Role of the forkhead protein FoxO1 in   cell compensation to insulin resistance

Abstract

Diabetes is associated with defective β cell function and altered β cell mass. The mechanisms regulating β cell mass and its adaptation to insulin resistance are unknown. It is unclear whether compensatory β cell hyperplasia is achieved via proliferation of existing β cells or neogenesis from progenitor cells embedded in duct epithelia. We have used transgenic mice expressing a mutant form of the forkhead-O1 transcription factor (FoxO1) in both pancreatic ductal and endocrine β cells to assess the contribution of these 2 compartments to islet expansion. We show that the mutant FoxO1 transgene prevents β cell replication in 2 models of β cell hyperplasia, 1 due to peripheral insulin resistance (Insulin receptor transgenic knockouts) and 1 due to ectopic local expression of IGF2 (Elastase-IGF2 transgenics), without affecting insulin secretion. In contrast, we failed to detect a specific effect of the FoxO1 transgene on the number of periductal β cells. We propose that β cell compensation to insulin resistance is a proliferative response of existing β cells to growth factor signaling and requires FoxO1 nuclear exclusion.

FoxO1 Deacetylation Decreases Fatty Acid Oxidation in β-Cells and Sustains Insulin Secretion in Diabetes

“…First, at the time of our prior experiments, our understanding of the function of FoxO1 in ␤-cells was not nearly as advanced as it is today, and most relevant parameters were simply not analyzed. Second, the phosphorylation-defective mutant analyzed in those studies has a strong effect on ␤-cell proliferation that likely masked some of the subtler effects on ␤-cell differentiation and metabolism (30). And finally, the deacetylated mutant used in the present studies is expressed as a knock-in, preserving both transcriptional and some of the post-translational regulation of FoxO1 function through phosphorylation (31).…”

Peroxisome Proliferator-activated Receptor γ (PPARγ) and Its Target Genes Are Downstream Effectors of FoxO1 Protein in Islet β-Cells

“…FoxO1-haplodeficient mice (17) and mice that overexpress a constitutively nuclear FoxO1 transgene (FoxO1 S253A ) in ␤-cells and liver (13,22) were obtained from D. Accili (Columbia University) on a mixed background and were backcrossed for Ͼ10 generations to the C57BL/6 background. Mice with PPAR␥ deficiency restricted to pancreatic epithelium (PANC PPAR␥ Ϫ/Ϫ ) were generated by crossing Pdx1-Cre mice (original source, D. Melton, Harvard University) and mice with two floxed PPAR␥ alleles as detailed previously (5).…”

“…FoxO1 is a member of the family of winged-helix/forkhead transcription factors that serve important roles in cellular differentiation, proliferation, apoptosis, and the response to cellular stress in many tissues. FoxO1 is highly expressed in ␤-cells and is a key regulator of ␤-cell development, mass, and function (13)(14)(15)(16). The best described FoxO1 target gene in ␤-cells is Pdx1 (17).…”

“…We next studied mice that hyperexpress a constitutively nuclear FoxO1 transgene in ␤-cells and liver; the transgene encodes an amino acid substitution at the Ser 253 phosphorylation site that prevents insulin-stimulated translocation of the mutant FoxO1 to the cytoplasm and is under control of the transthyretin promoter that directs expression to liver and ␤-cells (22). Others have shown that these mice on a mixed background have reductions in islet Pdx1 levels and early onset mild diabetes (13,22). We backcrossed the transgene to the C57BL/6 background and confirmed glucose intolerance in 8 -10-week-old mice, also noting a 25% reduction in ␤-cell mass compared with the littermate WT mice (Fig.…”

“…In summary, our results are consistent with a novel mechanism for ␤-cell compensation and failure based on an integral relationship between FoxO1 and PPAR␥, whereby FoxO1 exerts hierarchal control over several key ␤-cell genes, and PPAR␥ is a vital intermediate. FoxO1 is well poised to be a master transcriptional regulator over ␤-cell adaptive responses, as its expression and activity are influenced by numerous stimuli such as nutrient overload, growth factors, incretin hormones, and oxidative stress (13,14). Downstream from PPAR␥ is a network of genes that exert important regulatory control over prodifferentiation processes, incretin effects, glucose and mitochondrial fuel metabolism, and ␤-cell compensation to obesity and insulin resistance (13,27,32,33).…”