Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing

Defective insulin processing is associated with obesity and diabetes. Prohormone convertase 1/3 (PC1/3) is an endopeptidase required for the processing of neurotransmitters and hormones. PC1/3 deficiency and genome-wide association studies relate PC1/3 with early onset obesity. Here, we find that deletion of PC1/3 in obesity-related neuronal cells expressing proopiomelanocortin mildly and transiently change body weight and fail to produce a phenotype when targeted to Agouti-related peptide- or nestin-expressing tissues. In contrast, pancreatic β cell-specific PC1/3 ablation induces hyperphagia with consecutive obesity despite uncontrolled diabetes with glucosuria. Obesity develops not due to impaired pro-islet amyloid polypeptide processing but due to impaired insulin maturation. Proinsulin crosses the blood-brain-barrier but does not induce central satiety. Accordingly, insulin therapy prevents hyperphagia. Further, islet PC1/3 expression levels negatively correlate with body mass index in humans. In this work, we show that impaired PC1/3-mediated proinsulin processing, as observed in human prediabetes, promotes hyperphagic obesity

Lung versus gut exposure to air pollution particles differentially affect metabolic health in mice

BACKGROUND Air pollution has emerged as an unexpected risk factor for diabetes. However, the mechanism behind remains ill-defined. So far, the lung has been considered as the main target organ of air pollution. In contrast, the gut has received little scientific attention. Since air pollution particles can reach the gut after mucociliary clearance from the lungs and through contaminated food, our aim was to assess whether exposure deposition of air pollution particles in the lung or the gut drive metabolic dysfunction in mice. METHODS To study the effects of gut versus lung exposure, we exposed mice on standard diet to diesel exhaust particles (DEP; NIST 1650b), particulate matter (PM; NIST 1649b) or phosphate-buffered saline by either intratracheal instillation (30 µg 2 days/week) or gavage (12 µg 5 days/week) over at least 3 months (total dose of 60 µg/week for both administration routes, equivalent to a daily inhalation exposure in humans of 160 µg/m$^{3}$ PM$_{2.5}$) and monitored metabolic parameters and tissue changes. Additionally, we tested the impact of the exposure route in a "prestressed" condition (high-fat diet (HFD) and streptozotocin (STZ)). RESULTS Mice on standard diet exposed to particulate air pollutants by intratracheal instillation developed lung inflammation. While both lung and gut exposure resulted in increased liver lipids, glucose intolerance and impaired insulin secretion was only observed in mice exposed to particles by gavage. Gavage with DEP created an inflammatory milieu in the gut as shown by up-regulated gene expression of pro-inflammatory cytokines and monocyte/macrophage markers. In contrast, liver and adipose inflammation markers were not increased. Beta-cell secretory capacity was impaired on a functional level, most likely induced by the inflammatory milieu in the gut, and not due to beta-cell loss. The differential metabolic effects of lung and gut exposures were confirmed in a "prestressed" HFD/STZ model. CONCLUSIONS We conclude that separate lung and gut exposures to air pollution particles lead to distinct metabolic outcomes in mice. Both exposure routes elevate liver lipids, while gut exposure to particulate air pollutants specifically impairs beta-cell secretory capacity, potentially instigated by an inflammatory milieu in the gut

CSF1R inhibition with PLX5622 affects multiple immune cell compartments and induces tissue-specific metabolic effects in lean mice

AIMS/HYPOTHESIS Colony stimulating factor 1 (CSF1) promotes the proliferation, differentiation and survival of macrophages, which have been implicated in both beneficial and detrimental effects on glucose metabolism. However, the physiological role of CSF1 signalling in glucose homeostasis and the potential therapeutic implications of modulating this pathway are not known. We aimed to study the composition of tissue macrophages (and other immune cells) following CSF1 receptor (CSF1R) inhibition and elucidate the metabolic consequences of CSF1R inhibition. METHODS We assessed immune cell populations in various organs by flow cytometry, and tissue-specific metabolic effects by hyperinsulinaemic-euglycaemic clamps and insulin secretion assays in mice fed a chow diet containing PLX5622 (a CSF1R inhibitor) or a control diet. RESULTS CSF1R inhibition depleted macrophages in multiple tissues while simultaneously increasing eosinophils and group 2 innate lymphoid cells. These immunological changes were consistent across different organs and were sex independent and reversible after cessation of the PLX5622. CSF1R inhibition improved hepatic insulin sensitivity but concomitantly impaired insulin secretion. In healthy islets, we found a high frequency of IL-1β$^{+}$ islet macrophages. Their depletion by CSF1R inhibition led to downregulation of macrophage-related pathways and mediators of cytokine activity, including Nlrp3, suggesting IL-1β as a candidate insulin secretagogue. Partial restoration of physiological insulin secretion was achieved by injecting recombinant IL-1β prior to glucose stimulation in mice lacking macrophages. CONCLUSIONS/INTERPRETATION Macrophages and macrophage-derived factors, such as IL-1β, play an important role in physiological insulin secretion. A better understanding of the tissue-specific effects of CSF1R inhibition on immune cells and glucose homeostasis is crucial for the development of targeted immune-modulatory treatments in metabolic disease. DATA AVAILABILITY The RNA-Seq dataset is available in the Gene Expression Omnibus (GEO) under the accession number GSE189434 ( http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE189434 )

Specific immune modulation of experimental colitis drives enteric alpha-synuclein accumulation and triggers age-related Parkinson-like brain pathology

Background: In some people with Parkinson’s disease (PD), a-synuclein (αSyn) accumulation may begin in the enteric nervous system (ENS) decades before development of brain pathology and disease diagnosis. Objective: To determine how different types and severity of intestinal inflammation could trigger αSyn accumulation in the ENS and the subsequent development of αSyn brain pathology. Methods: We assessed the effects of modulating short- and long-term experimental colitis on αSyn accumulation in the gut of αSyn transgenic and wild type mice by immunostaining and gene expression analysis. To determine the long-term effect on the brain, we induced dextran sulfate sodium (DSS) colitis in young αSyn transgenic mice and aged them under normal conditions up to 9 or 21 months before tissue analyses. Results: A single strong or sustained mild DSS colitis triggered αSyn accumulation in the submucosal plexus of wild type and αSyn transgenic mice, while short-term mild DSS colitis or inflammation induced by lipopolysaccharide did not have such an effect. Genetic and pharmacological modulation of macrophage-associated pathways modulated the severity of enteric αSyn. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain (including the substantia nigra), in 21- but not 9-month-old αSyn transgenic mice. This increase in midbrain αSyn accumulation is accompanied by the loss of tyrosine hydroxylase-immunoreactive nigral neurons. Conclusions: Our data suggest that specific types and severity of intestinal inflammation, mediated by monocyte/macrophage signaling, could play a critical role in the initiation and progression of PD

Bridging the gap: integrating deep brain stimulation imaging and clinical data in a unified data management system

International audienceWe present a novel data management system tailored for Deep Brain Stimulation (DBS) research. It addresses challenges in heterogeneous data collection and management during the patient journey and subsequent data analyses. The system integrates an Electronic Data Capture platform (REDCap), a relational database (SQLite), and a brain imaging file structure standard (BIDS), facilitating efficient data capture, storage, and analysis. The system demonstrates improved data quality, organization, analysis, and collaboration potential

REDCAP AND SQLITE: A powerful combination for streamlining metadata capture in deep brain stimulation research

International audienceThe field of Neurosciences research faces significant challenges in managing heterogeneous data types. While the Brain Imaging Data Structure (BIDS) offers a standardized format for brain imaging data organization, its limitations in capturing detailed clinical metadata, such as longitudinal clinical scores or demographic information become apparent in data analysis pipelines. To address this critical limitation, this work proposes a framework for enhanced metadata capture based on the example of Deep Brain Stimulation (DBS). It leverages BIDS with Research Electronic Data Capture (REDCap), a secure web-based platform designed for validated data collection, and SQLite, a lightweight relational database management system capable of storing structured metadata. BIDS offers organization of data in neuroscience research, and RedCap user-friendly clinical data entry for clinicians. Patient-related metadata (e.g. demographics, medication, neurological assessments) is collected via structured forms within REDCap. Medical image data, originating from Brainlab Elements neurosurgical planning station, is stored and transferred in the anonymized DICOMDIR format. To ensureBIDS compliance, a custom Python script extracts relevant information from the DICOMDIR data. This extracted data is converted into the Neuroimaging Informatics Technology Initiative (NIfTI) format, and the resulting files are stored in a BIDS-compliant directory structure. Additionally, image references are established within the SQLite database, which also serves as repository for metadata extracted from REDCap. To validate the proposed framework, data was collected and analyzed from two medical institutions: the University Hospitals Basel and Clermont-Ferrand. Our framework has successfully captured data for 107 patients, with an average of 35 imaging files including MRI and CT scans and labeled anatomical structures. This data is stored and managed within the patient-centric SQLite database. The database schema comprises 28 tables, 230 data fields (e.g. patient ID, age, implanted position, image file path) and 33 established relationships between these tables. The advantages of using such a system can be particularly appreciated in the use-case of group-level analysis. The system design facilitates efficient retrieval of structured clinical data. Furthermore, the framework effectively handles and stores files generated during post-processing steps, ensuring data integrity and traceability. This work demonstrates the successful integration of a translational tool for streamlining data collection and organization between clinics and research institutes. Our framework captures both standardized imaging data and comprehensive patient-metadata within a unified system. This enables researchers not only in the field of DBS but from the Neurosciences in general to leverage the richness of both types of data, potentially leading to improved clinical decision-making and ultimately, better patient outcomes

Pancreatic α Cell-Derived Glucagon-Related Peptides Are Required for β Cell Adaptation and Glucose Homeostasis

Pancreatic α cells may process proglucagon not only to glucagon but also to glucagon-like peptide-1 (GLP-1). However, the biological relevance of paracrine GLP-1 for β cell function remains unclear. We studied effects of locally derived insulin secretagogues on β cell function and glucose homeostasis using mice with α cell ablation and with α cell-specific GLP-1 deficiency. Normally, intestinal GLP-1 compensates for the lack of α cell-derived GLP-1. However, upon aging and metabolic stress, glucose tolerance is impaired. This was partly rescued with the DPP-4 inhibitor sitagliptin, but not with glucagon administration. In isolated islets from these mice, glucose-stimulated insulin secretion was heavily impaired and exogenous GLP-1 or glucagon rescued insulin secretion. These data highlight the importance of α cell-derived GLP-1 for glucose homeostasis during metabolic stress and may impact on the clinical use of systemic GLP-1 agonists versus stabilizing local α cell-derived GLP-1 by DPP-4 inhibitors in type 2 diabetes

The Cephalic Phase of Insulin Release is Modulated by Il-1β

The initial cephalic phase of insulin secretion is mediated through the vagus nerve and is not due to glycemic stimulation of pancreatic β-cells. Recently, IL-1β was shown to stimulate postprandial insulin secretion. Here, we describe that this incretin-like effect of IL-1β involves neuronal transmission. Further we found that cephalic phase insulin release was mediated by IL-1β originating from long-lived CX3CR1+ myeloid cells. Moreover, IL-1β activated the vagus nerve to induce insulin secretion and regulated the activity of neurons of the paraventricular nucleus of the hypothalamus in response to cephalic stimulation. Notably, cephalic phase insulin release was impaired in obesity, in both mice and humans, and in mice this was due to dysregulated IL-1β signaling. Our findings attribute a regulatory role to IL-1β in the integration of nutrient-derived sensory information, subsequent neuronally-mediated insulin secretion and the dysregulation of autonomic cephalic phase responses in obesity

Proteogenomics analysis unveils a TFG-RET gene fusion and druggable targets in papillary thyroid carcinomas

Papillary thyroid cancer (PTC) is the most common type of endocrine malignancy. By RNA-seq analysis, we identify a RET rearrangement in the tumour material of a patient who does not harbour any known RAS or BRAF mutations. This new gene fusion involves exons 1–4 from the 5′ end of the Trk fused Gene (TFG) fused to the 3′ end of RET tyrosine kinase leading to a TFG-RET fusion which transforms immortalized human thyroid cells in a kinase-dependent manner. TFG-RET oligomerises in a PB1 domain-dependent manner and oligomerisation of TFG-RET is required for oncogenic transformation. Quantitative proteomic analysis reveals the upregulation of E3 Ubiquitin ligase HUWE1 and DUBs like USP9X and UBP7 in both tumor and metastatic lesions, which is further confirmed in additional patients. Expression of TFG-RET leads to the upregulation of HUWE1 and inhibition of HUWE1 significantly reduces RET-mediated oncogenesis

Interleukin-33-Activated Islet-Resident Innate Lymphoid Cells Promote Insulin Secretion through Myeloid Cell Retinoic Acid Production

Pancreatic-islet inflammation contributes to the failure of β cell insulin secretion during obesity and type 2 diabetes. However, little is known about the nature and function of resident immune cells in this context or in homeostasis. Here we show that interleukin (IL)-33 was produced by islet mesenchymal cells and enhanced by a diabetes milieu (glucose, IL-1β, and palmitate). IL-33 promoted β cell function through islet-resident group 2 innate lymphoid cells (ILC2s) that elicited retinoic acid (RA)-producing capacities in macrophages and dendritic cells via the secretion of IL-13 and colony-stimulating factor 2. In turn, local RA signaled to the β cells to increase insulin secretion. This IL-33-ILC2 axis was activated after acute β cell stress but was defective during chronic obesity. Accordingly, IL-33 injections rescued islet function in obese mice. Our findings provide evidence that an immunometabolic crosstalk between islet-derived IL-33, ILC2s, and myeloid cells fosters insulin secretion