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@ARTICLE{Dieterle:143918,
      author       = {V. Dieterle$^*$ and S. Herzer$^*$ and H.-J. Gröne$^*$ and
                      R. Jennemann$^*$ and V. Nordström$^*$},
      title        = {{G}anglioside deficiency in hypothalamic {POMC} neurons
                      promotes body weight gain.},
      journal      = {International journal of obesity},
      volume       = {44},
      number       = {2},
      issn         = {0307-0565},
      address      = {Avenel, NJ},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2019-01476},
      pages        = {510-524},
      year         = {2020},
      note         = {44 (2), 510-524Feb 2020 #EA:G130#LA:G130#},
      abstract     = {Glucosylceramide synthase (GCS; gene: UDP-glucose:ceramide
                      glucosyltransferase (Ugcg))-derived gangliosides comprise a
                      specific class of lipids in the plasma membrane that
                      modulate the activity of transmembrane receptors. GCS
                      deletion in hypothalamic arcuate nucleus (Arc) neurons leads
                      to prominent obesity. However, it has not yet been studied
                      how ganglioside depletion affects individual Arc neuronal
                      subpopulations. The current study investigates the effects
                      of GCS deletion specifically in anorexigenic
                      pro-opiomelanocortin (POMC) neurons. Additionally, we
                      investigate insulin receptor (IR) signaling and
                      phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) binding to
                      ATP-dependent K+ (KATP) channels of GCS-deficient POMC
                      neurons.We generated Ugcgf/f-Pomc-Cre mice with ganglioside
                      deficiency in POMC neurons. Moreover, the CRISPR (clustered
                      regulatory interspaced short palindromic repeats)/Cas9
                      technology was used to inhibit GCS-dependent ganglioside
                      biosynthesis in cultured mouse POMC neurons, yielding
                      UgcgΔ-mHypoA-POMC cells that were used to study mechanistic
                      aspects in further detail. Proximity ligation assays (PLAs)
                      visualized interactions between gangliosides, IR, and KATP
                      channel subunit sulfonylurea receptor-1 (SUR-1), as well as
                      intracellular IR substrate 2 (IRS-2) phosphorylation and
                      PIP3.Chow-fed Ugcgf/f-Pomc-Cre mice showed a moderate but
                      significant increase in body weight gain and they failed to
                      display an increase of anorexigenic neuropeptide expression
                      during the fasting-to-re-feeding transition. IR, IRS-2, p85,
                      and overall insulin-evoked IR and IRS-2 phosphorylation were
                      elevated in ganglioside-depleted UgcgΔ-mHypoA-POMC neurons.
                      A PLA demonstrated that more insulin-evoked complex
                      formation occurred between PIP3 and SUR-1 in
                      ganglioside-deficient POMC neurons in vitro and in vivo.Our
                      work suggests that GCS deletion in POMC neurons promotes
                      body weight gain. Gangliosides are required for an
                      appropriate adaptation of anorexigenic neuropeptide
                      expression in the Arc during the fasting-to-re-feeding
                      transition. Moreover, gangliosides might modulate KATP
                      channel activity by restraining PIP3 binding to the KATP
                      channel subunit SUR-1. Increased PIP3/SUR-1 interactions in
                      ganglioside-deficient neurons could in turn potentially lead
                      to electrical silencing. This work highlights that
                      gangliosides in POMC neurons of the hypothalamic Arc are
                      important regulators of body weight.},
      cin          = {G130},
      ddc          = {610},
      cid          = {I:(DE-He78)G130-20160331},
      pnm          = {319H - Addenda (POF3-319H)},
      pid          = {G:(DE-HGF)POF3-319H},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31168055},
      doi          = {10.1038/s41366-019-0388-y},
      url          = {https://inrepo02.dkfz.de/record/143918},
}