATPchannels and partly via SST. The involvement of SST increases with the glucose concentration, and one major effect of SST is to keep α-cell [Ca2+]c at low levels by counteracting the effect of an entrainment of α-cells by β-cells when β-cells become stimulated by glucose. All these [Ca2+]c changes induce parallel changes in glucagon release. Glucose also decreases the efficacy of Ca2+ on exocytosis by an attenuating pathway that is opposite to the well-established amplifying pathway controlling insulin release in β-cells.
Objective
Mitochondrial “retrograde” signaling may stimulate organelle biogenesis as a compensatory adaptation to aberrant activity of the oxidative phosphorylation (OXPHOS) system. To maintain energy-consuming processes in OXPHOS deficient cells, alternative metabolic pathways are functionally coupled to the degradation, recycling and redistribution of biomolecules across distinct intracellular compartments. While transcriptional regulation of mitochondrial network expansion has been the focus of many studies, the molecular mechanisms promoting mitochondrial maintenance in energy-deprived cells remain poorly investigated.
Methods
We performed transcriptomics, quantitative proteomics and lifespan assays to identify pathways that are mechanistically linked to mitochondrial network expansion and homeostasis in Caenorhabditis elegans lacking the mitochondrial calcium uptake protein 1 (MICU-1/MICU1). To support our findings, we carried out biochemical and image analyses in mammalian cells and mouse-derived tissues.
Results
We report that micu-1(null) mutations impair the OXPHOS system and promote C. elegans longevity through a transcriptional program that is independent of the mitochondrial calcium uniporter MCU-1/MCU and the essential MCU regulator EMRE-1/EMRE. We identify sphingosine phosphate lyase SPL-1/SGPL1 and the ATFS-1-target HOPS complex subunit VPS-39/VPS39 as critical lifespan modulators of micu-1(null) mutant animals. Cross-species investigation indicates that SGPL1 upregulation stimulates VPS39 recruitment to the mitochondria, thereby enhancing mitochondria-lysosome contacts. Consistently, VPS39 downregulation compromises mitochondrial network maintenance and basal autophagic flux in MICU1 deficient cells. In mouse-derived muscles, we show that VPS39 recruitment to the mitochondria may represent a common signature associated with altered OXPHOS system.
Conclusions
Our findings reveal a previously unrecognized SGPL1/VPS39 axis that stimulates intracellular organelle interactions and sustains autophagy and mitochondrial homeostasis in OXPHOS deficient cells.
- Abstract
SERPINA3C ameliorates adipose tissue inflammation through the Cathepsin G/Integrin/AKT pathway
Objective
Due to the increasing prevalence of obesity and insulin resistance, there is an urgent need for better treatment of obesity and its related metabolic disorders. This study aimed to elucidate the role of SERPINA3C, an adipocyte secreted protein, in obesity and related metabolic disorders.
Methods
Male wild type (WT) and knockout (KO) mice were fed with high-fat diet (HFD) for 16 weeks, adiposity, insulin resistance, and inflammation were assessed. AAV-mediated overexpression of SERPINA3C was injected locally in inguinal white adipose tissue (iWAT) to examine the effect of SERPINA3C. In vitro analyses were conducted in 3T3-L1 adipocytes to explore the molecular pathways underlying the function of SERPINA3C.
Results
Functional exploration of the SERPINA3C knockout mice revealed that SERPINA3C deficiency led to an impaired metabolic phenotype (more severe obesity, lower metabolic rates, worse glucose intolerance and insulin insensitivity), which was associated with anabatic inflammation and apoptosis of white adipose tissues. Consistent with these results, overexpression of SERPINA3C in inguinal adipose tissue protected mice against diet-induced obesity and metabolic disorders with less inflammation and apoptosis in adipose tissue. Mechanistically, SERPINA3C inhibited Cathepsin Gactivity, acting as a serine protease inhibitor, which blocked Cathepsin G-mediated turnover of α5/β1 Integrin protein. Then, the preserved integrity (increase) of α5/β1 Integrin signaling activated AKT to decrease JNK phosphorylation, thereby inhibiting inflammation and promoting insulin sensitivity in adipocytes.
Conclusions/interpretation
These findings demonstrate a previously unknown SERPINA3C/Cathepsin G/Integrin/AKT pathway in regulating adipose tissue inflammation, and suggest the therapeutic potential of targeting SERPINA3C/Cathepsin G axis in adipose tissue for the treatment of obesity and metabolic diseases.
Objective
IL-6 is an important contributor to glucose and energy homeostasis through changes in whole-body glucose disposal, insulin sensitivity, food intake and energy expenditure. However, the relative contributions of peripheral versus central IL-6 signaling to these metabolic actions are presently unclear. A conditional mouse model with reduced brain IL-6Ra expression was used to explore how blunted central IL-6 signaling alters metabolic status in lean and obese mice.
Methods
Transgenic mice with reduced levels of central IL-6 receptor alpha (IL-6Ra) (IL-6Ra KD mice) and Nestin Cre controls (Cre+/- mice) were fed standard chow or high-fat diet for 20 weeks. Obese and lean mouse cohorts underwent metabolic phenotyping with various measures of energy and glucose homeostasis determined. Glucose-stimulated insulin secretionwas assessed in vivo and ex vivo in both mouse groups.
Results
IL-6Ra KD mice exhibited altered body fat mass, liver steatosis, plasma insulin, IL-6 and NEFA levels versus Cre+/- mice in a diet-dependent manner. IL-6Ra KD mice had increased food intake, higher RER, decreased energy expenditure with diminished cold tolerance compared to Cre+/- controls. Standard chow-fed IL-6Ra KD mice displayed reduced plasma insulin and glucose-stimulated insulin secretion with impaired glucose disposal and unchanged insulin sensitivity. Isolated pancreatic islets from standard chow-fed IL-6Ra KD mice showed comparable morphology and glucose-stimulated insulin secretion to Cre+/- controls. The diminished in vivo insulin secretion exhibited by IL-6Ra KD mice was recovered by blockade of autonomic ganglia.
Conclusions
This study shows that central IL-6Ra signaling contributes to glucose and energy control mechanisms by regulating food intake, energy expenditure, fuel flexibility and insulin secretion. A plausible mechanism linking central IL-6Ra signaling and pancreatic insulin secretion is through the modulation of autonomic output activity. Thus, brain IL-6 signaling may contribute to the central adaptive mechanisms engaged in response to metabolic stress.
Objective
Exercise is a critical component of a healthy lifestyle and a key strategy for the prevention and management of metabolic disease. Identifying molecular mechanisms underlying adaptation in response to chronic physical activity is of critical interest in metabolic physiology. Circadian rhythms broadly modulate metabolism, including muscle substrate utilizationand exercise capacity. Here, we define the molecular and physiological changes induced across the daily cycle by voluntary low intensity daily exercise.
Methods
Wildtype C57BL6/J male and female mice were housed with or without access to a running wheel for six weeks. Maximum running speed was measured at four different zeitgeber times (ZTs, hours after lights on) using either electrical or manual stimulation to motivate continued running on a motorized treadmill. RNA isolated from plantaris muscles at six ZTs was sequenced to establish the impact of daily activity on genome-wide transcription. Patterns of gene expression were analyzed using Gene Set Enrichment Analysis (GSEA) and Detection of Differential Rhythmicity (DODR). Blood glucose, lactate, and ketones, and muscle and liver glycogen were measured before and after exercise.
Results
We demonstrate that the use of mild electrical shocks to motivate running negatively impacts maximum running speed in mice, and describe a manual method to motivate running in rodent exercise studies. Using this method, we show that time of day influences the increase in exercise capacity afforded by six weeks of voluntary wheel running: when maximum running speed is measured at the beginning of the nighttime active period in mice, there is no measurable benefit from a history of daily voluntary running, while maximum increase in performance occurs at the end of the night. We show that daily voluntary exercise dramatically remodels the murine muscle circadian transcriptome. Finally, we describe daily rhythms in carbohydrate metabolism associated with the time-dependent response to moderate daily exercise in mice.
Conclusions
Collectively, these data indicate that chronic nighttime physical activity dramatically remodels daily rhythms of murine muscle gene expression, which in turn support daily fluctuations in exercise performance.
Objectives
Tirzepatide, a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to selective GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes (T2D). These results have fueled mechanistic studies focused on understanding how tirzepatide achieves its therapeutic efficacy. Recently, we found that treatment with tirzepatide improves insulin sensitivity in humans with T2D and obese mice in concert with a reduction in circulating levels of branched-chain amino (BCAAs) and keto (BCKAs) acids, metabolites associated with development of systemic insulin resistance (IR) and T2D. Importantly, these systemic effects were found to be coupled to increased expression of BCAA catabolic genes in thermogenic brown adipose tissue (BAT) in mice. These findings led us to hypothesize that tirzepatide may lower circulating BCAAs/BCKAs by promoting their catabolism in BAT.
Methods
To address this question, we utilized a murine model of diet-induced obesity and employed stable-isotope tracer studies in combination with metabolomic analyses in BAT and other tissues.
Results
Treatment with tirzepatide stimulated catabolism of BCAAs/BCKAs in BAT, as demonstrated by increased labeling of BCKA-derived metabolites, and increases in levels of byproducts of BCAA breakdown, including glutamate, alanine, and 3-hydroxyisobutyric acid (3-HIB). Further, chronic administration of tirzepatide increased levels of multiple amino acids in BAT that have previously been shown to be elevated in response to cold exposure. Finally, chronic treatment with tirzepatide led to a substantial increase in several TCA cycle intermediates (α-ketoglutarate, fumarate, and malate) in BAT.
Conclusions
These findings suggest that tirzepatide induces a thermogenic-like amino acid profile in BAT, an effect that may account for reduced systemic levels of BCAAs in obese IR mice.
The circadian clock aligns physiology with the 24-hour rotation of Earth. Light and food are the main environmental cues (zeitgebers) regulating circadian rhythms in mammals. Yet, little is known about the interaction between specific dietary components and light in coordinating circadian homeostasis. Herein, we focused on essential amino acids and identified tryptophan as a key circadian modulator. Through a multi-omics approach and combinatory diet/light interventions, we demonstrated that tryptophan metabolism modulates temporal regulation of metabolism and transcription programs by buffering photic cues. Specifically, tryptophan metabolites regulate central circadian functions of the suprachiasmatic nucleus and the core clock machinery in the liver. Taken together, our findings propose tryptophan metabolism as a potential point for pharmacologic intervention to modulate phenotypes associated with disrupted circadian rhythms.
- Abstract
- https://www.sciencedirect.com/science/article/pii/S2212877822001247/pdfft?md5=52f77ad6208f84b31d0faabce2b7f23a&pid=1-s2.0-S2212877822001247-main.pdf
Objective
Coactivator-associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of arginine residues on target proteins to regulate critical processes in health and disease. A mechanistic understanding of the role(s) of CARM1 in skeletal muscle biology is only gradually emerging. The purpose of this study was to elucidate the function of CARM1 in regulating the maintenance and plasticity of skeletal muscle.
Methods
We used transcriptomic, methylproteomic, molecular, functional, and integrative physiological approaches to determine the specific impact of CARM1 in muscle homeostasis.
Results
Our data defines the occurrence of arginine methylation in skeletal muscle and demonstrates that this mark occurs on par with phosphorylation and ubiquitination. CARM1 skeletal muscle-specific knockout (mKO) mice displayed altered transcriptomic and arginine methylproteomic signatures with molecular and functional outcomes confirming remodeled skeletal muscle contractile and neuromuscular junction characteristics, which presaged decreased exercise tolerance. Moreover, CARM1 regulates AMPK-PGC-1α signalling during acute conditions of activity-induced muscle plasticity.
Conclusions
This study uncovers the broad impact of CARM1 in the maintenance and remodelling of skeletal muscle biology.
The gut microbiome influences host physiology and disease by interacting directly with cells in the intestine or by producing molecules that enter the host circulation. Since there are a large number of microbial species and since the gut microbiome composition is influenced by many factors, it is challenging to understand the mechanisms involved. One approach involves simultaneously examining individuals in populations for gut microbiome composition, molecular traits using “omics” technologies, such as circulating metabolites quantified using mass spectrometry, and clinical traits. Thus far, such studies in both mice and humans have led to the identification of numerous metabolites that mediate gut microbiome–host interactions. We discuss these findings as well as future applications of the approach.
Objective
Cellular senescence, an irreversible proliferative cell arrest, is caused by excessive intracellular or extracellular stress/damage. Increased senescent cells have been identified in multiple tissues in different metabolic and other aging-related diseases. Recently, several human and mouse studies emphasized the involvement of senescence in development and progression of NAFLD. Hyperinsulinemia, seen in obesity, metabolic syndrome, and other conditions of insulin resistance, has been linked to senescence in adipocytes and neurons. Here, we investigate the possible direct role of chronic hyperinsulinemia in the development of senescence in human hepatocytes.
Methods
Using fluorescence microscopy, immunoblotting, and gene expression, we tested senescence markers in human hepatocytes subjected to chronic hyperinsulinemia in vitro and validated the data in vivo by using liver-specific insulin receptor knockout (LIRKO) mice. The consequences of hyperinsulinemia were also studied in senescent hepatocytes following doxorubicin as a model of stress-induced senescence. Furthermore, the effects of senolytic agents in insulin- and doxorubicin-treated cells were analyzed.
Results
Results showed that exposing the hepatocytes to prolonged hyperinsulinemia promotes the onset of senescence by increasing the expression of p53 and p21. It also further enhanced the senescent phenotype in already senescent hepatocytes. Addition of insulin signaling pathway inhibitors prevented the increase in cell senescence, supporting the direct contribution of insulin. Furthermore, LIRKO mice, in which insulin signaling in the liver is abolished due to deletion of the insulin receptor gene, showed no differences in senescence compared to their wild-type counterparts despite having marked hyperinsulinemia indicating these are receptor-mediated effects. In contrast, the persistent hyperinsulinemia in LIRKO mice enhanced senescence in white adipose tissue. In vitro, senolytic agents dasatinib and quercetin reduced the prosenescent effects of hyperinsulinemia in hepatocytes.
Conclusion
Our findings demonstrate a direct link between chronic hyperinsulinemia and hepatocyte senescence. This effect can be blocked by reducing the levels of insulin receptors or administration of senolytic drugs, such as dasatinib and quercetin.
Dietary glucose is a robust elicitor of central reward responses and ingestion, but the key peripheral sensors triggering these orexigenic mechanisms are not entirely known. Here, we provide the first evidence that glucokinase, an enzyme involved in glucose metabolism and glucosensing, in the taste bud cells, is regulated by metabolic state, dietary factors, and contributes to glucose appetite. These results expand our understanding of sensory inputs underlying nutrition, metabolism, and food reward.
Considerable attention is currently focused on the potential to switch on brown adipose tissue (BAT), or promote browning of white adipose tissue, to elevate energy expenditure and thereby reduce obesity levels. These processes are already known to be switched on by cold exposure. Yet humans living in colder regions do not show lower levels of obesity. This could be because humans shield themselves from external temperatures, or because the resultant changes in BAT and thermogenesis are offset by elevated food intake, or reductions in other components of expenditure. We exposed mice to 11 different ambient temperatures between 5 and 35 °C and characterized their energy balance and body weight/composition. As it got colder mice progressively increased their energy expenditure coincident with changes in thyroid hormone levels and increased BAT activity. Simultaneously, these increases in expenditure were matched by elevated food intake, and body mass remained stable. Nevertheless, within this envelope of unchanged body mass there were significant changes in body composition – with increases in the sizes of the liver and small intestine, presumably to support the greater food intake, and reductions in the level of stored fat – maximally providing about 10% of the total elevated energy demands. Elevating activity of BAT may be a valid strategy to reduce fat storage even if overall body mass is unchanged but if it is mostly offset by elevated food intake, as found here, then the impacts may be small.
Objectives
Cardiorenal syndrome type-3 (CRS-3) is an abrupt worsening of cardiac function secondary to acute kidney injury. Mitochondrial dysfunction is a key pathological mechanism of CRS-3, and empagliflozin can improve mitochondrial biology by promoting mitophagy. Here, we assessed the effects of empagliflozin on mitochondrial quality surveillance in a mouse model of CRS-3.
Methods
Cardiomyocyte-specific FUNDC1-knockout (FUNDC1CKO) mice were subjected to CRS-3 prior to assessment of mitochondrial homeostasis in the presence or absence of empagliflozin.
Results
CRS-3 model mice exhibited lower heart function, increased inflammatory responses and exacerbated myocardial oxidative stress than sham-operated controls; however, empagliflozin attenuated these alterations. Empagliflozin stabilized the mitochondrial membrane potential, suppressed mitochondrial reactive oxygen species production, increased mitochondrial respiratory complex activity and restored the oxygen consumption rate in cardiomyocytes from CRS-3 model mice. Empagliflozin also normalized the mitochondrial morphology, mitochondrial dynamics and mitochondrial permeability transition pore opening rate in cardiomyocytes. Cardiomyocyte-specific ablation of FUN14 domain-containing protein 1 (FUNDC1) in mice abolished the protective effects of empagliflozin on mitochondrial homeostasis and myocardial performance. Empagliflozin activated β-catenin and promoted its nuclear retention, thus increasing FUNDC1-induced mitophagy in heart tissues; however, a β-catenin inhibitor reversed these effects.
Conclusions
In summary, empagliflozin activated Wnt/β-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance, ultimately improving mitochondrial function and cardiac performance during CRS-3. Thus, empagliflozin could be considered for the clinical management of heart function following acute kidney injury.
Objective
Cyclin C (CCNC) is the most conserved subunit of the Mediator complex, which is an important transcription cofactor. Recently, we have found that CCNC facilitates brown adipogenesis in vitro by activating C/EBPα-dependent transcription. However, the role of CCNC in brown adipose tissue (BAT) in vivo remains unclear.
Methods
We generated conditional knock-out mice by crossing Ccncflox/flox mice with Myf5Cre, Ucp1Cre or AdipoqCre transgenic mice to investigate the role of CCNC in BAT development and function. We applied glucose and insulin tolerance test, cold exposure and indirect calorimetry to capture the physiological phenotypes and used immunostaining, immunoblotting, qRT-PCR, RNA-seq and cell culture to elucidate the underlying mechanisms.
Results
Here, we show that deletion of CCNC in Myf5+ progenitor cells caused BAT paucity, despite the fact that there was significant neonatal lethality. Mechanistically different from in vitro, CCNC deficiency impaired the proliferation of embryonic brown fat progenitor cells without affecting brown adipogenesis or cell death. Interestingly, CCNC deficiency robustly reduced age-dependent lipid accumulation in differentiated brown adipocytes in all three mouse models. Mechanistically, CCNC in brown adipocytes is required for lipogenic gene expression through the activation of the C/EBPα/GLUT4/ChREBP axis. Consistent with the importance of de novo lipogenesis under carbohydrate-rich diets, high-fat diet (HFD) feeding abolished CCNC deficiency -caused defects of lipid accumulation in BAT. Although insulin sensitivity and response to acute cold exposure were not affected, CCNC deficiency in Ucp1+ cells enhanced the browning of white adipose tissue (beiging) upon prolonged cold exposure.
Conclusions
Together, these data indicate an important role of CCNC-Mediator in the regulation of BAT development and lipid accumulation in brown adipocytes.
Background
Bariatric or weight loss surgery is currently the most effective treatment for obesity and metabolic disease. Unlike dieting and pharmacology, its beneficial effects are sustained over decades in most patients, and mortality is among the lowest for major surgery. Because there are not nearly enough surgeons to implement bariatric surgery on a global scale, intensive research efforts have begun to identify its mechanisms of action on a molecular level in order to replace surgery with targeted behavioral or pharmacological treatments. To date, however, there is no consensus as to the critical mechanisms involved.
Scope of review
The purpose of this non-systematic review is to evaluate the existing evidence for specific molecular and inter-organ signaling pathways that play major roles in bariatric surgery-induced weight loss and metabolic benefits, with a focus on Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), in both humans and rodents.
Major conclusions
Gut-brain communication and its brain targets of food intake control and energy balance regulation are complex and redundant. Although the relatively young science of bariatric surgery has generated a number of hypotheses, no clear and unique mechanism has yet emerged. It seems increasingly likely that the broad physiological and behavioral effects produced by bariatric surgery do not involve a single mechanism, but rather multiple signaling pathways. Besides a need to improve and better validate surgeries in animals, advanced techniques, including inducible, tissue-specific knockout models, and the use of humanized physiological traits will be necessary. State-of-the-art genetically-guided neural identification techniques should be used to more selectively manipulate function-specific pathways.
2021 impact factor: 8.568
The 60 Second Metabolist
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