المؤلفون: Cody Durrer, Hashim Islam, Haoning Howard Cen, Maria Dolores Moya Garzon, Xuchao Lyu, Sean McKelvey, Joel Singer, Alan M. Batterham, Jonathan Z. Long, James D. Johnson, Jonathan P. Little

المصدر: Nutrition & Metabolism, Vol 21, Iss 1, Pp 1-10 (2024)

مصطلحات موضوعية: Nutrition. Foods and food supply, TX341-641, Nutritional diseases. Deficiency diseases, RC620-627

الوصف: Abstract Background Substantial weight loss in people living with type 2 diabetes (T2D) can reduce the need for glucose-lowering medications while concurrently lowering glycemia below the diagnostic threshold for the disease. Furthermore, weight-loss interventions have also been demonstrated to improve aspects of underlying T2D pathophysiology related to ectopic fat in the liver and pancreatic beta-cell function. As such, the purpose of this secondary analysis was to explore the extent to which a low-carbohydrate and energy-restricted (LCER) diet intervention improves markers of beta-cell stress/function, liver fat accumulation, and metabolic related liver function in people with type 2 diabetes. Methods We conducted secondary analyses of blood samples from a larger pragmatic community-based parallel-group randomized controlled trial involving a 12-week pharmacist implemented LCER diet (Pharm-TCR:

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1743-7075Test

الوصول الحر: https://doaj.org/article/93f13911ef7b4a3c8ed58a8449e3284aTest

المؤلفون: Tobias Boothe, Gareth E. Lim, Haoning Cen, Søs Skovsø, Micah Piske, Shu Nan Li, Ivan R. Nabi, Patrick Gilon, James D. Johnson

المصدر: Molecular Metabolism, Vol 83, Iss , Pp 101935- (2024)

مصطلحات موضوعية: Internal medicine, RC31-1245

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877824000668Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/8d13a52234dc4c16ac9fc7f22cbbd870Test

المؤلفون: Marisol Castillo-Castrejon, Barbara Mensah Sankofi, Stevi Johnson Murguia, Abasi-ama Udeme, Hoaning Howard Cen, Yi Han Xia, Nisha S. Thomas, William L. Berry, Kenneth L. Jones, Vincent R. Richard, Rene P. Zahedi, Christoph H. Borchers, James D. Johnson, Elizabeth A. Wellberg

المصدر: Breast Cancer Research, Vol 25, Iss 1, Pp 1-21 (2023)

مصطلحات موضوعية: Breast cancer, Adipose, Obesity, Estrogen receptor, Fibroblast growth factor, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Obesity increases breast cancer risk and breast cancer-specific mortality, particularly for people with estrogen receptor (ER)-positive tumors. Body mass index (BMI) is used to define obesity, but it may not be the best predictor of breast cancer risk or prognosis on an individual level. Adult weight gain is an independent indicator of breast cancer risk. Our previous work described a murine model of obesity, ER-positive breast cancer, and weight gain and identified fibroblast growth factor receptor (FGFR) as a potential driver of tumor progression. During adipose tissue expansion, the FGF1 ligand is produced by hypertrophic adipocytes as a stimulus to stromal preadipocytes that proliferate and differentiate to provide additional lipid storage capacity. In breast adipose tissue, FGF1 production may stimulate cancer cell proliferation and tumor progression. Methods We explored the effects of FGF1 on ER-positive endocrine-sensitive and resistant breast cancer and compared that to the effects of the canonical ER ligand, estradiol. We used untargeted proteomics, specific immunoblot assays, gene expression profiling, and functional metabolic assessments of breast cancer cells. The results were validated in tumors from obese mice and breast cancer datasets from women with obesity. Results FGF1 stimulated ER phosphorylation independently of estradiol in cells that grow in obese female mice after estrogen deprivation treatment. Phospho- and total proteomic, genomic, and functional analyses of endocrine-sensitive and resistant breast cancer cells show that FGF1 promoted a cellular phenotype characterized by glycolytic metabolism. In endocrine-sensitive but not endocrine-resistant breast cancer cells, mitochondrial metabolism was also regulated by FGF1. Comparison of gene expression profiles indicated that tumors from women with obesity shared hallmarks with endocrine-resistant breast cancer cells. Conclusions Collectively, our data suggest that one mechanism by which obesity and weight gain promote breast cancer progression is through estrogen-independent ER activation and cancer cell metabolic reprogramming, partly driven by FGF/FGFR. The first-line treatment for many patients with ER-positive breast cancer is inhibition of estrogen synthesis using aromatase inhibitors. In women with obesity who are experiencing weight gain, locally produced FGF1 may activate ER to promote cancer cell metabolic reprogramming and tumor progression independently of estrogen.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1465-542XTest

الوصول الحر: https://doaj.org/article/ddd8615423954129a10ae74ab8936c7bTest

المؤلفون: Paula T. Littlejohn, Haggai Bar-Yoseph, Karlie Edwards, Hong Li, Cynthia Y. Ramirez-Contreras, Ravi Holani, Avril Metcalfe-Roach, Yiyun M. Fan, Tom Min-Shih Yang, Nina Radisavljevic, Xiaoke Hu, James D. Johnson, B. Brett Finlay

المصدر: Frontiers in Nutrition, Vol 10 (2023)

مصطلحات موضوعية: multiple micronutrient deficiencies, glucose dysregulation, stunting, gut microbiome, insulin dysregulation, Nutrition. Foods and food supply, TX341-641

الوصف: IntroductionMicronutrients perform a wide range of physiological functions essential for growth and development. However, most people still need to meet the estimated average requirement worldwide. Globally, 2 billion people suffer from micronutrient deficiency, most of which are co-occurring deficiencies in children under age five. Despite decades of research, animal models studying multiple micronutrient deficiencies within the early-life period are lacking, which hinders our complete understanding of the long-term health implications and may contribute to the inefficacy of some nutritional interventions. Evidence supporting the Developmental Origins of Health and Disease (DOHaD) theory demonstrates that early-life nutritional deficiencies carry life-long consequences mediated through various mechanisms such as abnormal metabolic programming, stunting, altered body composition, and the gut microbiome. However, this is largely unexplored in the multiple micronutrient deficient host.Methodswe developed a preclinical model to examine undernutrition’s metabolic and functional impact on the host and gut microbiome early in life. Three-week-old weanling C57BL/6N male mice were fed a low-micronutrient diet deficient in zinc, folate, iron, vitamin A, and vitamin B12 or a control diet for 4-weeks.ResultsOur results showed that early-life multiple micronutrient deficiencies induced stunting, altered body composition, impaired glucose and insulin tolerance, and altered the levels of other micronutrients not depleted in the diet within the host. In addition, functional metagenomics profiling and a carbohydrate fermentation assay showed an increased microbial preference for simple sugars rather than complex ones, suggestive of a less developed microbiome in the low-micronutrient-fed mice. Moreover, we found that a zinc-only deficient diet was not sufficient to induce these phenotypes, further supporting the importance of studying co-occurring deficiencies.DiscussionTogether, these findings highlight a previously unappreciated role of early-life multiple micronutrient deficiencies in shaping the metabolic phenome of the host and gut microbiome through altered glucose energy metabolism, which may have implications for metabolic disease later in life in micronutrient-deficient survivors.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fnut.2023.1151670/fullTest; https://doaj.org/toc/2296-861XTest

الوصول الحر: https://doaj.org/article/b4ffca3968ed454d99e7b9e36376f9cdTest

المؤلفون: Tanner Stokes, Haoning Howard Cen, Philipp Kapranov, Iain J Gallagher, Andrew A. Pitsillides, Claude‐Henry Volmar, William E Kraus, James D. Johnson, Stuart M. Phillips, Claes Wahlestedt, James A. Timmons

المصدر: Advanced Genetics, Vol 4, Iss 2, Pp n/a-n/a (2023)

مصطلحات موضوعية: arrays, cDNA, cRNA, diagnostics, drug repurposing, lncRNA, Genetics, QH426-470

الوصف: Abstract Sequencing the human genome empowers translational medicine, facilitating transcriptome‐wide molecular diagnosis, pathway biology, and drug repositioning. Initially, microarrays are used to study the bulk transcriptome; but now short‐read RNA sequencing (RNA‐seq) predominates. Positioned as a superior technology, that makes the discovery of novel transcripts routine, most RNA‐seq analyses are in fact modeled on the known transcriptome. Limitations of the RNA‐seq methodology have emerged, while the design of, and the analysis strategies applied to, arrays have matured. An equitable comparison between these technologies is provided, highlighting advantages that modern arrays hold over RNA‐seq. Array protocols more accurately quantify constitutively expressed protein coding genes across tissue replicates, and are more reliable for studying lower expressed genes. Arrays reveal long noncoding RNAs (lncRNA) are neither sparsely nor lower expressed than protein coding genes. Heterogeneous coverage of constitutively expressed genes observed with RNA‐seq, undermines the validity and reproducibility of pathway analyses. The factors driving these observations, many of which are relevant to long‐read or single‐cell sequencing are discussed. As proposed herein, a reappreciation of bulk transcriptomic methods is required, including wider use of the modern high‐density array data—to urgently revise existing anatomical RNA reference atlases and assist with more accurate study of lncRNAs.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2641-6573Test

الوصول الحر: https://doaj.org/article/e905fbd859144cbe92af1c8b24906620Test

المؤلفون: George P. Brownrigg, Yi Han Xia, Chieh Min Jamie Chu, Su Wang, Charlotte Chao, Jiashuo Aaron Zhang, Søs Skovsø, Evgeniy Panzhinskiy, Xiaoke Hu, James D. Johnson, Elizabeth J. Rideout

المصدر: Molecular Metabolism, Vol 69, Iss , Pp 101678- (2023)

مصطلحات موضوعية: Pancreatic islets, β cells, Diabetes mellitus, Endoplasmic reticulum stress, Protein synthesis, Transcriptomics, Internal medicine, RC31-1245

الوصف: Objective: Pancreatic β cells play a key role in maintaining glucose homeostasis; dysfunction of this critical cell type causes type 2 diabetes (T2D). Emerging evidence points to sex differences in β cells, but few studies have examined male-female differences in β cell stress responses and resilience across multiple contexts, including diabetes. Here, we address the need for high-quality information on sex differences in β cell and islet gene expression and function using both human and rodent samples. Methods: In humans, we compared β cell gene expression and insulin secretion in donors with T2D to non-diabetic donors in both males and females. In mice, we generated a well-powered islet RNAseq dataset from 20-week-old male and female siblings with similar insulin sensitivity. Our unbiased gene expression analysis pointed to a sex difference in the endoplasmic reticulum (ER) stress response. Based on this analysis, we hypothesized female islets would be more resilient to ER stress than male islets. To test this, we subjected islets isolated from age-matched male and female mice to thapsigargin treatment and monitored protein synthesis, cell death, and β cell insulin production and secretion. Transcriptomic and proteomic analyses were used to characterize sex differences in islet responses to ER stress. Results: Our single-cell analysis of human β cells revealed sex-specific changes to gene expression and function in T2D, correlating with more robust insulin secretion in human islets isolated from female donors with T2D compared to male donors with T2D. In mice, RNA sequencing revealed differential enrichment of unfolded protein response pathway-associated genes, where female islets showed higher expression of genes linked with protein synthesis, folding, and processing. This differential expression was physiologically significant, as islets isolated from female mice were more resilient to ER stress induction with thapsigargin. Specifically, female islets showed a greater ability to maintain glucose-stimulated insulin production and secretion during ER stress compared with males. Conclusions: Our data demonstrate sex differences in β cell gene expression in both humans and mice, and that female β cells show a greater ability to maintain glucose-stimulated insulin secretion across multiple physiological and pathological contexts.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877823000121Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/374b1790b35f4f059d15bf42060d49eaTest

المؤلفون: Austin J. Taylor, Evgeniy Panzhinskiy, Paul C. Orban, Francis C. Lynn, David F. Schaeffer, James D. Johnson, Janel L. Kopp, C. Bruce Verchere

المصدر: Molecular Metabolism, Vol 68, Iss , Pp 101667- (2023)

مصطلحات موضوعية: Islet amyloid polypeptide, Amylin, Pancreatic ductal adenocarcinoma, Diabetes, Tumor suppressor, Internal medicine, RC31-1245

الوصف: Objectives: Pancreatic cancer risk is elevated approximately two-fold in type 1 and type 2 diabetes. Islet amyloid polypeptide (IAPP) is an abundant beta-cell peptide hormone that declines with diabetes progression. IAPP has been reported to act as a tumour-suppressor in p53-deficient cancers capable of regressing tumour volumes. Given the decline of IAPP during diabetes development, we investigated the actions of IAPP in pancreatic ductal adenocarcinoma (PDAC; the most common form of pancreatic cancer) to determine if IAPP loss in diabetes may increase the risk of pancreatic cancer. Methods: PANC-1, MIA PaCa-2, and H1299 cells were treated with rodent IAPP, and the IAPP analogs pramlintide and davalintide, and assayed for changes in proliferation, death, and glycolysis. An IAPP-deficient mouse model of PDAC (Iapp−/−; Kras+/LSL-G12D; Trp53flox/flox; Ptf1a+/CreER) was generated for survival analysis. Results: IAPP did not impact glycolysis in MIA PaCa-2 cells, and did not impact cell death, proliferation, or glycolysis in PANC-1 cells or in H1299 cells, which were previously reported as IAPP-sensitive. Iapp deletion in Kras+/LSL-G12D; Trp53flox/flox; Ptf1a+/CreER mice had no effect on survival time to lethal tumour burden. Conclusions: In contrast to previous reports, we find that IAPP does not function as a tumour suppressor. This suggests that loss of IAPP signalling likely does not increase the risk of pancreatic cancer in individuals with diabetes.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877823000017Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/3b960dd09db649a3b0d27836178a6badTest

المؤلفون: Søs Skovsø, Evgeniy Panzhinskiy, Jelena Kolic, Haoning Howard Cen, Derek A. Dionne, Xiao-Qing Dai, Rohit B. Sharma, Lynda Elghazi, Cara E. Ellis, Katharine Faulkner, Stephanie A. M. Marcil, Peter Overby, Nilou Noursadeghi, Daria Hutchinson, Xiaoke Hu, Hong Li, Honey Modi, Jennifer S. Wildi, J. Diego Botezelli, Hye Lim Noh, Sujin Suk, Brian Gablaski, Austin Bautista, Ryekjang Kim, Corentin Cras-Méneur, Stephane Flibotte, Sunita Sinha, Dan S. Luciani, Corey Nislow, Elizabeth J. Rideout, Eric N. Cytrynbaum, Jason K. Kim, Ernesto Bernal-Mizrachi, Laura C. Alonso, Patrick E. MacDonald, James D. Johnson

المصدر: Nature Communications, Vol 13, Iss 1, Pp 1-22 (2022)

مصطلحات موضوعية: Science

الوصف: Insulin receptor protein is present in pancreatic β-cells, but the consequences of β-cell insulin resistance are incompletely understood. Here the authors use a combination of mouse studies and mathematical modelling to show that loss of beta-cell insulin receptor affects male and female mice differently and can contribute to hyperinsulinemia in the context of glucose stimulation.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/34fcff15f65143fa8ca0bab84b4cd93eTest

المؤلفون: Anni M. Y. Zhang, Ken H. Chu, Brian F. Daly, Titine Ruiter, Yan Dou, Jenny C. C. Yang, Twan J. J. de Winter, Justin Chhuor, Su Wang, Stephane Flibotte, Yiwei Bernie Zhao, Xiaoke Hu, Hong Li, Elizabeth J. Rideout, David F. Schaeffer, James D. Johnson, Janel L. Kopp

المصدر: Cancer & Metabolism, Vol 10, Iss 1, Pp 1-18 (2022)

مصطلحات موضوعية: Pancreatic intraepithelial neoplasia, Pancreatic ductal adenocarcinoma, Insulin, Obesity, Type 2 diabetes, Single-cell RNA sequencing, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that genetically reduced insulin production resulted in ~ 50% suppression of pancreatic intraepithelial neoplasia (PanIN) precancerous lesions in mice. However, only female mice remained normoglycemic, and only the gene dosage of the rodent-specific Ins1 alleles was tested in our previous model. Moreover, we did not delve into the molecular and cellular mechanisms associated with modulating hyperinsulinemia. Methods We studied how reduced Ins2 gene dosage affects PanIN lesion development in both male and female Ptf1a CreER;Kras LSL-G12D mice lacking the rodent-specific Ins1 gene (Ins1 -/-). We generated control mice having two alleles of the wild-type Ins2 gene (Ptf1a CreER;Kras LSL-G12D;Ins1 -/-;Ins2 +/+) and experimental mice having one allele of Ins2 gene (Ptf1a CreER;Kras LSL-G12D;Ins1 -/-;Ins2 +/-). We then performed thorough histopathological analyses and single-cell transcriptomics for both genotypes and sexes. Results High-fat diet–induced hyperinsulinemia was transiently or modestly reduced in female and male mice, respectively, with only one allele of Ins2. This occurred without dramatically affecting glucose tolerance. Genetic reduction of insulin production resulted in mice with a tendency for less PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia affected multiple cell types in the pancreas, with the most statistically significant effects on local immune cell types that were highly represented in our sampled cell population. Specifically, hyperinsulinemia modulated pathways associated with protein translation, MAPK-ERK signaling, and PI3K-AKT signaling, which were changed in epithelial cells and subsets of immune cells. Conclusions These data suggest a potential role for the immune microenvironment in hyperinsulinemia-driven PanIN development. Together with our previous work, we propose that mild suppression of insulin levels may be useful in preventing pancreatic cancer by acting on multiple cell types.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2049-3002Test

الوصول الحر: https://doaj.org/article/ff9b541c39684bccacb601c1a9c7f635Test

المؤلفون: Chae Syng Lee, Yajie Zhai, Rui Shang, Trevor Wong, Aurora J. Mattison, Haoning Howard Cen, James D. Johnson, Israel Vlodavsky, Bahira Hussein, Brian Rodrigues

المصدر: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, Vol 11, Iss 23 (2022)

مصطلحات موضوعية: cardiomyocytes, endothelial cells, heparanase, lipoprotein lipase, mechanosensors, Diseases of the circulatory (Cardiovascular) system, RC666-701

الوصف: Background Lipoprotein lipase (LPL)‐derived fatty acid is a major source of energy for cardiac contraction. Synthesized in cardiomyocytes, LPL requires translocation to the vascular lumen for hydrolysis of lipoprotein triglyceride, an action mediated by endothelial cell (EC) release of heparanase. We determined whether flow‐mediated biophysical forces can cause ECs to secrete heparanase and thus regulate cardiac metabolism. Methods and Results Isolated hearts were retrogradely perfused. Confluent rat aortic ECs were exposed to laminar flow using an orbital shaker. Cathepsin L activity was determined using gelatin‐zymography. Diabetes was induced in rats with streptozotocin. Despite the abundance of enzymatically active heparanase in the heart, it was the enzymatically inactive, latent heparanase that was exceptionally responsive to flow‐induced release. EC exposed to orbital rotation exhibited a similar pattern of heparanase secretion, an effect that was reproduced by activation of the mechanosensor, Piezo1. The laminar flow‐mediated release of heparanase from EC required activation of both the purinergic receptor and protein kinase D, a kinase that assists in vesicular transport of proteins. Heparanase influenced cardiac metabolism by increasing cardiomyocyte LPL displacement along with subsequent replenishment. The flow‐induced heparanase secretion was augmented following diabetes and could explain the increased heparin‐releasable pool of LPL at the coronary lumen in these diabetic hearts. Conclusions ECs sense fluid shear‐stress and communicate this information to subjacent cardiomyocytes with the help of heparanase. This flow‐induced mechanosensing and its dynamic control of cardiac metabolism to generate ATP, using LPL‐derived fatty acid, is exquisitely adapted to respond to disease conditions, like diabetes.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2047-9980Test

الوصول الحر: https://doaj.org/article/b682a2631d454208892d84b6c7a7e8a2Test