Forkhead Box Protein 1 (FoxO1) Inhibits Accelerated β Cell Aging in Pancreas-specific SMAD7 Mutant Mice

Abstract

Edited by Jeffrey E. PessinThe mechanisms underlying the effects of exocrine dysfunction on the development of diabetes remain largely unknown. Here we show that pancreatic depletion of SMAD7 resulted in age-dependent increases in ␤ cell dysfunction with accelerated glucose intolerance, followed by overt diabetes. The accelerated ␤ cell dysfunction and loss of proliferation capacity, two features of ␤ cell aging, appeared to be non-cell-autonomous, secondary to the adjacent exocrine failure as a "bystander effect." Increased Forkhead box protein 1 (FoxO1) acetylation and nuclear retention was followed by progressive FoxO1 loss in ␤ cells that marked the onset of diabetes. Moreover, forced FoxO1 expression in ␤ cells prevented ␤ cell dysfunction and loss in this model. Thus, we present a model of accelerated ␤ cell aging that may be useful for studying the mechanisms underlying ␤ cell failure in diabetes. Moreover, we provide evidence highlighting a critical role of FoxO1 in maintaining ␤ cell identity in the context of SMAD7 failure.␤ Cell dysfunction and failure are hallmarks of type 2 diabetes (1-4). Oxidative stress, endoplasmic reticulum stress, hypoxic stress, and cytokine toxicity can all lead to ␤ cell apoptosis, autophagy, and replication defects, resulting in global ␤ cell failure (3, 4). Thus, ␤ cell replacement may be an ideal strategy for treating diabetes (5). Although ␤ cell neogenesis from non-␤ cell sources has been extensively studied, most evidence suggests that postnatal ␤ cell expansion predominantly results from ␤ cell replication (6 -11). However, normally, the ␤ cell replication ratio is fairly low in young adult mice and then gets progressively lower with increasing age (4, 12-16). Meanwhile, recent studies strongly suggest that protection of the differentiated phenotype of existing ␤ cells is critical for the maintenance of a functional ␤ cell mass and for the prevention of type 2 diabetes (2,(17)(18)(19), in which the transcription factor Forkhead box protein 1 (FoxO1) 3 appears to play a key protective role against ␤ cell senescence and failure.TGF␤ superfamily signaling pathways are essential for pancreas development (20), postnatal ␤ cell homeostasis, and proper function (21-23). Binding of TGF␤ superfamily ligands to a type II receptor catalyzes the phosphorylation of a type I receptor to trigger downstream signaling cascades. SMAD7 is a general inhibitor of all TGF␤ superfamily pathways, and we have shown recently that SMAD7 plays a critical role during pancreas development and ␤ cell replication (20,(22)(23)(24). Here we studied ␤ cell function in a model of pancreatic SMAD7 depletion (SMAD7 Ptf1a ). ResultsPancreas-specific (SMAD7 Ptf1a ) SMAD7 Knockout Mice-To characterize the role of SMAD7 in ␤ cell development and postnatal ␤ cell mass homeostasis, we deleted pancreatic SMAD7 by crossing SMAD7fx/fx mice with Ptf1a-Cre mice to generate Ptf1a-Cre; SMAD7fx/fx mice, simplified as SMAD7 Ptf1a (supplemental Fig. 1, A and B). In Ptf1a-Cre mice, in which SMAD7 was deleted in the major...

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“…Moreover, members of the FoxO subfamily shuttle from the cytoplasm to the nucleus and play an important role in cell proliferation, apoptosis, differentiation and oxidative stress resistance [35,36]. As the expression level and activity of FoxO1 are significantly increased in the liver tissues of patients with severe fatty liver disease and type 2 diabetes mellitus, FoxO1 has an important role in the occurrence and progression of human metabolic syndrome [37][38][39][40]. Moreover, FoxO1 is located at the intersection of many signal transduction pathways and may become a target for the treatment or intervention of many diseases [36,41,42].…”

SMAD3/Stat3 Signaling Mediates β-Cell Epithelial-Mesenchymal Transition in Chronic Pancreatitis–Related Diabetes

“…In line with this concept, the β-cell–specific transcription factors Pdx1, NeuroD1, Nkx6.1, and MafA seem to be required for β-cells to be fully functional, whereas their loss correlates with β-cell dysfunction and β-cell loss (23–25). As such, we performed PDL on MIP-GFP mice, and sorted β-cells via FACS at serial time points after PDL to asses Pdx1, NeuroD1, Nkx6.1, and MafA mRNA levels in β-cells by quantitative RT-PCR and Western blotting.…”

“…FoxO1 is a transcription factor that plays a key protective role against β-cell failure during stress (23–25). Previous reports have shown that FoxO1 and Stat3 antagonize each other in the regulation of T-cell function (34,35) and leptin signaling transduction (36,37).…”

“…FoxO1 is predominantly expressed by β-cells in the adult pancreas. We and others have shown that FoxO1 nuclear translocation increases NeuroD1, MafA, and Nkx6.1 expression in β-cells, contributing to the maintenance of a functional differentiated phenotype to resist stress-induced dedifferentiation, dysfunction, and failure (23–25). Nevertheless, a role for FoxO1 during the pathogenesis of CPRD is unknown.…”

“…AAV serotype 8 vectors were used to generate AAV-RIP-null and AAV-RIP-FoxO1 viruses, as described before (25). …”