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@ARTICLE{Maida:125325,
      author       = {A. Maida and J. S. K. Chan and K. A. Sjøberg and A.
                      Zota$^*$ and D. Schmoll and B. Kiens and S. Herzig$^*$ and
                      A. J. Rose},
      title        = {{R}epletion of branched chain amino acids reverses m{TORC}1
                      signaling but not improved metabolism during dietary protein
                      dilution.},
      journal      = {Molecular metabolism},
      volume       = {6},
      number       = {8},
      issn         = {2212-8778},
      address      = {Oxford [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2017-01458},
      pages        = {873 - 881},
      year         = {2017},
      abstract     = {Dietary protein dilution (PD) has been associated with
                      metabolic advantages such as improved glucose homeostasis
                      and increased energy expenditure. This phenotype involves
                      liver-induced release of FGF21 in response to amino acid
                      insufficiency; however, it has remained unclear whether
                      dietary dilution of specific amino acids (AAs) is also
                      required. Circulating branched chain amino acids (BCAAs) are
                      sensitive to protein intake, elevated in the serum of obese
                      humans and mice and thought to promote insulin resistance.
                      We tested whether replenishment of dietary BCAAs to an
                      AA-diluted (AAD) diet is sufficient to reverse the
                      glucoregulatory benefits of dietary PD.We conducted AA
                      profiling of serum from healthy humans and lean and high
                      fat-fed or New Zealand obese (NZO) mice following dietary
                      PD. We fed wildtype and NZO mice one of three amino acid
                      defined diets: control, total AAD, or the same diet with
                      complete levels of BCAAs (AAD + BCAA). We quantified serum
                      AAs and characterized mice in terms of metabolic efficiency,
                      body composition, glucose homeostasis, serum FGF21, and
                      tissue markers of the integrated stress response (ISR) and
                      mTORC1 signaling.Serum BCAAs, while elevated in serum from
                      hyperphagic NZO, were consistently reduced by dietary PD in
                      humans and murine models. Repletion of dietary BCAAs
                      modestly attenuated insulin sensitivity and metabolic
                      efficiency in wildtype mice but did not restore
                      hyperglycemia in NZO mice. While hepatic markers of the ISR
                      such as P-eIF2α and FGF21 were unabated by dietary BCAA
                      repletion, hepatic and peripheral mTORC1 signaling were
                      fully or partially restored, independent of changes in
                      circulating glucose or insulin.Repletion of BCAAs in dietary
                      PD is sufficient to oppose changes in somatic mTORC1
                      signaling but does not reverse the hepatic ISR nor induce
                      insulin resistance in type 2 diabetes during dietary PD.},
      cin          = {A170 / A171},
      ddc          = {610},
      cid          = {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:28752051},
      pmc          = {pmc:PMC5518726},
      doi          = {10.1016/j.molmet.2017.06.009},
      url          = {https://inrepo02.dkfz.de/record/125325},
}