FOXO1 inhibition synergizes with FGF21 to normalize glucose control in diabetic mice

Lee, Yunkyoung; Diaz, Bryan; Deroose, Marianne; Lee, Samuel X.; Belvedere, Sandro; Accili, Domenico; Leibel, Rudolph L.; Lin, Hua

doi:10.1016/j.molmet.2021.101187

Cited by 17 publications

(27 citation statements)

References 20 publications

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“…Next, we examined the effect of FBT432 on endogenous FOXO1 function using mouse primary hepatocytes as previously described (11). Five-point dose-response treatment of primary hepatocytes with FBT432 showed an inhibition of cyclic AMP (cAMP) and dexamethasone (Dex)-induced G6pc expression at concentrations above 1 μM, with an estimated IC 50 of 5.28 μM (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…All procedures were approved by the CUNY-Advanced Science Research Center (ASRC) Institutional Animal Care and Use Committee (IACUC). Hepatocytes were isolated from 8- to 10-week-old male C57/BL6 mice as described (11). The isolated hepatocytes were seeded at 150,000 cells/well in M199 medium (Gibco) containing 10% FBS, 1x penicillin-streptomycin, and 50 mg/ml of G418 (Gibco) onto collagen-coated 24 well plates.…”

Section: Methodsmentioning

confidence: 99%

“…Reporter gene assays were performed as previously (11). Briefly, HEK293 cells were seeded at 7,500 cells/well in EMEM supplemented with 1% fetal bovine serum (FBS) and 1x penicillinstreptomycin (Gibco) onto 384-well plates.…”

Section: Reporter Gene Assaysmentioning

confidence: 99%

“…FBT432 is orally bioavailable in mouse, with good tissue distribution, including liver and intestine (Supplementary Table 2). To evaluate its in vivo efficacy, we used pyruvate tolerance tests (PTT) as a pharmacodynamic (PD) measure of the compound's ability to suppress hepatic glucose production, an acute consequence of FOXO1 inhibition (11). Normoglycemic mice received three oral doses at 15 and 50 mg/kg on a b.i.d.…”

Section: Fbt432 Activity In Cell-based Assays and In Vivo Efficacymentioning

confidence: 99%

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Single-agent Foxo1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice

Lee¹,

Nie²,

Diaz

et al. 2022

Preprint

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Insulin treatment remains the sole effective intervention for Type 1 Diabetes. Here, we investigated the therapeutic potential of converting intestinal epithelial cells to insulin-producing, glucose-responsive β-like cells by targeted inhibition of Foxo1. We have shown that this can be achieved by genetic ablation in gut Neurogenin3 progenitors, adenoviral or shRNA-mediated inhibition in human gut organoids, and chemical inhibition in Akita mice, a model of insulin-deficient diabetes. In the present study, we provide evidence that two novel Foxo1 inhibitors, FBT432 and FBT374 have glucose-lowering and gut β-like cell-inducing properties in mice rendered insulin-deficient by administration of streptozotocin. FBT432 is also highly effective in combination with a Notch inhibitor in this model. The data add to a growing body of evidence suggesting that Foxo1 inhibition be pursued as an alternative treatment to insulin administration in diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Reporter Gene Assaysmentioning

confidence: 99%

Section: Fbt432 Activity In Cell-based Assays and In Vivo Efficacymentioning

confidence: 99%

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Single-agent Foxo1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice

Lee¹,

Nie²,

Diaz

et al. 2022

Preprint

Self Cite

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“…In sorted 5HT-positive cells from hGOs, insulin mRNA was induced ~ six-fold by incubation in EEC medium, and 30-fold by addition of another FoxO1 inhibitor, FBT10 (Fig. 3G) (Langlet et al, 2017; Lee et al, 2021). These data are consistent with the hypothesis that FOXO1 inhibition facilitates conversion of 5HT cells into β-like cells.…”

Section: Resultsmentioning

confidence: 99%

Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals

Wang

Kuo

et al. 2022

Preprint

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Insulin is the essential treatment of Type 1 (T1D) and is often used in Type 2 Diabetes. For nearly five decades, efforts have been focused on replenishing β-cells in T1D patients as a more durable treatment. Gut endocrine cells can be converted into insulin-producing cells, but their numbers are limited. In this study we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine, in addition to enteroendocrine cells. Accordingly, lineage tracing experiments show that, besides enterochromaffin cells, the Paneth/goblet lineage can undergo conversion to the insulin lineage upon genetic or pharmacologic Foxo1 ablation in mice. We leveraged these data to design a screening platform in organoids to accurately quantitate β-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process by expanding the intestinal secretory lineage. We identified a triple blockade of FoxO1, Notch, and Tgfβ that, when tested in insulin-deficient diabetic animals resulted in a near-normalization of glucose levels, associated with the appearance of gut insulin-producing cells. The findings illustrate a therapeutic approach to replace insulin treatment in diabetes.

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FOXO1 promotes the expression of canonical WNT target genes in examined basal‐like breast and glioblastoma multiforme cancer cells

Pintor,

Lopez,

Flores

et al. 2023

FEBS Open Bio

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Basal‐like breast cancer (BBC) and glioblastoma multiforme (GBM) are aggressive cancers associated with poor prognosis. BBC and GBM have stem‐cell‐like gene expression signatures, which are in part driven by forkhead box O (FOXO) transcription factors. To gain further insight into the impact of FOXO1 in BBC, we treated BT549 cells with AS1842856 and performed RNA sequencing. AS1842856 binds to unphosphorylated FOXO1 and inhibits its ability to directly bind to DNA. Gene Set Enrichment Analysis (GSEA) indicated that a set of WNT pathway target genes, including lymphoid enhancer‐binding factor 1 (LEF1) and transcription factor 7 (TCF7), were robustly induced after AS1842856 treatment. These same genes were also induced in GBM cell lines U87MG, LN18, LN229, A172 and DBTRG upon AS1842856 treatment. In contrast, follow‐up RNA interference (RNAi) targeting of FOXO1 led to reduced LEF1 and TCF7 gene expression in BT549 and U87MG cells. In agreement with RNAi experiments, CRISPR Cas9‐mediated FOXO1 disruption reduced the expression of canonical WNT genes LEF1 and TCF7 in U87MG cells. The loss of TCF7 gene expression in FOXO1 disruption mutants was restored by exogenous expression of the DNA‐binding‐deficient FOXO1‐H215R. Therefore, FOXO1 induces TCF7 in a DNA‐binding‐independent manner, similar to other published FOXO1‐activated genes such as TCF4 and hes family bHLH transcription factor 1 (HES1). Our work demonstrates that FOXO1 promotes canonical WNT gene expression in examined BBC and GBM cells, similar to results found in Drosophila melanogaster, T‐cell development and murine acute myeloid leukemia (AML) models.

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FOXO1 inhibition synergizes with FGF21 to normalize glucose control in diabetic mice

Cited by 17 publications

References 20 publications

Single-agent Foxo1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice

Single-agent Foxo1 inhibition normalizes glycemia and induces gut β-like cells in streptozotocin-diabetic mice

Triple Notch/Tgfβ/FoxO1 blockade converts multiple intestinal sub-lineages into β-like cells and lowers glycemia in diabetic animals

FOXO1 promotes the expression of canonical WNT target genes in examined basal‐like breast and glioblastoma multiforme cancer cells

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