Endocrine system and metabolic diseases articles within Nature Communications

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  • Article
    | Open Access

    Many genetic loci have been linked to obesity, but knowledge of their functional mechanisms is limited. Here, the authors perform reporter assays and temporal functional genomics data generation to characterize obesity genetic loci and find that loci often harbor multiple functional variants.

    • Amelia C. Joslin
    • , Débora R. Sobreira
    •  & Marcelo A. Nóbrega

  • Article
    | Open Access

    p53 regulates signalling pathways involved in metabolic homeostasis. Here the authors show that O-GlcNAcylation of p53 in the liver plays a key role in the physiological regulation of glucose homeostasis, potentially via controlling the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase.

    • Maria J. Gonzalez-Rellan
    • , Marcos F. Fondevila
    •  & Ruben Nogueiras

  • Article
    | Open Access

    Diabetes is characterized by dysfunction and loss of beta-cells, and promoting beta-cell survival is of therapeutic interest. Here the authors show that Large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, induces beta-cell failure through mTORC1 hyperactivation and autophagic flux suppression.

    • Ting Yuan
    • , Karthika Annamalai
    •  & Amin Ardestani

  • Article
    | Open Access

    The mechanisms that mediate the effects of weight loss surgeries such as vertical sleeve gastrectomy (VSG) are incompletely understood. Here the authors show that intestinal FGF15 is necessary to improve glucose tolerance and to prevent the loss of muscle and bone mass after VSG, potentially via protection against bile acid toxicity.

    • Nadejda Bozadjieva-Kramer
    • , Jae Hoon Shin
    •  & Randy J. Seeley

  • Article
    | Open Access

    Gut microbiota deficient mice demonstrate enhanced glucose clearance, but which tissues are responsible for this improvement are still unclear. Here the authors report that brown adipose tissue contributes to the enhanced glucose clearance in gut microbiota depleted mice and that this response is dissociated from adaptive thermogenesis.

    • Min Li
    • , Li Li
    •  & John R. Speakman

  • Article
    | Open Access

    The cellular identity and function of the pancreatic polypeptide (Ppy)-producing γ-cells are incompletely understood. Here the authors show that these cells are heterogeneous and display adaptive plasticity to engage in insulin production following β-cell injury, but loss of the Ppy gene or γ-cells in mice does not affect weight or glycemia under basal conditions.

    • Marta Perez-Frances
    • , Léon van Gurp
    •  & Pedro L. Herrera

  • Article
    | Open Access

    A SNP distant from the human insulin (INS) gene near the KRTAP5-6 gene confers increased susceptibility to type 2 diabetes when present on the paternal allele while decreased susceptibility when on the maternal allele. Here the authors show that long-range contacts between the INS locus and the KRTAP5-6 gene locus distinguish paternal and maternal alleles.

    • Xing Jian
    •  & Gary Felsenfeld

  • Article
    | Open Access

    Mosaic loss of chromosome Y (LOY) is a common form of clonal mosaicism in leukocytes. Here, the authors extend genetic association analyses to rare variation using exome-sequence data from 82,277 males, finding that loss-of-function alleles in GIGYF1 are associated with six-fold higher susceptibility to both LOY and Type 2 Diabetes.

    • Yajie Zhao
    • , Stasa Stankovic
    •  & John R. B. Perry

  • Article
    | Open Access

    The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal signals to control metabolism. Here the authors investigate the effects of constitutive nutrient signaling through genetic activation of RagA in adult mice and show that constitutive nutrient signaling regulates the response to feeding-fasting cycles and does not drive liver cancer.

    • Celia de la Calle Arregui
    • , Ana Belén Plata-Gómez
    •  & Alejo Efeyan

  • Article
    | Open Access

    New-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients, however, the underlying mechanisms are not fully understood. Here, the authors show that SARS-CoV-2 is detectable in both endocrine and exocrine cells of the pancreata of patients with COVID-19.

    • Charlotte Steenblock
    • , Stefanie Richter
    •  & Stefan R. Bornstein

  • Article
    | Open Access

    Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

    • Julia K. Goodrich
    • , Moriel Singer-Berk
    •  & Miriam S. Udler

  • Article
    | Open Access

    Genetic variants in CD36 have been associated with metabolic syndrome. Here, the authors found that lymphatic vessel integrity and lipid transport are influenced by CD36 expression, and lymphatic endothelial cell CD36 deficiency causes visceral obesity and insulin resistance, which are risk factors for metabolic syndrome and diabetes.

    • Vincenza Cifarelli
    • , Sila Appak-Baskoy
    •  & Nada A. Abumrad

  • Article
    | Open Access

    Human pluripotent stem cell (hPSC) derived pancreatic beta cells are a promising and potentially limitless source for cell replacement therapy. Here the authors perform stage-wise chemical screening to develop an improved protocol for hPSC differentiation to functional pancreatic beta cells at high efficiency.

    • Haisong Liu
    • , Ronghui Li
    •  & Juan Carlos Izpisua Belmonte

  • Article
    | Open Access

    Hepatic gluconeogenesis is important for glucose homeostasis and a therapeutic target for type 2 diabetes. Here, the authors show that the RNA-binding adaptor protein Sam68 promotes the expression level of gluconeogenic genes and increases blood glucose levels by stabilizing the transcriptional coactivator CRTC2, while hepatic Sam68 deletion alleviates hyperglycemia in mice.

    • Aijun Qiao
    • , Junlan Zhou
    •  & Gangjian Qin

  • Article
    | Open Access

    Impaired wound healing is a serious complication in diabetic patients, and is associated with reduced HIF1α stability. Here, the authors design a small molecule that stabilizes HIF1α by blocking its interaction with VHL and show that it promotes wound healing in mouse models of diabetes.

    • Guodong Li
    • , Chung-Nga Ko
    •  & Chung-Hang Leung

  • Article
    | Open Access

    During insulin-resistance, the compensatory expansion of beta-cell mass is able to delay or the onset of overt type 2 diabetes. Here, the authors report that beta-arrestin-1, an intracellular protein known to regulate signalling through G protein-coupled receptors, is essential for beta-cell replication and function in insulin-resistant mice.

    • Luiz F. Barella
    • , Mario Rossi
    •  & Jürgen Wess

  • Article
    | Open Access

    Regeneration of insulin-producing beta-cells may become a future alternative treatment of diabetes. Here the authors report a genetic screen in a zebrafish model that mimics the loss of beta-cells in diabetes, and identified that the folate receptor Folr1 or folinic acid treatment can stimulate beta-cell regeneration.

    • Christos Karampelias
    • , Habib Rezanejad
    •  & Olov Andersson

  • Article
    | Open Access

    LncRNAs are implicated in the pathogenesis of a number of diseases. Here, the authors show that the lncRNA Nron suppresses bone resorption, and show that delivery of a functional motif of Nron increases bone mass in mouse models of osteoporosis.

    • Fujun Jin
    • , Junhui Li
    •  & Xiaogang Wang

  • Article
    | Open Access

    As the leading cause of vision loss in working-age adults, diabetic retinopathy requires routinely retinal screening. Here the authors develop a deep learning system that can facilitate the screening by providing real-time image quality assessment, lesions detection, and grades across the disease spectrum.

    • Ling Dai
    • , Liang Wu
    •  & Weiping Jia

  • Article
    | Open Access

    Heterozygous HNF1A mutations can give rise to maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. Here the authors show that MODY3-related HNF1A mutation in patient hiPSCderived pancreatic cells decreases glucose transporter GLUT2 expression due to compromised DNA binding.

    • Blaise Su Jun Low
    • , Chang Siang Lim
    •  & Adrian Kee Keong Teo

  • Article
    | Open Access

    The soluble bioactive form of the transmembrane protein fibronectin type III domain containing 4 (sFNDC4) has anti-inflammatory effects and improves insulin sensitivity. Here the authors show that liver derived sFNDC4 signals through adipose tissue GPCR GPR116 to promote insulin-mediated glucose uptake.

    • Anastasia Georgiadi
    • , Valeria Lopez-Salazar
    •  & Stephan Herzig

  • Article
    | Open Access

    Interactions between the immune system and adipose tissue contribute to the regulation of body weight, however, the underlying mechanisms remain incompletely understood. Here the authors dissect the role of two structurally and functionally similar immune mediators, BAFF and APRIL, in modifying diet-induced weight gain and adipocyte lipid handling.

    • Calvin C. Chan
    • , Isaac T. W. Harley
    •  & Senad Divanovic

  • Review Article
    | Open Access

    At the centre of intestinal health and the fight against obesity and metabolic syndrome is the intestinal microbiota and its interaction with our immune systems. Here the authors Review the current understanding of how these systems interact and how we can capitalize on recent advances to provide better therapeutic options.

    • Saad Khan
    • , Helen Luck
    •  & Daniel A. Winer

  • Article
    | Open Access

    There are few treatments for male infertility. Here, the authors show that the receptor activator of NF-κB ligand (RANKL) signalling pathway has important functions in sperm production and maturation, improves fertility in male mice and shows potential as a male infertility target.

    • Martin Blomberg Jensen
    • , Christine Hjorth Andreassen
    •  & Anders Juul

  • Article
    | Open Access

    The SARS-CoV-2 receptor ACE2 is involved in the Renin-Angiotensin-Aldosterone System (RAAS). Over-activation of RAAS in swine results in a disease state similar to that of COVID-19 in human patients, suggesting that COVID-19 pathophysiology may be driven, at least in part, by an imbalance of this hormonal system.

    • Susanne Rysz
    • , Jonathan Al-Saadi
    •  & Johan Lundberg

  • Article
    | Open Access

    Insulin resistance and lower muscle strength in relation to mass are hallmarks of type 2 diabetes. Here, the authors report alterations in muscle stem cells from individuals with type 2 diabetes that may contribute to these phenotypes through VPS39 mediated effects on autophagy and epigenetics.

    • Cajsa Davegårdh
    • , Johanna Säll
    •  & Charlotte Ling

  • Article
    | Open Access

    The editing of primary human islets could provide insight into diabetes pathogenesis. Here the authors use CRISPR-Cas9 to target regulatory elements associated with T2D susceptibility.

    • Romina J. Bevacqua
    • , Xiaoqing Dai
    •  & Seung K. Kim

  • Article
    | Open Access

    The endothelial glucocorticoid receptor plays a key role in the regulation of many diseases, including diabetes. Loss of this receptor results in accelerated renal fibrosis, a heightened inflammatory milieu, augmented Wnt signaling and suppression of fatty acid oxidation in diabetic kidneys.

    • Swayam Prakash Srivastava
    • , Han Zhou
    •  & Julie Goodwin

  • Article
    | Open Access

    Mutations in components of the MAP kinase pathway are associated with a group of syndromes known as RASopathies. Here, the authors identify gain-of-function mutations in BRAF in patients with RASopathies and congenital hypopituitarisms.  This article demonstrates a central role for BRAF in the development of the hypothalamo-pituitary axis leading to endocrine deficiencies in patients with RASopathies.

    • Angelica Gualtieri
    • , Nikolina Kyprianou
    •  & Carles Gaston-Massuet

  • Article
    | Open Access

    Type 2 diabetes is associated with chronic inflammation and is characterized by insulin resistance. Here, the authors identify a crucial role for endothelial BMPER function in glucose homeostasis, and BMPER overexpression was shown to alleviate insulin resistance and hyperglycemia in diabetic mice.

    • Hua Mao
    • , Luge Li
    •  & Xinchun Pi

  • Perspective
    | Open Access

    Endocrine therapy has been the mainstay for hormone responsive breast cancer treatment. Here, Garcia-Martinez and colleagues discuss epigenetic mechanisms regulating ER + breast cancer and endocrine therapy resistance, and highlight approaches to rewire the cancer epigenome to improve targeted therapies for this cancer.

    • Liliana Garcia-Martinez
    • , Yusheng Zhang
    •  & Lluis Morey

  • Article
    | Open Access

    Cold acclimation has been shown to have beneficial metabolic effects, including improved insulin sensitivity in patients with type 2 diabetes. Here the authors show that a mild cold acclimation regiment during which overt shivering was prevented did not result in improved insulin sensitivity in a small group of patients with type 2 diabetes.

    • Carlijn M. E. Remie
    • , Michiel P. B. Moonen
    •  & Patrick Schrauwen

  • Article
    | Open Access

    The early identification of metabolic disorders could improve or prevent overt disease. Here the authors show that the circulating concentration of hyocholic acid (HCA) species is decreased in the context of obesity and diabetes and increased after gastric bypass surgery in humans, and further that serum HCA species are predictive of metabolic outcomes in healthy individuals.

    • Xiaojiao Zheng
    • , Tianlu Chen
    •  & Wei Jia

  • Article
    | Open Access

    Dietary changes can impact the microbial constitution of the gastrointestinal tract and modulate the local immune response. Here, the authors show supplementation using lysates of Methylococcus capsulatus Bath result in changes to the microbiota, modulate Treg populations and metabolic read outs in a dietary control murine model.

    • Benjamin A. H. Jensen
    • , Jacob B. Holm
    •  & Tor E. Lea

  • Article
    | Open Access

    Autoimmune Addison’s disease is a rare complex disease, which has not yet been characterized by non-biased genetic studies. Here, the authors perform the first GWAS for the disease, identifying nine loci including two coding variants in the gene Autoimmune Regulator (AIRE).

    • Daniel Eriksson
    • , Ellen Christine Røyrvik
    •  & Eystein Sverre Husebye

  • Article
    | Open Access

    The genetic basis of daytime napping and the directional effect of daytime napping on cardiometabolic health are unknown. Here, the authors perform a genome-wide association study on self-reported daytime napping in the UK Biobank and Mendelian randomization to explore causal associations.

    • Hassan S. Dashti
    • , Iyas Daghlas
    •  & Richa Saxena

  • Article
    | Open Access

    Obesity and its associated metabolic changes, including hyperinsulinemia and aberrant circadian rhythms, increases the risk for a variety of cancers including postmenopausal breast cancer. Here, the authors show that restricting when mice eat, but not what or how much they eat, delays breast cancer initiation and reduces tumor growth in obese mice in addition to improving insulin sensitivity and restoring circadian rhythms.

    • Manasi Das
    • , Lesley G. Ellies
    •  & Nicholas J. G. Webster

  • Article
    | Open Access

    High-fat diet plays a role in development of insulin resistance. Here, the authors report a mechanism that underlies the development of diet induced insulin resistance through the activation of an aryl hydrocarbon receptor mediated signalling pathway in the liver by faecal exosomes derived from intestinal cells.

    • Anil Kumar
    • , Kumaran Sundaram
    •  & Huang-Ge Zhang

  • Article
    | Open Access

    Islet amyloid polypeptide (IAPP) deposition is associated with islet cell loss in diabetes. Here the authors show that a small molecule autophagy enhancer reduces IAPP accumulation in vitro, and also improves glucose tolerance in hIAPP+ mice fed high-fat diet, accompanied by reduced hIAPP accumulation, in vivo.

    • Jinyoung Kim
    • , Kihyoun Park
    •  & Myung-Shik Lee

  • Article
    | Open Access

    Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

    • Vasiliki Lagou
    • , Reedik Mägi
    •  & Inga Prokopenko

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