Obesity is a growing global health epidemic with limited orally administered therapeutics. Serotonin (5-HT) is one neurotransmitter which remains an excellent target for new weight-loss therapies, but a gap remains in understanding the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using an optogenetic feeding paradigm, we showed that the 5-HTDRN➔arcuate nucleus (ARH) circuit plays a role in meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the role of dopaminergic inputs via dopamine receptor D2 in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, for the initiation of a meal.
Aims: A number of studies have suggested that pancreatic α cells produce intact GLP-1, thereby constituting a gut-independent paracrine incretin system. However, the debate on whether human α cells contain intact GLP-1 and whether this relates to the presence of diabetes is still ongoing. This study aimed to determine the presence of proglucagon-derived peptides, including GLP-1 isoforms, in pancreas biopsies obtained during partial pancreatectomy from metabolically profiled human donors, stratified according to pre-surgery glucose tolerance.
Methods: We enrolled 61 individuals with no known history of type 2 diabetes (31F/30M, age 64.6 ± 10.6 yrs., BMI 24.2 ± 3.68 kg/m2) scheduled for partial pancreatectomy for periampullary neoplasm. Differences in glucose tolerance and insulin secretion/sensitivity were assessed using preoperative 2 h OGTT, 4 h-Mixed Meal Test and Hyperinsulinemic Euglycemic Clamp. Subjects were subsequently classified as normal glucose tolerant (NGT, n = 19), impaired glucose tolerant (IGT, n = 20) or newly diagnosed diabetes (DM) (n = 22). We measured total GLP-1, intact GLP-1, glucagon, insulin, and C-peptide in pancreas biopsies and plasma from these subjects and correlated the results with their secretory and metabolic parameters.
Results: Extractable levels of total GLP-1 were 23.9 ± 2.66 pmol/g, while intact GLP-1 levels were 1.15 ± 0.18 pmol/g. When we examined proglucagon derived peptides (adjusted for glucagon levels), in subjects classified according to glucose tolerance, we observed similar levels of total GLP-1, however, intact GLP-1 was significantly increased in IGT and DM groups and inversely associated with beta cell glucose sensitivity and insulin secretion in vivo.
Conclusions: Our data show that development of glucose intolerance and beta cell dysfunction are significantly associated with increased levels of intra-islet intact GLP-1, a potentially beneficial adaptation of the paracrine regulation of insulin secretion in type 2 diabetes.
Pancreatic islet cells harbor primary cilia, small sensory organelles that detect environmental changes to regulate hormone secretion and intercellular communication. While the sensory and signaling capacity of primary cilia are well-appreciated, it is less recognized that these organelles also possess active motility, including in dense multicellular tissues such as the pancreatic islet. In this manuscript, we use transgenic cilia reporter mice and an intravital imaging approach to quantitate primary cilia dynamics as it occurs in live mouse pancreatic islets. We validate this imaging workflow as suitable for studying islet cilia motion in real time in vivo and demonstrate that glucose stimulation corresponds to a change in cilia motility, which may be a physiologic measure of nutrient-dependent fluxes in islet cell function. Complementary ex vivo analysis of isolated islets further demonstrates that metabolic stress in the form of lipotoxicity impairs cilia motility and these effects can be reversed by glucose elevation. These findings suggest that cilia motility is sensitive to metabolic stress and highlight its potential functional role in beta cell adaptation.
Background: There are no known non-invasive tests (NITs) designed for accurately detecting metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis stages F2-F3, excluding cirrhosis-the FDA-defined range for prescribing Resmetirom and other drugs in clinical trials. We aimed to validate and re-optimize known NITs, and most importantly to develop new machine learning (ML)-based NITs to accurately detect MASH F2-F3.
Methods: Clinical and metabolomic data were collected from 443 patients across three countries and two clinic types (metabolic surgery, gastroenterology/hepatology) covering the entire spectrum of biopsy-proven MASH, including cirrhosis and healthy controls. Three novel types of ML models were developed using a categorical gradient boosting machine pipeline under a classic 4:1 split and a secondary independent validation analysis. These were compared with twenty-three biomarker, imaging, and algorithm-based NITs with both known and re-optimized cutoffs for MASH F2-F3.
Results: The NAFLD (Non-Alcoholic Fatty Liver Disease) Fibrosis Score (NFS) at a - 1.455 cutoff attained an area under the receiver operating characteristic curve (AUC) of 0.59, the highest sensitivity (90.9 %), and a negative predictive value (NPV) of 87.2 %. FIB-4 risk stratification followed by elastography (8 kPa) had the best specificity (86.9 %) and positive predictive value (PPV) (63.3 %), with an AUC of 0.57. NFS followed by elastography improved the PPV to 65.3 % and AUC to 0.62. Re-optimized FibroScan-AST (FAST) at a 0.22 cutoff had the highest PPV (69.1 %). ML models using aminotransferases, metabolic syndrome components, BMI, and 3-ureidopropionate achieved an AUC of 0.89, which further increased to 0.91 following hyperparameter optimization and the addition of alpha-ketoglutarate. These new ML models outperformed all other NITs and displayed accuracy, sensitivity, specificity, PPV, and NPV up to 91.2 %, 85.3 %, 97.0 %, 92.4 %, and 90.7 % respectively. The models were reproduced and validated in a secondary sensitivity analysis, that used one of the cohorts as feature selection/training, and the rest as independent validation, likewise outperforming all other applicable NITs.
Conclusions: We report for the first time the diagnostic characteristics of non-invasive, metabolomics-based biomarker models to detect MASH with fibrosis F2-F3 required for Resmetirom treatment and inclusion in ongoing phase-III trials. These models may be used alone or in combination with other NITs to accurately determine treatment eligibility.
Background: In light of the new nomenclature of steatotic liver disease (SLD), we aimed to enhance the existing knowledge on the epidemiology and clinical outcomes of metabolic and alcohol related/associated liver disease (MetALD).
Methods: A systematic review and meta-analysis were performed in Medline/PubMed, Embase, Scopus and Cochrane databases to evaluate the prevalence and outcomes of MetALD within the SLD population and to compare the characteristics between MetALD patients and those with metabolic dysfunction associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD). Nineteen studies from nine countries that evaluated 4,543,341 adult participants with SLD were included.
Results: The pooled overall prevalence of MetALD among the SLD population was 10 % (95%CI:7-13 %) without significant difference between Asian and non-Asian populations. However, MetALD was more frequent in men than women (86 % vs 14 %, p < 0.01), while Asian MetALD patients, were more frequent men (92 % vs 66 %, p < 0.01) compared to non-Asians. Additionally, in terms of metabolic characteristics there were no significant differences between MetALD, MASLD and ALD patients. Regarding outcomes, patients with MetALD, compared to non-SLD, were at increased risk of all-cause [HR 1.44 (95%CI:1.24-1.66)], cardiovascular disease (CVD) [HR 1.17 (95%CI:1.12-1.21)] and cancer-related mortality [HR 2.07 (95%CI:1.32-3.25)]. Finally, patients with MetALD, had increased incidence of CVD and liver decompensating events, compared to non-SLD participants [HR 1.49 (95%CI:1.03-2.15); HR 10.55 (95%CI:3.46-32.16) respectively].
Conclusions: Based on the existing literature, patients with MetALD consist a significant part of the SLD population, with high all-cause, CVD and cancer-related mortality and increased risk for CVD and hepatic decompensation.
PPARγ functions as a master ligand-dependent transcription factor that regulates the expressions of a variety of key genes related to metabolic homeostasis and inflammatory immunity. It has been recognized as a popular and druggable target in modern drug discovery. Similar to other nuclear receptors, PPARγ is a phosphoprotein, and its biological functions are regulated by phosphorylation, especially at Ser273 site which is mediated by CDK5 or ERK. In the past decade, the excessive level of PPARγ-Ser273 phosphorylation has been confirmed to be a crucial factor in promoting the occurrence and development of some major diseases. Ligands capable of inhibiting PPARγ-Ser273 phosphorylation have shown great potentials for treatment. Despite these achievements, to our knowledge, no related review focusing on this topic has been conducted so far. Therefore, we herein summarize the basic knowledge of PPARγ and CDK5/ERK-mediated PPARγ-Ser273 phosphorylation as well as its physiopathological role in representative diseases. We also review the developments and therapeutic applications of PPARγ-targeted ligands based on this mechanism. Finally, we suggest several directions for future investigations. We expect that this review can evoke more inspiration of scientific communities, ultimately facilitating the promotion of the PPARγ-Ser273 phosphorylation-involved mechanism as a promising breakthrough point for addressing the clinical treatment of human diseases.
Background and aims: Atherosclerotic cardiovascular diseases are the leading cause of death. Apolipoprotein A-I (apoA-I) mediates cholesterol efflux to lower the risks of atherosclerosis. Elevating circulating apoA-I is an effective strategy for atheroprotection. However, the regulatory mechanisms of apoA-I have been elusive.
Methods: Protein-protein interactions were examined by co-immunoprecipitations. Chemical biology tools were used to determine the binding of 5PP-InsP5 to its target proteins and its roles in mediating protein-protein interactions. The mouse atherosclerotic model was generated by injecting AAV-PCSK9 and feeding a Western diet. Atherosclerotic plaques were determined by Oil Red O and H&E staining.
Results: We show that blocking IP6K1 activity increases apoA-I production in hepatocytes. IP6K1 binds to apoA-I and via its product 5PP-InsP5 to induce apoA-I degradation, which requires ubiquitination factor E4A (UBE4A). Depleting 5PP-InsP5 by deleting IP6K1 or blocking IP6K1 activity disrupts the interaction between UBE4A and apoA-I, preventing apoA-I degradation, leading to increased production of apoA-I. Hepatocyte-specific deletion of IP6K1 elevates circulating apoA-I levels, which augments cholesterol efflux and lowers the burden of atherosclerosis. Mice with both apoA-I KO and hepatocyte-specific IP6K1 KO were generated to validate that IP6K1 deletion-induced atheroprotection requires apoA-I.
Conclusions: Our findings reveal a mechanism by which blocking IP6K1 boosts apoA-I production. Blocking IP6K1 represents a potential treatment strategy to elevate circulating apoA-I for atheroprotection.
Diabetic cardiomyopathy (DCM) is the primary cause of heart failure in patients with diabetes and is characterised by contractile dysfunction and left ventricular hypertrophy. The complex pathological and physiological mechanisms underlying DCM have contributed to a limited number of available treatment options. A substantial body of evidence has established that DCM is a low-grade inflammatory cardiovascular disorder, with the interleukin-1 (IL-1) family of cytokines playing crucial roles in initiating inflammatory responses and shaping innate and adaptive immunity. In this review, we aim to provide an overview of the underlying mechanisms of the IL-1 family and their relevance in DCM of various aetiologies. Furthermore, we highlighted potential therapeutic targets within the IL-1 family for the management of DCM.
Background & aims: Noninvasive tools (NITs) are currently used to stratify the risk of having or developing hepatic steatosis or fibrosis. Their performance and a proteomic-enabled improvement in forecasting long-term cardio-renal-metabolic morbidity, malignancies, as well as cause-specific and all-cause mortality, are lacking. Therefore, the performance of established NITs needs to be investigated in identifying cardio-renal-metabolic morbidity, malignancies, cause-specific and overall mortality and improve their performance with novel, proteomic-enabled NITs, including growth differentiation factor 15 (GDF-15), allowing multipurpose utilization.
Methods: 502,359 UK Biobank participants free of the study outcomes at baseline with a 14-year median follow-up were grouped into three categories: a) general population, b) potentially metabolic dysfunction-associated steatotic liver disease (MASLD) population, c) individuals with type 2 diabetes mellitus. The investigated NITs include Aspartate aminotransferase to Platelet Ratio Index (APRI), Fibrosis 4 Index (FIB-4), Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), Lipid Accumulation Product (LAP), and metabolic dysfunction-associated fibrosis (MAF-5) score.
Results: Adding GDF-15 to the existing NITs led to significantly increased prognostic performance compared to the traditional NITs in almost all instances, reaching substantially high C-indices, ranging between 0.601 and 0.808, with an overall >0.2 improvement in C-index. Overall, with the GDF-15 enhanced NITs, up to more than seven times fewer individuals need to be screened to identify more incident cases of adverse outcomes compared to the traditional NITs. The cumulative incidence of all outcomes, based on the continuous value percentiles of NITs, is increasing exponentially in the upper quintile of the GDF-15 enhanced NITs.
Conclusions: The herein-developed GDF-15 enhanced indices demonstrate higher screening effectiveness and significantly improved prognostic abilities, which are reduced to practice through an easy-to-use web-based calculator tool (https://clinicalpredictor.shinyapps.io/multimorbidity-mortality-risk/).
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