Early peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass.

TitleEarly peroxisome proliferator-activated receptor gamma regulated genes involved in expansion of pancreatic beta cell mass.
Publication TypeJournal Article
Year of Publication2011
AuthorsVivas, Y, Martinez-Garcia, C, Izquierdo, A, Garcia-Garcia, F, Callejas, S, Velasco, I, Campbell, M, Ros, M, Dopazo, A, Dopazo, J, Vidal-Puig, A, Medina-Gomez, G
JournalBMC Med Genomics
Date Published2011 Dec 30
KeywordsAnimals; Cell Proliferation; Cell Survival; Cholesterol; Down-Regulation; Female; Gene Expression Regulation; Gene Knockout Techniques; Insulin Resistance; Insulin-Secreting Cells; Mice; obesity; Oxidation-Reduction; Phosphorylation; PPAR gamma; Signal Transduction; Transcription, Genetic; Transforming Growth Factor beta

BACKGROUND: The progression towards type 2 diabetes depends on the allostatic response of pancreatic beta cells to synthesise and secrete enough insulin to compensate for insulin resistance. The endocrine pancreas is a plastic tissue able to expand or regress in response to the requirements imposed by physiological and pathophysiological states associated to insulin resistance such as pregnancy, obesity or ageing, but the mechanisms mediating beta cell mass expansion in these scenarios are not well defined. We have recently shown that ob/ob mice with genetic ablation of PPARγ2, a mouse model known as the POKO mouse failed to expand its beta cell mass. This phenotype contrasted with the appropriate expansion of the beta cell mass observed in their obese littermate ob/ob mice. Thus, comparison of these models islets particularly at early ages could provide some new insights on early PPARγ dependent transcriptional responses involved in the process of beta cell mass expansionRESULTS: Here we have investigated PPARγ dependent transcriptional responses occurring during the early stages of beta cell adaptation to insulin resistance in wild type, ob/ob, PPARγ2 KO and POKO mice. We have identified genes known to regulate both the rate of proliferation and the survival signals of beta cells. Moreover we have also identified new pathways induced in ob/ob islets that remained unchanged in POKO islets, suggesting an important role for PPARγ in maintenance/activation of mechanisms essential for the continued function of the beta cell.CONCLUSIONS: Our data suggest that the expansion of beta cell mass observed in ob/ob islets is associated with the activation of an immune response that fails to occur in POKO islets. We have also indentified other PPARγ dependent differentially regulated pathways including cholesterol biosynthesis, apoptosis through TGF-β signaling and decreased oxidative phosphorylation.

Alternate JournalBMC Med Genomics
PubMed ID22208362
PubMed Central IDPMC3315430
Grant ListG0802051 / / Medical Research Council / United Kingdom
BFU2008-04901-C03-03 / MR / Medical Research Council / United Kingdom
BFU2009-10006 / MR / Medical Research Council / United Kingdom