title: Metabolic regulation of cellular plasticity in the pancreas.
abstract: Obese individuals exhibit an increase in pancreatic β cell mass; conversely, scarce nutrition during pregnancy has been linked to β cell insufficiency in the offspring [reviewed in 1, 2]. These phenomena are thought to be mediated mainly through effects on β cell proliferation, given that a nutrient-sensitive β cell progenitor population in the pancreas has not been identified. Here, we employed the fluorescent ubiquitination-based cell-cycle indicator system to investigate β cell replication in real time and found that high nutrient concentrations induce rapid β cell proliferation. Importantly, we found that high nutrient concentrations also stimulate β cell differentiation from progenitors in the intrapancreatic duct (IPD). Furthermore, using a new zebrafish line where β cells are constitutively ablated, we show that β cell loss and high nutrient intake synergistically activate these progenitors. At the cellular level, this activation process causes ductal cell reorganization as it stimulates their proliferation and differentiation. Notably, we link the nutrient-dependent activation of these progenitors to a downregulation of Notch signaling specifically within the IPD. Furthermore, we show that the nutrient sensor mechanistic target of rapamycin (mTOR) is required for endocrine differentiation from the IPD under physiological conditions as well as in the diabetic state. Thus, this study reveals critical insights into how cells modulate their plasticity in response to metabolic cues and identifies nutrient-sensitive progenitors in the mature pancreas.
authors.affiliation: Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, the Diabetes Center, Institute for Regeneration Medicine and Liver Center, University of California, San Francisco, 1550 4(th) Street, San Francisco, CA 94158, USA. nikolay.ninov@mpi-bn.mpg.de
authors.forename: Nikolay
authors.initials: N
authors.lastname: Ninov
authors.forename: Daniel
authors.initials: D
authors.lastname: Hesselson
authors.forename: Philipp
authors.initials: P
authors.lastname: Gut
authors.forename: Amy
authors.initials: A
authors.lastname: Zhou
authors.forename: Kevin
authors.initials: K
authors.lastname: Fidelin
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
mesh_terms: D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D030801:Animals, Genetically Modified / Q000254:growth & development / Q000502:physiology; D002454:Cell Differentiation; D049109:Cell Proliferation; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D007814:Larva / Q000254:growth & development / Q000502:physiology; D008164:Luminescent Proteins / Q000378:metabolism; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D054875:Ubiquitination; D015027:Zebrafish / Q000254:growth & development / Q000502:physiology*; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D008164:Luminescent Proteins; D051880:Receptors, Notch; D029961:Zebrafish Proteins; D058570:TOR Serine-Threonine Kinases