title: Extreme obesity induces massive beta cell expansion in mice through self-renewal and does not alter the beta cell lineage.
abstract: Understanding the developmental biology of beta cell regeneration is critical for developing new diabetes therapies. Obesity is a potent but poorly understood stimulus for beta cell expansion. Current models of obesity are complicated by developmental compensation or concurrent diabetes, limiting their usefulness for identifying the lineage mechanism(s) of beta cell expansion. We aimed to determine whether acute inducible obesity stimulates beta cell expansion and to determine the lineage mechanism of beta cell growth in obesity.
  
  
  
  We created whole-body tamoxifen-inducible leptin receptor (LepR)-deficient mice (Ubc-Cre (ERT2) LepR (loxP/loxP) ) as a novel model of acute obesity. Beta cell mass and proliferation were quantified after short-term LepR deletion. Clonal analysis of beta cell expansion using the Brainbow2.1 reporter was performed 6 months post tamoxifen initiation.
  
  
  
  LepR deficiency induced a doubling of body mass within 3 weeks, with moderate glucose intolerance (unlike typical LepR mutant mice [db/db], which have frank diabetes). Beta cell mass expanded threefold through increased beta cell proliferation, without evidence for contribution from specialised progenitors or stem cells (via sequential thymidine labelling and Brainbow2.1 reporter). Thus, self-renewal is the primary lineage mechanism in obesity-induced beta cell expansion. However, even the rapid beta cell proliferation could not exceed the restrictions of the replication refractory period.
  
  
  
  In summary, we created a novel model of inducible obesity demonstrating that even extreme metabolic demand does not alter beta cell lineage.
authors.affiliation: Section of Pediatric Diabetes and Endocrinology, McNair Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA.|Diabetes and Endocrinology, Feigin Center, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Cox
authors.affiliation: Section of Pediatric Diabetes and Endocrinology, McNair Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA.|Diabetes and Endocrinology, Feigin Center, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Lam
authors.affiliation: Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Rankin
authors.affiliation: Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Kourtney A
authors.initials: KA
authors.lastname: King
authors.affiliation: Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.affiliation: Section of Pediatric Diabetes and Endocrinology, McNair Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA.|Diabetes and Endocrinology, Feigin Center, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Ramon
authors.initials: R
authors.lastname: Martinez
authors.affiliation: Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Section of Pediatric Diabetes and Endocrinology, McNair Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA. kushner@bcm.edu.|Diabetes and Endocrinology, Feigin Center, Texas Children's Hospital, Houston, TX, USA. kushner@bcm.edu.|Diabetes and Endocrinology Service, Texas Children's Hospital, Houston, TX, USA. kushner@bcm.edu.
authors.forename: Jake A
authors.initials: JA
authors.lastname: Kushner
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000473:pathology*; D054411:Receptors, Leptin / Q000172:deficiency / Q000235:genetics
chemical_list: D054411:Receptors, Leptin; C515447:leptin receptor, mouse
keywords: Beta cell expansion; Cell fate; Lineage tracing; Obesity