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@ARTICLE{Maida:129107,
      author       = {A. Maida and A. Zota and K. A. Sjøberg and J.
                      Schumacher$^*$ and T. Sijmonsma$^*$ and A. Pfenninger and M.
                      M. Christensen and T. Gantert$^*$ and J. Fuhrmeister$^*$ and
                      U. Rothermel$^*$ and D. Schmoll and M. Heikenwälder$^*$ and
                      J. L. Iovanna and K. Stemmer and B. Kiens and S. Herzig and
                      A. J. Rose$^*$},
      title        = {{A} liver stress-endocrine nexus promotes metabolic
                      integrity during dietary protein dilution.},
      journal      = {The journal of clinical investigation},
      volume       = {126},
      number       = {9},
      issn         = {1558-8238},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DKFZ-2017-05112},
      pages        = {3263 - 3278},
      year         = {2016},
      abstract     = {Dietary protein intake is linked to an increased incidence
                      of type 2 diabetes (T2D). Although dietary protein dilution
                      (DPD) can slow the progression of some aging-related
                      disorders, whether this strategy affects the development and
                      risk for obesity-associated metabolic disease such as T2D is
                      unclear. Here, we determined that DPD in mice and humans
                      increases serum markers of metabolic health. In lean mice,
                      DPD promoted metabolic inefficiency by increasing
                      carbohydrate and fat oxidation. In nutritional and polygenic
                      murine models of obesity, DPD prevented and curtailed the
                      development of impaired glucose homeostasis independently of
                      obesity and food intake. DPD-mediated metabolic inefficiency
                      and improvement of glucose homeostasis were independent of
                      uncoupling protein 1 (UCP1), but required expression of
                      liver-derived fibroblast growth factor 21 (FGF21) in both
                      lean and obese mice. FGF21 expression and secretion as well
                      as the associated metabolic remodeling induced by DPD also
                      required induction of liver-integrated stress
                      response-driven nuclear protein 1 (NUPR1). Insufficiency of
                      select nonessential amino acids (NEAAs) was necessary and
                      adequate for NUPR1 and subsequent FGF21 induction and
                      secretion in hepatocytes in vitro and in vivo. Taken
                      together, these data indicate that DPD promotes improved
                      glucose homeostasis through an NEAA insufficiency-induced
                      liver NUPR1/FGF21 axis.},
      keywords     = {Basic Helix-Loop-Helix Transcription Factors (NLM
                      Chemicals) / DNA-Binding Proteins (NLM Chemicals) / Dietary
                      Proteins (NLM Chemicals) / Neoplasm Proteins (NLM Chemicals)
                      / Nupr1 protein, mouse (NLM Chemicals) / P8 protein, human
                      (NLM Chemicals) / UCP1 protein, human (NLM Chemicals) / Ucp1
                      protein, mouse (NLM Chemicals) / Uncoupling Protein 1 (NLM
                      Chemicals) / fibroblast growth factor 21 (NLM Chemicals) /
                      Fibroblast Growth Factors (NLM Chemicals) / Glucose (NLM
                      Chemicals)},
      cin          = {F180 / G130 / A170 / A171},
      ddc          = {610},
      cid          = {I:(DE-He78)F180-20160331 / I:(DE-He78)G130-20160331 /
                      I:(DE-He78)A170-20160331 / I:(DE-He78)A171-20160331},
      pnm          = {323 - Metabolic Dysfunction as Risk Factor (POF3-323)},
      pid          = {G:(DE-HGF)POF3-323},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:27548521},
      pmc          = {pmc:PMC5004939},
      doi          = {10.1172/JCI85946},
      url          = {https://inrepo02.dkfz.de/record/129107},
}