Endocrine system and metabolic diseases

  • Article |

    Therapeutic administration of IL-27—serum levels of which are decreased in individuals with obesity—improves thermogenesis, protects against diet-induced obesity and ameliorates insulin resistance in mouse models of obesity.

    • Qian Wang
    • , Dehai Li
    •  & Zhinan Yin
  • Article |

    Cryo-EM structures of human calcium-sensing receptor reveal intrinsic asymmetry in the receptor homodimer upon activation that is stabilized by calcimimetic drugs adopting distinct poses in the two protomers, priming one protomer for G-protein coupling.

    • Yang Gao
    • , Michael J. Robertson
    •  & Georgios Skiniotis
  • Article |

    Metabolically-mature human islet-like organoids generated from induced pluripotent stem cells are able to recapitulate insulin-responsive pancreatic islet function and avoid immunologic cell death in diabetic mouse transplantation models.

    • Eiji Yoshihara
    • , Carolyn O’Connor
    •  & Ronald M. Evans
  • Article |

    A role and mechanism of action are identified for INSP3R1 in the stimulation of hepatic gluconeogenesis and mitochondrial oxidation by glucagon, suggesting that INSP3R1 may be a target for ameliorating dysregulation of hepatic glucose metabolism.

    • Rachel J. Perry
    • , Dongyan Zhang
    •  & Gerald I. Shulman
  • Article |

    The cryo-electron microscopy structure of human thyroglobulin reveals that proximity, flexibility and solvent exposure are key characteristics of its hormonogenic tyrosine pairs, and provides a framework for understanding the formation of thyroid hormones.

    • Francesca Coscia
    • , Ajda Taler-Verčič
    •  & Jan Löwe
  • Article |

    In mouse studies, metformin treatment results in increased secretion of growth/differentiation factor 15 (GDF15), which prevents weight gain in response to high-fat diet, and GDF15-independent lowering of circulating blood glucose.

    • Anthony P. Coll
    • , Michael Chen
    •  & Stephen O’Rahilly
  • Review Article |

    A Review of studies into insulin resistance and hepatic gluconeogenesis associated with obesity and type 2 diabetes.

    • Michael Roden
    •  & Gerald I. Shulman
  • Perspective
    | Open Access

    Over ten years, the Human Microbiome Project has provided resources for studying the microbiome and its relationship to disease; this Perspective summarizes the key achievements and findings of the project and its relationship to the broader field.

    • Lita M. Proctor
    • , Heather H. Creasy
    •  & Curtis Huttenhower
  • Article
    | Open Access

    Deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, alongside changes in the microbiome, in samples from individuals with and without prediabetes reveal insights into inter-individual variability and associations between changes in the microbiome and other factors.

    • Wenyu Zhou
    • , M. Reza Sailani
    •  & Michael Snyder
  • Article |

    Osteoclasts secrete small extracellular vesicles that stimulate osteoblasts, promoting bone formation via receptor activator of nuclear factor-kappa B ligand (RANKL), thereby linking bone formation and resorption.

    • Yuki Ikebuchi
    • , Shigeki Aoki
    •  & Hiroshi Suzuki
  • Brief Communications Arising |

    • John Collinge
    • , Zane Jaunmuktane
    •  & Sebastian Brandner
  • Article |

    Increased potential for branched-chain amino acid and lipopolysaccharide biosynthesis in the gut microbiome of insulin-resistant individuals suggests that changes in the serum metabolome induced by dysbiosis, and driven by only a handful of species, contribute to the development of diabetes.

    • Helle Krogh Pedersen
    • , Valborg Gudmundsdottir
    •  & Oluf Pedersen
  • Article |

    Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease.

    • Christian Fuchsberger
    • , Jason Flannick
    •  & Mark I. McCarthy
  • Letter |

    Neurotensin, a peptide expressed in the enteroendocrine cells of the small intestine that is released upon fat ingestion, is shown to increase fatty acid absorption, with neurotensin-deficient mice being protected from obesity induced by a high-fat diet.

    • Jing Li
    • , Jun Song
    •  & B. Mark Evers
  • Letter |

    Activation of glucose-sensing neurons in the ventromedial hypothalamic nucleus using radio waves or magnetic fields remotely and non-invasively in vivo increases plasma glucose and glucagon, and suppresses plasma insulin; conversely, remote inhibition of glucose-sensing neurons decreased blood glucose and increased plasma insulin.

    • Sarah A. Stanley
    • , Leah Kelly
    •  & Jeffrey M. Friedman
  • Letter |

    Group 2 innate lymphoid cells are shown to have a critical role in energy homeostasis by producing methionine-enkephalin peptides in response to interleukin 33, thus promoting the beiging of white adipose tissue; increased numbers of beige (also known as brown-like or brite) fat cells in white adipose tissue leads to increased energy expenditure and decreased adiposity.

    • Jonathan R. Brestoff
    • , Brian S. Kim
    •  & David Artis
  • Article |

    Non-caloric artificial sweeteners (NAS), widely used food additives considered to be safe and beneficial alternatives to sugars, are shown here to lead to the development of glucose intolerance through compositional and functional changes in the gut microbiota of mice, and the deleterious metabolic effects are transferred to germ-free mice by faecal transplant; NAS-induced dysbiosis and glucose intolerance are also demonstrated in healthy human subjects.

    • Jotham Suez
    • , Tal Korem
    •  & Eran Elinav
  • Letter |

    An investigation of the influence of age on the generation of insulin-producing cells after β-cell loss in mice reveals that, whereas α-cells can reprogram to produce insulin from puberty to adulthood, efficient reconstitution in the very young is through δ-cell reprogramming, leading to complete diabetes recovery.

    • Simona Chera
    • , Delphine Baronnier
    •  & Pedro L. Herrera
  • Letter |

    An association mapping study of type-2-diabetes-related quantitative traits in the Greenlandic population identified a common variant in TBC1D4 that increases plasma glucose levels and serum insulin levels after an oral glucose load and type 2 diabetes risk, with effect sizes several times larger than any previous findings of large-scale genome-wide association studies for these traits.

    • Ida Moltke
    • , Niels Grarup
    •  & Torben Hansen
  • Letter |

    Obesity-associated noncoding sequences within FTO are functionally connected with IRX3, and long-range enhancers in this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval is part of IRX3 regulation; Irx3-deficient mice have lower body weight and are resistant to diet-induced obesity, suggesting IRX3 as a novel determinant of body mass and composition.

    • Scott Smemo
    • , Juan J. Tena
    •  & Marcelo A. Nóbrega
  • Letter |

    The three-dimensional structure of the insulin–insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein; here is the first glimpse of the interaction between insulin and its primary binding site on the insulin receptor, a view based on four crystal structures of insulin bound to truncated insulin receptor complexes.

    • John G. Menting
    • , Jonathan Whittaker
    •  & Michael C. Lawrence
  • Article |

    The authors have developed a new method, metagenome-wide association study (MGWAS), to compare the combined genetic content of the faecal microbiota of healthy people versus patients with type 2 diabetes; they identify multiple microbial species and metabolic pathways that are associated with either cohort and show that some of these may be used as biomarkers.

    • Junjie Qin
    • , Yingrui Li
    •  & Jun Wang
  • Letter |

    A meta-analysis of genome-wide association studies of phenotypic variation for height and body mass index in human populations using 170,000 samples shows that one single nucleotide polymorphism at the FTO locus, which is associated with obesity, is also associated with phenotypic variation.

    • Jian Yang
    • , Ruth J. F. Loos
    •  & Peter M. Visscher
  • Article |

    Downregulation of the glucose transporter GLUT4 in adipose tissue occurs early in the development of type 2 diabetes; here GLUT4-mediated glucose uptake is shown to induce a novel form of the transcription factor ChREBP, which regulates de novo lipogenesis and systemic glucose metabolism.

    • Mark A. Herman
    • , Odile D. Peroni
    •  & Barbara B. Kahn
  • Letter |

    A non-coding region on chromosome 9p21 was previously shown to associate with coronary artery disease and type 2 diabetes, and the region has been implicated in regulating neighbouring genes. Here, 33 distinct enhancers within this region are identified, showing that SNPs in one of the enhancers affect STAT1 binding. Furthermore, it is shown that in human vascular endothelial cells the enhancer interval physically interacts with a number of specific loci and that IFN-γ activation strongly affects the chromatin structure and transcriptional regulation of the 9p21 locus, including STAT1 binding, long-range enhancer interactions and expression of neighbouring genes.

    • Olivier Harismendy
    • , Dimple Notani
    •  & Kelly A. Frazer
  • Article |

    β-adrenergic receptor signalling in adipocytes stimulates energy expenditure via cAMP-dependent increases in lipolysis and fatty-acid oxidation, and this signalling mechanism is thought to be disrupted in obesity. Here, the cAMP-responsive CREB coactivator Crtc3 is shown to promote obesity in mice by attenuating β adrenergic receptor signalling in adipose tissue.

    • Youngsup Song
    • , Judith Altarejos
    •  & Marc Montminy