Author:

Keywords:

Activating Transcription Factor 4, Animals, Apoptosis, Cells, Cultured, Female, Insulin, Islets of Langerhans, Lactation, Models, Animal, Phosphorylation, Prolactin, Protein Kinases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Rats, Rats, Wistar, Signal Transduction, Transcription Factor CHOP, Unfolded Protein Response, Science & Technology, Life Sciences & Biomedicine, Physiology, endocrine pancreas, pregnancy, lactation, beta-cell apoptosis, unfolded protein response, ENDOPLASMIC-RETICULUM STRESS, UNFOLDED PROTEIN RESPONSE, PANCREATIC BETA-CELLS, ER STRESS, GLUCOSE-HOMEOSTASIS, INSULIN-SECRETION, CHEMICAL CHAPERONES, LACTOGENIC HORMONES, OXIDATIVE STRESS, GENE-EXPRESSION, Protein Serine-Threonine Kinases, 06 Biological Sciences, 11 Medical and Health Sciences, 31 Biological sciences, 32 Biomedical and clinical sciences, 42 Health sciences

Abstract:

Endocrine pancreas from pregnant rats undergoes several adaptations that comprise increase in β-cell number, mass and insulin secretion, and reduction of apoptosis. Lactogens are the main hormones that account for these changes. Maternal pancreas, however, returns to a nonpregnant state just after the delivery. The precise mechanism by which this reversal occurs is not settled but, in spite of high lactogen levels, a transient increase in apoptosis was already reported as early as the 3rd day of lactation (L3). Our results revealed that maternal islets displayed a transient increase in DNA fragmentation at L3, in parallel with decreased RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation (pAKT), a known prosurvival kinase. Wortmannin completely abolished the prosurvival action of prolactin (PRL) in cultured islets. Decreased pAKT in L3-islets correlated with increased Tribble 3 (TRB3) expression, a pseudokinase inhibitor of AKT. PERK and eIF2α phosphorylation transiently increased in islets from rats at the first day after delivery, followed by an increase in immunoglobulin heavy chain-binding protein (BiP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) in islets from L3 rats. Chromatin immunoprecipitation (ChIP) and Re-ChIP experiments further confirmed increased binding of the heterodimer ATF4/CHOP to the TRB3 promoter in L3 islets. Treatment with PBA, a chemical chaperone that inhibits UPR, restored pAKT levels and inhibited the increase in apoptosis found in L3. Moreover, PBA reduced CHOP and TRB3 levels in β-cell from L3 rats. Altogether, our study collects compelling evidence that UPR underlies the physiological and transient increase in β-cell apoptosis after delivery. The UPR is likely to counteract prosurvival actions of PRL by reducing pAKT through ATF4/CHOP-induced TRB3 expression.