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Glucagon-like peptide 1 (GLP-1) is a peptide hormone that is released from the gut in response to nutrient ingestion and that has a range of metabolic effects, including enhancing insulin secretion and decreasing food intake. Postprandial GLP-1 secretion is greatly enhanced in rats and humans after some bariatric procedures, including vertical sleeve gastrectomy (VSG), and has been widely hypothesized to contribute to reduced intake, weight loss, and the improvements in glucose homeostasis after VSG. We tested this hypothesis using two separate models of GLP-1 receptor deficiency. We found that VSG-operated GLP-1 receptor–deficient mice responded similarly to wild-type controls in terms of body weight and body fat loss, improved glucose tolerance, food intake reduction, and altered food selection. These data demonstrate that GLP-1 receptor activity is not necessary for the metabolic improvements induced by VSG surgery.

ObjectiveTo explore partial jejunal diversion (PJD) via a side-to-side jejuno-jejunostomy for improved glycemic control in type 2 diabetes mellitus (T2DM). PJD is an anatomy-sparing, technically simple surgery in comparison to the predominate metabolic procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). Positive results in a rodent model prompted a human proof-of-concept study.Research design and methodsPre-clinically, 71 rats were studied in a model of metabolic dysfunction induced by a high-fat diet; 33 animals undergoing one of two lengths of PJD were compared with 18 undergoing sham, 10 RYGB and 10 jejuno-ileal bypass. Clinically, 15 adult subjects with treated but inadequately controlled T2DM (hemoglobin A1c (HbA1c) of 8.0%–11.0%), body mass index of 27.0–40.0 kg/m2, and C peptide ≥3 ng/mL were studied. Follow-up was at 2 weeks, and 3, 6, 9, and 12 months post-PJD.ResultsPre-clinically, positive impacts with PJD on glucose homeostasis, cholesterol, and body composition versus sham control were demonstrated. Clinically, PJD was performed successfully without serious complications. Twelve months post-surgery, the mean (SD) reduction from baseline in HbA1c was 2.3% (1.3) (p<0.01).ConclusionsPJD may provide an anatomy sparing, low-risk, intervention for poorly controlled T2DM without significant alteration of the patient’s lifestyle. The proof-of-concept study is limited by a small sample size and advanced disease, with 80% of participants on insulin and a mean time since diagnosis of over 10 years. Further study is warranted.Trial registration numberNCT02283632; Pre-results.

The cannabinoid 1 (CB1) receptor has been implicated in the regulation of food intake. Here, we examine the effect of the CB1 receptor antagonist AM 251 on food intake and body weight over a prolonged period. Further, we examine whether AM 251 produces conditioned taste aversion (CTA) and if sustained antagonism at central receptors contributes to its anorectic effect. The effect of AM 251 of food intake and body weight was examined in daily (1 mg kg−1) and 5‐day (5 mg kg−1) dosing schedules. Matching reductions in food intake and body weight were observed in both paradigms. A single administration of AM 251 (5 mg kg−1) significantly reduced food intake for 4 days. Tolerance to the anorectic effects of AM 251 did not develop in either dosing strategy. Active avoidance of AM 251 (3; 5 mg kg−1, i.p.) was examined using a CTA assay. Rats showed no evidence of CTA associated with AM 251. We investigated the sustained effect of AM 251 (5 mg kg−1, i.p.) on CB1 receptors in the hypothalamus using Δ9‐tetrahydrocannabinol (8 mg kg−1, i.p.) induced hypothermia. AM 251 initially blocked hypothermia, but this effect was not seen 2 or 4 days later. The results demonstrate that smaller, or infrequent, administrations of AM 251 can produce sustained reductions in food intake and body weight in rat. Reductions in food intake were sustained longer than AM 251 antagonized the effects of a CB1 receptor agonist in the hypothalamus, and occurred independently of CTA. British Journal of Pharmacology (2006) 147, 109–116. doi:10.1038/sj.bjp.0706439

OBJECTIVE: Diets high in fat are implicated in the development and maintenance of obesity, and obese individuals display greater preferences for high-fat foods than do their lean counterparts. Weight-reduction bariatric surgery is associated with changes in food choice. In particular, after Roux-en-Y gastric bypass (RYGB), humans and rodents select or prefer foods that are lower in fat content. We asked whether a bariatric surgical procedure limited to the stomach, vertical sleeve gastrectomy (VSG), causes a similar reduction of fat intake/preference. RESEARCH DESIGN AND METHODS: Rats received VSG or Sham surgery or remained surgically naïve, and were assessed for food preference using three diet-choice paradigms. Using progressive-ratio (PR) and conditioned taste aversion paradigms, we further asked whether surgically induced changes in food choice are secondary to changes in the reward value of food and/or to the formation of a food aversion. Finally, food choice was compared between VSG- and RYGB-operated rats. RESULTS: VSG rats decreased their intake of dietary fat, and shifted their preference toward lower caloric-density foods. This change in food choice was not associated with changes in motivated responding on a PR schedule for either a fat or a carbohydrate food reinforcer. When VSG and RYGB were compared directly, both procedures caused comparable changes in food choice. The conditioned taste aversion paradigm revealed that VSG rats form an aversion to an intra-gastric oil administration whereas RYGB rats do not. CONCLUSIONS: VSG and RYGB, two anatomically distinct bariatric procedures, produce similar changes in food choice.

Information is needed on the safety of adalimumab when used in pregnancy for the treatment of certain autoimmune diseases. Between 2004 and 2016, the Organization of Teratology Information Specialists Research Center at the University of California San Diego conducted a prospective controlled observational cohort study in 602 pregnant women who had or had not taken adalimumab. Women in the adalimumab-exposed cohort had received at least one dose of the drug in the first trimester for the treatment of rheumatoid arthritis or Crohn's Disease (N = 257). Women in the disease comparison cohort had not used adalimumab in pregnancy (N = 120). Women in the healthy comparison cohort had no rheumatic or inflammatory bowel diseases (N = 225). Women and their infants were followed to one year postpartum with maternal interviews, medical records abstraction, and physical examinations. Study outcomes were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, pre and post-natal growth deficiency, serious or opportunistic infections and malignancies. 42/602 (7.0%) of pregnancies were lost-to-follow-up. 22/221 (10.0%) in the adalimumab-exposed cohort had a live born infant with a major birth defect compared to 8/106 (7.5%) in the diseased unexposed cohort (adjusted odds ratio 1.10, 95% confidence interval [CI] 0.45 to 2.73). Women in the adalimumab-exposed cohort were more likely to deliver preterm compared to the healthy cohort (adjusted hazard ratio [aHR] 2.59, 95% CI 1.22 to 5.50), but not compared to the diseased unexposed cohort (aHR 0.82, 95% CI 0.66 to 7.20). No significant increased risks were noted with adalimumab exposure for any other study outcomes. Adalimumab exposure in pregnancy compared to diseased unexposed pregnancies was not associated with an increased risk for any of the adverse outcomes examined. Women with rheumatoid arthritis or Crohn's Disease were at increased risk of preterm delivery, irrespective of adalimumab exposure.

Myofibroblasts are the key effector cells responsible for excessive extracellular matrix deposition in multiple fibrotic conditions, including idiopathic pulmonary fibrosis (IPF). The PI3K/Akt/mTOR axis has been implicated in fibrosis, with pan-PI3K/mTOR inhibition currently under clinical evaluation in IPF. Here we demonstrate that rapamycin-insensitive mTORC1 signaling via 4E-BP1 is a critical pathway for TGF-β 1 stimulated collagen synthesis in human lung fibroblasts, whereas canonical PI3K/Akt signaling is not required. The importance of mTORC1 signaling was confirmed by CRISPR-Cas9 gene editing in normal and IPF fibroblasts, as well as in lung cancer-associated fibroblasts, dermal fibroblasts and hepatic stellate cells. The inhibitory effect of ATP-competitive mTOR inhibition extended to other matrisome proteins implicated in the development of fibrosis and human disease relevance was demonstrated in live precision-cut IPF lung slices. Our data demonstrate that the mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis with potential implications for the development of novel anti-fibrotic strategies. The PI3K/Akt/mTOR pathway has been previously implicated in fibrosis and a pan-PI3K/mTOR inhibitor is currently under clinical evaluation for the treatment of IPF. Here the authors show that the mTORC1/4E-BP1 axis is critical for TGF-β1-induced fibrogenesis in in vitro and ex vivo models and that canonical PI3K/Akt signalling is dispensable.

The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing or remaining static. The cellular basis of this clinical observation is unknown. Here, we profile the genomic, transcriptomic, and epigenomic landscape of CIS in a unique patient cohort with longitudinally monitored pre-invasive disease. Predictive modeling identifies which lesions will progress with remarkable accuracy. We identify progression-specific methylation changes on a background of widespread heterogeneity, alongside a strong chromosomal instability signature. We observed mutations and copy number changes characteristic of cancer and chart their emergence, offering a window into early carcinogenesis. We anticipate that this new understanding of cancer precursor biology will improve early detection, reduce overtreatment, and foster preventative therapies targeting early clonal events in lung cancer. A multi-omics survey of progressive compared to regressive carcinoma in situ lesions provides a molecular map of early lung cancer development.

IntroductionFibroblastic foci represent the cardinal pathogenic lesion in idiopathic pulmonary fibrosis (IPF) and comprise activated fibroblasts and myofibroblasts, the key effector cells responsible for dysregulated extracellular matrix deposition in multiple fibrotic conditions. The aim of this study was to define the major transcriptional programmes involved in fibrogenesis in IPF by profiling unmanipulated myofibroblasts within fibrotic foci in situ by laser capture microdissection.MethodsThe challenges associated with deriving gene calls from low amounts of RNA and the absence of a meaningful comparator cell type were overcome by adopting novel data mining strategies and by using weighted gene co-expression network analysis (WGCNA), as well as an eigengene-based approach to identify transcriptional signatures, which correlate with fibrillar collagen gene expression.ResultsWGCNA identified prominent clusters of genes associated with cell cycle, inflammation/differentiation, translation and cytoskeleton/cell adhesion. Collagen eigengene analysis revealed that transforming growth factor β1 (TGF-β1), RhoA kinase and the TSC2/RHEB axis formed major signalling clusters associated with collagen gene expression. Functional studies using CRISPR-Cas9 gene-edited cells demonstrated a key role for the TSC2/RHEB axis in regulating TGF-β1-induced mechanistic target of rapamycin complex 1 activation and collagen I deposition in mesenchymal cells reflecting IPF and other disease settings, including cancer-associated fibroblasts.ConclusionThese data provide strong support for the human tissue-based and bioinformatics approaches adopted to identify critical transcriptional nodes associated with the key pathogenic cell responsible for fibrogenesis in situ and further identify the TSC2/RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions.

The Guaymas Basin spreading center, at 2000 m depth in the Gulf of California, is overlain by a thick sedimentary cover. Across the basin, localized temperature anomalies, with active methane venting and seep fauna exist in response to magma emplacement into sediments. These sites evolve over thousands of years as magma freezes into doleritic sills and the system cools. Although several cool sites resembling cold seeps have been characterized, the hydrothermally active stage of an off-axis site was lacking good examples. Here, we present a multidisciplinary characterization of Ringvent, an ~1 km wide circular mound where hydrothermal activity persists ~28 km northwest of the spreading center. Ringvent provides a new type of intermediate-stage hydrothermal system where off-axis hydrothermal activity has attenuated since its formation, but remains evident in thermal anomalies, hydrothermal biota coexisting with seep fauna, and porewater biogeochemical signatures indicative of hydrothermal circulation. Due to their broad potential distribution, small size and limited life span, such sites are hard to find and characterize, but they provide critical missing links to understand the complex evolution of hydrothermal systems.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication ( n  = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen ( n  = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research. Trans-ancestry meta-analysis of estimated glomerular filtration rate (eGFR) from 1,046,070 individuals identifies 264 associated loci, providing a resource of molecular targets for translational research of chronic kidney disease.