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The identification of brown adipose tissue (BAT) as a thermogenic organ in human adults approximately 20 years ago raised the exciting possibility of activating this tissue as a new treatment for obesity and cardiometabolic disease. [18F]Fluoro-2-deoxyglucose (18F-FDG) combined positron emission tomography and computed tomography (PET/CT) scanning is the most commonly used imaging modality to detect and quantify human BAT activity in vivo. This technique exploits the substantial glucose uptake by BAT during thermogenesis as a marker for BAT metabolism. 18F-FDG PET has provided substantial insights into human BAT physiology, including its regulatory pathways and the effect of obesity and cardiometabolic disease on BAT function. The use of alternative PET tracers and the development of novel techniques such as magnetic resonance imaging, supraclavicular skin temperature measurements, contrast-enhanced ultrasound, near-infrared spectroscopy and microdialysis have all added complementary information to improve our understanding of human BAT. However, many questions surrounding BAT physiology remain unanswered, highlighting the need for further research and novel approaches to investigate this tissue. This review critically discusses current techniques to assess human BAT function in vivo, the insights gained from these modalities and their limitations. We also discuss other promising techniques in development that will help dissect the pathways regulating human thermogenesis and determine the therapeutic potential of BAT activation.
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Search for other papers by the JDRF-DiabetesUK-INNODIA-nPOD Stockholm Symposium 2022 in
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There is a growing understanding that the early phases of type 1 diabetes (T1D) are characterised by a deleterious dialogue between the pancreatic beta cells and the immune system. This, combined with the urgent need to better translate this growing knowledge into novel therapies, provided the background for the JDRF–DiabetesUK–INNODIA–nPOD symposium entitled ‘Islet cells in human T1D: from recent advances to novel therapies’, which took place in Stockholm, Sweden, in September 2022. We provide in this article an overview of the main themes addressed in the symposium, pointing to both promising conclusions and key unmet needs that remain to be addressed in order to achieve better approaches to prevent or reverse T1D.
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The mineralocorticoid receptor (MR) plays a critical role in the mammalian brain as a mediator of appropriate cellular and behavioural responses under both baseline and stressful conditions. In the hippocampus, the MR has been implicated in several processes, such as neuronal maintenance, adult neurogenesis, inhibitory control of the hypothalamic–pituitary–adrenal axis, and learning and memory. Because of its high affinity for endogenous glucocorticoid hormones, the MR has long been postulated to mediate tonic actions in the brain, but more recent data have expanded on this view, indicating that the MR elicits dynamic responses as well. The complexity of the diverse molecular, cellular, and physiological functions fulfilled by the human, rat and mouse MR could at least partially be explained by the existence of different isoforms of the receptor. The structural and functional characteristics of these isoforms, however, have remained largely unexplored. The present article will review the current knowledge concerning human, rat, and mouse MR isoforms and evaluate seminal studies concerning the roles of the brain MR, with the intent to shed light on the function of its specific isoforms.
Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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Cell protein biosynthesis is regulated by different factors, but implication of intercellular contacts on alpha and beta cell protein biosyntheses activity has not been yet investigated. Islet cell biosynthetic activity is essential in regulating not only the hormonal reserve within cells but also in renewing all the proteins involved in the control of secretion. Here we aimed to assess whether intercellular interactions affected similarly secretion and protein biosynthesis of rat alpha and beta cells. Insulin and glucagon secretion were analyzed by ELISA or reverse hemolytic plaque assay, and protein biosynthesis evaluated at single cell level using bioorthogonal noncanonical amino acid tagging. Regarding beta cells, we showed a positive correlation between insulin secretion and protein biosynthesis. We also observed that homologous contacts increased both activities at low or moderate glucose concentrations. By contrast, at high glucose concentration, homologous contacts increased insulin secretion and not protein biosynthesis. In addition, heterogeneous contacts between beta and alpha cells had no impact on insulin secretion and protein biosynthesis. Regarding alpha cells, we showed that when they were in contact with beta cells, they increased their glucagon secretion in response to a drop of glucose concentration, but, on the other hand, they decreased their protein biosynthesis under any glucose concentrations. Altogether, these results emphasize the role of intercellular contacts on the function of islet cells, showing that intercellular contacts increased protein biosynthesis in beta cells, except at high glucose, and decreased protein biosynthesis in alpha cells even when glucagon secretion is stimulated.
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Department of Physiology, Institute of Neuroscience and Physiology, Metabolic Research Unit, University of Gothenburg, Göteborg, Sweden
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CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
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Glucagon is the principal glucose-elevating hormone that forms the first-line defence against hypoglycaemia. Along with insulin, glucagon also plays a key role in maintaining systemic glucose homeostasis. The cells that secrete glucagon, pancreatic α-cells, are electrically excitable cells and use electrical activity to couple its hormone secretion to changes in ambient glucose levels. Exactly how glucose regulates α-cells has been a topic of debate for decades but it is clear that electrical signals generated by the cells play an important role in glucagon secretory response. Decades of studies have already revealed the key players involved in the generation of these electrical signals and possible mechanisms controlling them to tune glucagon release. This has offered the opportunity to fully understand the enigmatic α-cell physiology. In this review, we describe the current knowledge on cellular electrophysiology and factors regulating excitability, glucose sensing, and glucagon secretion. We also discuss α-cell pathophysiology and the perspective of addressing glucagon secretory defects in diabetes for developing better diabetes treatment, which bears the hope of eliminating hypoglycaemia as a clinical problem in diabetes care.
Simons Initiative for the Developing Brain, The University of Edinburgh, Edinburgh, UK
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In biomedicine and many other fields, there are growing concerns around the reproducibility of research findings, with many researchers being unable to replicate their own or others’ results. This raises important questions as to the validity and usefulness of much published research. In this review, we aim to engage researchers in the issue of research reproducibility and equip them with the necessary tools to increase the reproducibility of their research. We first highlight the causes and potential impact of non-reproducible research and emphasise the benefits of working reproducibly for the researcher and broader research community. We address specific targets for improvement and steps that individual researchers can take to increase the reproducibility of their work. We next provide recommendations for improving the design and conduct of experiments, focusing on in vivo animal experiments. We describe common sources of poor internal validity of experiments and offer practical guidance for limiting these potential sources of bias at different experimental stages, as well as discussing other important considerations during experimental design. We provide a list of key resources available to researchers to improve experimental design, conduct, and reporting. We then discuss the importance of open research practices such as study preregistration and the use of preprints and describe recommendations around data management and sharing. Our review emphasises the importance of reproducible work and aims to empower every individual researcher to contribute to the reproducibility of research in their field.
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Despite the existence of numerous studies supporting a pathological link between fructose consumption and the development of the metabolic syndrome and its sequelae, such as non-alcoholic fatty liver disease (NAFLD), this link remains a contentious issue. With this article, we shed a light on the impact of sugar/fructose intake on hepatic de novo lipogenesis (DNL), an outcome parameter known to be dysregulated in subjects with type 2 diabetes and/or NAFLD. In this review, we present findings from human intervention studies using physiological doses of sugar as well as mechanistic animal studies. There is evidence from both human and animal studies that fructose is a more potent inducer of hepatic lipogenesis than glucose. This is most likely due to the liver’s prominent physiological role in fructose metabolism, which may be disrupted under pathological conditions by increased hepatic expression of fructolytic and lipogenic enzymes. Increased DNL may not only contribute to ectopic fat deposition (i.e. in the liver), but it may also impair several metabolic processes through DNL-related fatty acids (e.g. beta-cell function, insulin secretion, or insulin sensitivity).
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Micronutrients consumed in excess or imbalanced amounts during pregnancy may increase the risk of metabolic diseases in offspring, but the mechanisms underlying these effects are unknown. Serotonin (5-hydroxytryptamine, 5-HT), a multifunctional indoleamine in the brain and the gut, may have key roles in regulating metabolism. We investigated the effects of gestational micronutrient intakes on the central and peripheral serotonergic systems as modulators of the offspring's metabolic phenotypes. Pregnant Wistar rats were fed an AIN-93G diet with 1-fold recommended vitamins (RV), high 10-fold multivitamins (HV), high 10-fold folic acid with recommended choline (HFolRC), or high 10-fold folic acid with no choline (HFolNC). Male and female offspring were weaned to a high-fat RV diet for 12 weeks. We assessed the central function using the 5-HT2C receptor agonist, 1-(3-chlorophenyl)piperazine (mCPP), and found that male offspring from the HV- or HFolRC-fed dams were less responsive (P < 0.05) whereas female HFolRC offspring were more responsive to mCPP (P < 0.01) at 6 weeks post-weaning. Male and female offspring from the HV and HFolNC groups, and male HFolRC offspring had greater food intake (males P < 0.001; females P < 0.001) and weight gain (males P < 0.0001; females P < 0.0001), elevated colon 5-HT (males P < 0.01; females P < 0.001) and fasting glucose concentrations (males P < 0.01; females P < 0.01), as well as body composition toward obesity (males P < 0.01; females P < 0.01) at 12 weeks post-weaning. Colon 5-HT was correlated with fasting glucose concentrations (males R2=0.78, P < 0.0001; females R2=0.71, P < 0.0001). Overall, the serotonergic systems are sensitive to the composition of gestational micronutrients, with alterations consistent with metabolic disturbances in offspring.
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Breast cancer (BC) is the most diagnosed cancer in women worldwide. In estrogen receptor (ER)-positive disease, anti-estrogens and aromatase inhibitors (AI) improve patient survival; however, many patients develop resistance. Dysregulation of apoptosis is a common resistance mechanism; thus, agents that can reinstate the activity of apoptotic pathways represent promising therapeutics for advanced drug-resistant disease. Emerging targets in this scenario include microRNAs (miRs). To identify miRs modulating apoptosis in drug-responsive and -resistant BC, a high-throughput miR inhibitor screen was performed, followed by high-content screening microscopy for apoptotic markers. Validation demonstrated that miR-361-3p inhibitor significantly increases early apoptosis and reduces proliferation of drug-responsive (MCF7), plus AI-/antiestrogen-resistant derivatives (LTED, TamR, FulvR), and ER- cells (MDA-MB-231). Importantly, proliferation-inhibitory effects were observed in vivo in a xenograft model, indicating the potential clinical application of miR-361-3p inhibition. RNA-seq of tumour xenografts identified FANCA as a direct miR-361-3p target, and validation suggested miR-361-3p inhibitor effects might be mediated in part through FANCA modulation. Moreover, miR-361-3p inhibition resulted in p53-mediated G1 cell cycle arrest through activation of p21 and reduced BC invasion. Analysis of publicly available datasets showed miR-361-3p expression is significantly higher in primary breast tumours vspaired normal tissue and is associated with decreased overall survival. In addition, miR-361-3p inhibitor treatment of BC patient explants decreased levels of miR-361-3p and proliferation marker, Ki67. Finally, miR-361-3p inhibitor showed synergistic effects on BC growth when combined with PARP inhibitor, Olaparib. Together, these studies identify miR-361-3p inhibitor as a potential new treatment for drug-responsive and -resistant advanced BC.
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The human body is inhabited by numerous bacteria, fungi, and viruses, and each part has a unique microbial community structure. The gastrointestinal tract harbors approximately 100 trillion strains comprising more than 1000 bacterial species that maintain symbiotic relationships with the host. The gut microbiota consists mainly of the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Of these, Firmicutes and Bacteroidetes constitute 70–90% of the total abundance. Gut microbiota utilize nutrients ingested by the host, interact with other bacterial species, and help maintain healthy homeostasis in the host. In recent years, it has become increasingly clear that a breakdown of the microbial structure and its functions, known as dysbiosis, is associated with the development of allergies, autoimmune diseases, cancers, and arteriosclerosis, among others. Metabolic diseases, such as obesity and diabetes, also have a causal relationship with dysbiosis. The present review provides a brief overview of the general roles of the gut microbiota and their relationship with metabolic disorders.
