title: Downregulation of Sfrp5 promotes beta cell proliferation during obesity in the rat.
abstract: OBJECTIVE
  During obesity, the increment in beta cell mass in response to the rising demand for insulin is essential to maintain normal glucose homeostasis. However, the precise cellular and molecular mechanisms involved in beta cell mass plasticity remain poorly understood. The Wnt signalling pathway has been suggested as one possible modulator of beta cell proliferation, which represents the principal process involved in beta cell mass expansion. Here, we sought to determine the mechanisms involved in beta cell mass proliferation using diet-induced obese rats.
  
  
  METHODS
  Wistar rats aged 8 weeks old were fed a standard or cafeteria diet. Global transcriptomic analysis of pancreatic rat islets was performed using microarray analysis. Genetic loss-of-function approaches were performed in dispersed primary rat islets and the beta cell line INS1E. Gene expression was measured by real-time PCR, protein levels by immunoblot analysis, proliferation rates by ELISA and apoptosis by flow cytometry.
  
  
  RESULTS
  Sfrp5, coding for secreted frizzled-related protein 5, is downregulated in the pancreatic islets of cafeteria-diet-fed rats as well as in the pancreatic islets of human obese patients. We demonstrate that silencing Sfrp5 increases beta cell proliferation, which correlates with activation of Wnt signalling and enhanced levels of proliferation markers. In addition, we show that expression of Sfrp5 in beta cells is modulated by IGF binding protein 3 (IGFBP3) secreted from visceral adipose tissue.
  
  
  CONCLUSIONS
  Together, these findings reveal an important role for SFRP5 and Wnt signalling in the regulation of beta cell proliferation in obesity.
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), c/Rosselló, 149-153, 08036, Barcelona, Spain.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Rebuffat
authors.forename: Joana M
authors.initials: JM
authors.lastname: Oliveira
authors.forename: Jordi
authors.initials: J
authors.lastname: Altirriba
authors.forename: Nuria
authors.initials: N
authors.lastname: Palau
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Garcia
authors.forename: Yaiza
authors.initials: Y
authors.lastname: Esteban
authors.forename: Belen
authors.initials: B
authors.lastname: Nadal
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D008565:Membrane Proteins