A neural circuit mechanism for mechanosensory feedback control of ingestion.

Mechanosensory feedback from the digestive tract to the brain is critical for limiting excessive food and water intake, but the underlying gut-brain communication pathways and mechanisms remain poorly understood1-12. Here we show that, in mice, neurons in the parabrachial nucleus that express the prodynorphin gene (hereafter, PBPdyn neurons) monitor the intake of both fluids and solids, using mechanosensory signals that arise from the upper digestive tract. Most individual PBPdyn neurons are activated by ingestion as well as the stimulation of the mouth and stomach, which indicates the representation of integrated sensory signals across distinct parts of the digestive tract. PBPdyn neurons are anatomically connected to the digestive periphery via cranial and spinal pathways; we show that, among these pathways, the vagus nerve conveys stomach-distension signals to PBPdyn neurons. Upon receipt of these signals, these neurons produce aversive and sustained appetite-suppressing signals, which discourages the initiation of feeding and drinking (fully recapitulating the symptoms of gastric distension) in part via signalling to the paraventricular hypothalamus. By contrast, inhibiting the same population of PBPdyn neurons induces overconsumption only if a drive for ingestion exists, which confirms that these neurons mediate negative feedback signalling. Our findings reveal a neural mechanism that underlies the mechanosensory monitoring of ingestion and negative feedback control of intake behaviours upon distension of the digestive tract.

PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress.

Molecular classification of gastric cancer (GC) identified a subgroup of patients showing chemoresistance and poor prognosis, termed SEM (Stem-like/Epithelial-to-mesenchymal transition/Mesenchymal) type in this study. Here, we show that SEM-type GC exhibits a distinct metabolic profile characterized by high glutaminase (GLS) levels. Unexpectedly, SEM-type GC cells are resistant to glutaminolysis inhibition. We show that under glutamine starvation, SEM-type GC cells up-regulate the 3 phosphoglycerate dehydrogenase (PHGDH)-mediated mitochondrial folate cycle pathway to produce NADPH as a reactive oxygen species scavenger for survival. This metabolic plasticity is associated with globally open chromatin structure in SEM-type GC cells, with ATF4/CEBPB identified as transcriptional drivers of the PHGDH-driven salvage pathway. Single-nucleus transcriptome analysis of patient-derived SEM-type GC organoids revealed intratumoral heterogeneity, with stemness-high subpopulations displaying high GLS expression, a resistance to GLS inhibition, and ATF4/CEBPB activation. Notably, coinhibition of GLS and PHGDH successfully eliminated stemness-high cancer cells. Together, these results provide insight into the metabolic plasticity of aggressive GC cells and suggest a treatment strategy for chemoresistant GC patients.

Child and adolescent participation measurement tools and their translations: A systematic review.

BACKGROUND: Numerous participation measurement tools targeting children and youth have been developed. Despite the translation of these tools into specific languages and cultures, the reliability and validity of the translated versions remain uncertain. To address this gap in knowledge, this study aims to identify tools for assessing the participation of children aged 5-18 years and to appraise the psychometric properties of their translated versions. METHODS: Four electronic databases were searched for peer-reviewed studies published in English. Preferred Reporting Items for Systematic Reviews guidelines was followed. Study titles and abstracts were screened by four independent reviewers. Data were extracted for both original and translated versions of eligible tools. Instrument quality assessments were performed using the Outcome Measures Rating Form Guidelines. Any discrepancies were resolved by consensus. RESULTS: Out of the 31 measurement tools examined, 18 tools had at least one translated version available, and among those original measurement tools, a total of 58 translated versions were identified. The most widely translated tool was the Physical Activity Questionnaire for Children (12 languages), and the most frequently translated language was Chinese (7 tools). Most translated versions verified internal consistency and content validity. Only three translated versions were verified inter-rater reliability, and seven translated versions were tested criterion validity with the gold standard tools assessing participation of children (e.g., accelerometer, Pediatric Evaluation of Disability Inventory and four 24-h recalls). None of the translated versions were tested for intra-rater reliability and responsiveness. CONCLUSIONS: These findings can support the selection of psychometrically sound tools for children with disabilities, given their culture and language, and tool quality.

Coordinated methyl readers: Functional communications in cancer.

Methylation is a major post-translational modification (PTM) generated by methyltransferase on target proteins; it is recognized by the epigenetic reader to expand the functional diversity of proteins. Methylation can occur on specific lysine or arginine residues localized within regulatory domains in both histone and nonhistone proteins, thereby allowing distinguished properties of the targeted protein. Methylated residues are recognized by chromodomain, malignant brain tumor (MBT), Tudor, plant homeodomain (PHD), PWWP, WD-40, ADD, and ankyrin repeats by an induced-fit mechanism. Methylation-dependent activities regulate distinct aspects of target protein function and are largely reliant on methyl readers of histone and nonhistone proteins in various diseases. Methylation of nonhistone proteins that are recognized by methyl readers facilitates the degradation of unwanted proteins, as well as the stabilization of necessary proteins. Unlike nonhistone substrates, which are mainly monomethylated by methyltransferase, histones are di- or trimethylated by the same methyltransferases and then connected to other critical regulators by methyl readers. These fine-tuned controls by methyl readers are significant for the progression or inhibition of diseases, including cancers. Here, current knowledge and our perspectives about regulating protein function by methyl readers are summarized. We also propose that expanded research on the strong crosstalk mechanisms between methylation and other PTMs via methyl readers would augment therapeutic research in cancer.

High-throughput genetic clustering of type 2 diabetes loci reveals heterogeneous mechanistic pathways of metabolic disease.

AIMS/HYPOTHESIS: Type 2 diabetes is highly polygenic and influenced by multiple biological pathways. Rapid expansion in the number of type 2 diabetes loci can be leveraged to identify such pathways. METHODS: We developed a high-throughput pipeline to enable clustering of type 2 diabetes loci based on variant-trait associations. Our pipeline extracted summary statistics from genome-wide association studies (GWAS) for type 2 diabetes and related traits to generate a matrix of 323 variants × 64 trait associations and applied Bayesian non-negative matrix factorisation (bNMF) to identify genetic components of type 2 diabetes. Epigenomic enrichment analysis was performed in 28 cell types and single pancreatic cells. We generated cluster-specific polygenic scores and performed regression analysis in an independent cohort (N=25,419) to assess for clinical relevance. RESULTS: We identified ten clusters of genetic loci, recapturing the five from our prior analysis as well as novel clusters related to beta cell dysfunction, pronounced insulin secretion, and levels of alkaline phosphatase, lipoprotein A and sex hormone-binding globulin. Four clusters related to mechanisms of insulin deficiency, five to insulin resistance and one had an unclear mechanism. The clusters displayed tissue-specific epigenomic enrichment, notably with the two beta cell clusters differentially enriched in functional and stressed pancreatic beta cell states. Additionally, cluster-specific polygenic scores were differentially associated with patient clinical characteristics and outcomes. The pipeline was applied to coronary artery disease and chronic kidney disease, identifying multiple overlapping clusters with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Our approach stratifies type 2 diabetes loci into physiologically interpretable genetic clusters associated with distinct tissues and clinical outcomes. The pipeline allows for efficient updating as additional GWAS become available and can be readily applied to other conditions, facilitating clinical translation of GWAS findings. Software to perform this clustering pipeline is freely available.

ROS inhibits RORα degradation by decreasing its arginine methylation in liver cancer.

Retinoic acid receptor-related orphan receptor α (RORα) is a transcription factor involved in nuclear gene expression and a known tumor suppressor. RORα was the first identified substrate of lysine methylation-dependent degradation. However, the mechanisms of other post-translational modifications (PTMs) that occur in RORα remain largely unknown, especially in liver cancer. Arginine methylation is a common PTM in arginine residues of nonhistone and histone proteins and affects substrate protein function and fate. We found an analogous amino acid disposition containing R37 at the ROR N-terminus compared to histone H3 residue, which is arginine methylated. Here, we provide evidence that R37 methylation-dependent degradation is carried out by protein arginine methyltransferase 5 (PRMT5). Further, we discovered that PRMT5 regulated the interaction between the E3 ubiquitin ligase ITCH and RORα through RORα arginine methylation. Arginine methylation-dependent ubiquitination-mediated RORα degradation reduced downstream target gene activation. H2 O2 -induced reactive oxygen species (ROS) decreased PRMT5 protein levels, consequently increasing RORα protein levels in HepG2 liver cancer cells. In addition, ROS inhibited liver cancer progression by inducing apoptosis via PRMT5-mediated RORα methylation and the ITCH axis. Our results potentiate PRMT5 as an elimination target in cancer therapy, and this additional regulatory level within ROS signaling may help identify new targets for therapeutic intervention in liver cancer.

Microlens array camera with variable apertures for single-shot high dynamic range (HDR) imaging.

We report a microlens array camera with variable apertures (MACVA) for high dynamic range (HDR) imaging by using microlens arrays with various sizes of apertures. The MACVA comprises variable apertures, microlens arrays, gap spacers, and a CMOS image sensor. The microlenses with variable apertures capture low dynamic range (LDR) images with different f-stops under single-shot exposure. The reconstructed HDR images clearly exhibit expanded dynamic ranges surpassing LDR images as well as high resolution without motion artifacts, comparable to the maximum MTF50 value observed among the LDR images. This compact camera provides, what we believe to be, a new perspective for various machine vision or mobile devices applications.

Regulation of autophagy by protein methylation and acetylation in cancer.

Autophagy is a highly conserved mechanism responsible for cellular homeostasis and integrity in a variety of physiological conditions. Materials targeted for degradation are directed to autophagosomes and autolysosomes, where they are broken down into their base components. Aberrant regulation of autophagy is significantly associated with various cancers and neurodegenerative diseases. Recently, accumulating evidence has revealed that the coordinated regulation of histone and non-histone protein modification is associated with autophagy. In this review, we highlight the recent progress that has been made in elucidating the molecular basis of protein methylation and acetylation associated with autophagy at the transcriptional and posttranslational levels. Furthermore, we discuss the importance of describing causality between protein methylation/acetylation and autophagy regulation as compelling therapeutic opportunities in cancer pathogenesis and progression.

AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy.

Autophagy is a highly conserved self-digestion process, which is essential for maintaining homeostasis and viability in response to nutrient starvation. Although the components of autophagy in the cytoplasm have been well studied, the molecular basis for the transcriptional and epigenetic regulation of autophagy is poorly understood. Here we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a crucial component of autophagy in mammals. Notably, CARM1 stability is regulated by the SKP2-containing SCF (SKP1-cullin1-F-box protein) E3 ubiquitin ligase in the nucleus, but not in the cytoplasm, under nutrient-rich conditions. Furthermore, we show that nutrient starvation results in AMP-activated protein kinase (AMPK)-dependent phosphorylation of FOXO3a in the nucleus, which in turn transcriptionally represses SKP2. This repression leads to increased levels of CARM1 protein and subsequent increases in histone H3 Arg17 dimethylation. Genome-wide analyses reveal that CARM1 exerts transcriptional co-activator function on autophagy-related and lysosomal genes through transcription factor EB (TFEB). Our findings demonstrate that CARM1-dependent histone arginine methylation is a crucial nuclear event in autophagy, and identify a new signalling axis of AMPK-SKP2-CARM1 in the regulation of autophagy induction after nutrient starvation.

Citric, succinic, and vanillic acid-functionalized magnetic-cored dendrimer for methylene blue adsorption.

A new functional composite was synthesized in this study comprising magnetic-cored dendrimer (MCD) modified with citric acid (CA), succinic acid (SA), and vanillic acid (VA) terminal groups. The CA-MCD, SA-MCD, and VA-MCD exhibited average particle size of 8-18 nm and superparamagnetic behavior. Adsorption potential of the composite was assessed by monitoring methylene blue (MB) removal from contaminated water. The CA-MCD attained adsorption equilibrium in 30 min while SA-MCD and VA-MCD achieved equilibrium in 60 min. The Langmuir model better fitted the adsorption results than the Freundlich model, indicating a monolayer mode of MB adsorption on the composite. Maximum adsorption capacity of CA-MCD, SA-MCD, and VA-MCD was 216.30 mg/g, 184.29 mg/g, and 196.58 mg/g, respectively. The CA-MCD exhibited best adsorption performance by removing 99% MB at pH = 11. In reusability experiments, the CA-MCD, SA-MCD, and VA-MCD maintained over 90% MB adsorption for both 15 mg/L and 50 mg/L solutions in the third cycle. Overall, the organic acid-functionalized MCDs with high adsorption capacity and reusability potential showed utility for practical application for wastewater decontamination.

Ultrathin arrayed camera for high-contrast near-infrared imaging.

We report an ultrathin arrayed camera (UAC) for high-contrast near infrared (NIR) imaging by using microlens arrays with a multilayered light absorber. The UAC consists of a multilayered composite light absorber, inverted microlenses, gap-alumina spacers and a planar CMOS image sensor. The multilayered light absorber was fabricated through lift-off and repeated photolithography processes. The experimental results demonstrate that the image contrast is increased by 4.48 times and the MTF 50 is increased by 2.03 times by eliminating optical noise between microlenses through the light absorber. The NIR imaging of UAC successfully allows distinguishing the security strip of authentic bill and the blood vessel of finger. The ultrathin camera offers a new route for diverse applications in biometric, surveillance, and biomedical imaging.

Peroxidasin is essential for endothelial cell survival and growth signaling by sulfilimine crosslink-dependent matrix assembly.

Peroxidasin (PXDN) has been reported to crosslink the C-terminal non-collagenous domains of collagen IV (Col IV) by forming covalent sulfilimine bond. Here, we explored the physiological role of PXDN and its mechanism of action in endothelial cell survival and growth. Silencing of PXDN using siRNAs decreased cell proliferation without increase of the number of detached cells and decreased cell viability under serum-starved condition with increased fragmented nuclei and caspase 3/7 activity. Conditioned medium (CM) containing wild-type PXDN restored the proliferation of PXDN-depleted cells, but CM containing mutant PXDN with deletion of either N-terminal extracellular matrix (ECM) motifs or peroxidase domain failed to restore PXDN function. Accordingly, anti-PXDN antibody [raised against IgC2 (3-4) subdomain within ECM motifs] and peroxidase inhibitor phloroglucinol prevented the rescue of the PXDN-depleted cells by PXDN-containing CM. PXDN depletion resulted in loss of sulfilimine crosslinks, and decreased dense fibrillar network assembly of not only Col IV, but also fibronectin and laminin like in Col IV knockdown. Exogenous PXDN-containing CM restored ECM assembly as well as proliferation of PXDN-depleted cells. Accordingly, purified recombinant PXDN protein restored the proliferation and ECM assembly, and prevented cell death of the PXDN-depleted cells. PXDN depletion also showed reduced growth factors-induced phosphorylation of FAK and ERK1/2. In addition, siPXDN-transfected cell-derived matrix failed to provide full ECM-mediated activation of FAK and ERK1/2. These results indicate that both the ECM motifs and peroxidase activity are essential for the cellular function of PXDN and that PXDN is crucial for ECM assembly for survival and growth signaling.

The Estimated Prevalence and Incidence of Endometriosis With the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC): A National Population-Based Study.

BACKGROUND: The incidence and prevalence of endometriosis remain unclear due to diagnostic difficulties. Especially, there has been little information regarding the population-based epidemiology of endometriosis. The purpose of this study is to estimate the prevalence and incidence of endometriosis in Korea based on the health insurance claims data. METHODS: This study is a retrospective cohort study using the Korean National Health Insurance Service-National Sample Cohort, which correspond to approximately 1 million Korean populations from 2002 to 2013. Patients aged 15-54 years were selected, and the prevalence and incidence of endometriosis were estimated by time and age groups. RESULTS: The age-adjusted prevalence rate of endometriosis also increased from 2.12 per 1,000 persons (95% confidence interval [CI], 2.01-2.24) in 2002 to 3.56 per 1,000 persons (95% CI, 3.40-3.71) in 2013. The average adjusted incidence showed no statistically significant increase. However, the age-specific incidence of the 15-19 and 20-24 years age groups increased significantly from 0.24 and 1.29 per 1,000 persons in 2003 to 2.73 and 2.71 per 1,000 persons in 2013 (R2 = 0.93 and 0.77, P < 0.001), while the incidence rate of the age group 40-44 and 45-49 years decreased from 2.36 and 1.72 per 1,000 persons in 2003 to 0.81 and 0.27 per 1,000 persons in 2013 (R2 = 0.83 and 0.89, P < 0.001). CONCLUSION: The prevalence and incidence of endometriosis in Korean women were lower than that of previous reports in high-risk population studies. Furthermore, we found a significant increase in the diagnosis of endometriosis in younger age groups.

KDM3A histone demethylase functions as an essential factor for activation of JAK2-STAT3 signaling pathway.

Janus tyrosine kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway is essential for modulating cellular development, differentiation, and homeostasis. Thus, dysregulation of JAK2-STAT3 signaling pathway is frequently associated with human malignancies. Here, we provide evidence that lysine-specific demethylase 3A (KDM3A) functions as an essential epigenetic enzyme for the activation of JAK2-STAT3 signaling pathway. KDM3A is tyrosine-phosphorylated by JAK2 in the nucleus and functions as a STAT3-dependent transcriptional coactivator. JAK2-KDM3A signaling cascade induced by IL-6 leads to alteration of histone H3K9 methylation as a predominant epigenetic event, thereby providing the functional and mechanistic link between activation of JAK2-STAT3 signaling pathway and its epigenetic control. Together, our findings demonstrate that inhibition of KDM3A phosphorylation could be a potent therapeutic strategy to control oncogenic effect of JAK2-STAT3 signaling pathway.

Lysine-specific demethylase 3A is important for autophagic occurrence.

Autophagy is an essential process to maintain cell survival and homeostasis under various stress conditions. Here, we report that lysine-specific demethylase 3A (KDM3A) plays an important role in starvation-induced autophagy. Using Kdm3a knockout mice, we demonstrate that KDM3A is crucial for proper hepatic autophagy in vivo. Hepatic mRNA expression analysis and ChIP assay in WT and Kdm3a knockout mouse livers reveal that KDM3A activates autophagy genes by reducing histone H3K9me2 levels upon fasting. Together, our finding represents previously unidentified function of KDM3A as a key regulator of autophagy, implicating potential therapeutic approaches for autophagy-related diseases.

Human induced pluripotent stem cell line banking for the production of rare blood type erythrocytes.

BACKGROUND: The in vitro production of mature human red blood cells (RBCs) from induced pluripotent stem cells (iPSCs) has been the focus of research to meet the high demand for blood transfusions. However, limitations like high costs and technological requirements restrict the use of RBCs produced by iPSC differentiation to specific circumstances, such as for patients with rare blood types or alloimmunized patients. In this study, we developed a detailed protocol for the generation of iPSC lines derived from peripheral blood of donors with O D-positive blood and rare blood types (D-and Jr(a-)) and subsequent erythroid differentiation. METHODS: Mononuclear cells separated from the peripheral blood of O D-positive and rare blood type donors were cultured to produce and expand erythroid progenitors and reprogrammed into iPSCs. A 31-day serum-free, xeno-free erythroid differentiation protocol was used to generate reticulocytes. The stability of iPSC lines was confirmed with chromosomal analysis and RT-PCR. Morphology and cell counts were determined by microscopy observations and flow cytometry. RESULTS: Cells from all donors were successfully used to generate iPSC lines, which were differentiated into erythroid precursors without any apparent chromosomal mutations. This differentiation protocol resulted in moderate erythrocyte yield per iPSC. CONCLUSIONS: It has previously only been hypothesized that erythroid differentiation from iPSCs could be used to produce RBCs for transfusion to patients with rare blood types or who have been alloimmunized. Our results demonstrate the feasibility of producing autologous iPSC-differentiated RBCs for clinical transfusions in patients without alternative options.

A Subset of Paracrine Factors as Efficient Biomarkers for Predicting Vascular Regenerative Efficacy of Mesenchymal Stromal/Stem Cells.

Mesenchymal stromal/stem cells (MSCs) have been developed as a promising source for cell-based therapies of ischemic disease. However, there are some hurdles in their clinical application such as poor cell engraftment and inconsistent stem cell potency. In this study, we sought to find biomarkers for predicting potency of MSCs for proangiogenic therapy to improve their beneficial effects. Large variations were observed in proangiogenic factor secretion profiles of conditioned media derived from nine different donor-derived Wharton's jelly (WJ)-derived MSCs and 8 factors among 55 angiogenesis-related factors were secreted at considerable levels. Two distinct WJ-MSCs that had the lowest or the highest secretion of these eight factors showed corresponding proangiogenic activities in in vitro angiogenesis assays. When four additional different donor-derived WJ-MSCs were further examined, proangiogenic activities in migration and tube formation of endothelial cells and in in vivo Matrigel plug assay were highly consistent with secretion levels of four major factors (angiogenin, interleukin-8, monocyte chemoattractant protein-1, and vascular endothelial growth factor). Such correlation was also observed in vascular regenerative effect in a mouse hind limb ischemia model. Blocking of these four factors by neutralizing antibodies or knockdown of them by siRNA treatment resulted in significant inhibition of proangiogenic activities of not only WJ-MSCs, but also bone marrow-derived MSCs. These results suggest that these four factors may represent efficient biomarkers for predicting vascular regenerative efficacy of MSCs. Stem Cells 2019;37:77-88.

EZH2 generates a methyl degron that is recognized by the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex.

Ubiquitination plays a major role in protein degradation. Although phosphorylation-dependent ubiquitination is well known for the regulation of protein stability, methylation-dependent ubiquitination machinery has not been characterized. Here, we provide evidence that methylation-dependent ubiquitination is carried out by damage-specific DNA binding protein 1 (DDB1)/cullin4 (CUL4) E3 ubiquitin ligase complex and a DDB1-CUL4-associated factor 1 (DCAF1) adaptor, which recognizes monomethylated substrates. Molecular modeling and binding affinity studies reveal that the putative chromo domain of DCAF1 directly recognizes monomethylated substrates, whereas critical binding pocket mutations of the DCAF1 chromo domain ablated the binding from the monomethylated substrates. Further, we discovered that enhancer of zeste homolog 2 (EZH2) methyltransferase has distinct substrate specificities for histone H3K27 and nonhistones exemplified by an orphan nuclear receptor, RORα. We propose that EZH2-DCAF1/DDB1/CUL4 represents a previously unrecognized methylation-dependent ubiquitination machinery specifically recognizing "methyl degron"; through this, nonhistone protein stability can be dynamically regulated in a methylation-dependent manner.

The effect of the look-back period for estimating incidence using administrative data.

BACKGROUND: The look-back period is needed to define baseline population for estimating incidence. However, short look-back period is known to overestimate incidence of diseases misclassifying prevalent cases to incident cases. The purpose of this study is to evaluate the impact of the various length of look-back period on the observed incidences of uterine leiomyoma, endometriosis and adenomyosis, and to estimate true incidences considering the misclassification errors in the longitudinal administrative data in Korea. METHODS: A total of 319,608 women between 15 to 54 years of age in 2002 were selected from Korea National Health Insurance Services (KNHIS) cohort database. In order to minimize misclassification bias incurred when applying various length of look-back period, we used 11 years of claim data to estimate the incidence by equally setting the look-back period to 11 years for each year using prediction model. The association between the year of diagnosis and the number of prevalent cases with the misclassification rates by each look-back period was investigated. Based on the findings, prediction models on the proportion of misclassified incident cases were developed using multiple linear regression. RESULTS: The proportion of misclassified incident cases of uterine leiomyoma, endometriosis and adenomyosis were 32.8, 10.4 and 13.6% respectively for the one-year look-back period in 2003. These numbers decreased to 6.3% in uterine leiomyoma and - 0.8% in both endometriosis and adenomyosis using all available look-back periods (11 years) in 2013. CONCLUSION: This study demonstrates approaches for estimating incidences considering the different proportion of misclassified cases for various length of look-back period. Although the prediction model used for estimation showed strong R-squared values, follow-up studies are required for validation of the study results.

ID1-Mediated BMP Signaling Pathway Potentiates Glucagon-Like Peptide-1 Secretion in Response to Nutrient Replenishment.

Glucagon-like peptide-1 (GLP-1) is a well-known incretin hormone secreted from enteroendocrinal L cells in response to nutrients, such as glucose and dietary fat, and controls glycemic homeostasis. However, the detailed intracellular mechanisms of how L cells control GLP-1 secretion in response to nutrients still remain unclear. Here, we report that bone morphogenetic protein (BMP) signaling pathway plays a pivotal role to control GLP-1 secretion in response to nutrient replenishment in well-established mouse enteroendocrinal L cells (GLUTag cells). Nutrient starvation dramatically reduced cellular respiration and GLP-1 secretion in GLUTag cells. Transcriptome analysis revealed that nutrient starvation remarkably reduced gene expressions involved in BMP signaling pathway, whereas nutrient replenishment rescued BMP signaling to potentiate GLP-1 secretion. Transient knockdown of inhibitor of DNA binding (ID)1, a well-known target gene of BMP signaling, remarkably reduced GLP-1 secretion. Consistently, LDN193189, an inhibitor of BMP signaling, markedly reduced GLP-1 secretion in L cells. In contrast, BMP4 treatment activated BMP signaling pathway and potentiated GLP-1 secretion in response to nutrient replenishment. Altogether, we demonstrated that BMP signaling pathway is a novel molecular mechanism to control GLP-1 secretion in response to cellular nutrient status. Selective activation of BMP signaling would be a potent therapeutic strategy to stimulate GLP-1 secretion in order to restore glycemic homeostasis.