Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function

Kuo, Taiyi; Du, Wen; Miyachi, Yukihisa; Dadi, Prasanna K.; Jacobson, David A.; Segrè, Daniel; Accili, Domenico

doi:10.1016/j.molmet.2021.101256

Cited by 5 publications

(5 citation statements)

References 49 publications

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“…We reckoned that this was compensatory in nature, and that in the absence of FoxO1, HNF4α compensates for some of its functions. But when we tested the hypothesis in vivo we found the opposite result [46]. Combined ablation of FoxO1 and HNF4α reversed the β-cell defects associated with single mutations of either gene, indicating that their interactions are antagonistic rather than compensatory.…”

Section: Genes Of Type 2 Diabetesmentioning

confidence: 87%

“…In our experiments with FoxO1 and HNF4α, gene expression analyses revealed that different gene families were regulated by these two transcription factors with different modalities. For example, the glycolysis pathway was regulated through antagonistic epistasis (i.e., the two factors had opposite effects), and the protocadherin gene family by synergistic epistasis (i.e., the two factors had additive effects) [46].…”

Section: Genes Of Type 2 Diabetesmentioning

confidence: 99%

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Reflections on the state of diabetes research and prospects for treatment

Accili

Kitamoto

et al. 2022

Diabetol Int

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Research on the etiology and treatment of diabetes has made substantial progress. As a result, several new classes of antidiabetic drugs have been introduced in clinical practice. Nonetheless, the number of patients achieving glycemic control targets has not increased for the past 20 years. Two areas of unmet medical need are the restoration of insulin sensitivity and the reversal of pancreatic beta cell failure. In this review, we integrate research advances in transcriptional regulation of insulin action and pathophysiology of beta cell dedifferentiation with their potential impact on prospects of a durable "cure" for patients suffering from type 2 diabetes.

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Section: Genes Of Type 2 Diabetesmentioning

confidence: 87%

Section: Genes Of Type 2 Diabetesmentioning

confidence: 99%

Reflections on the state of diabetes research and prospects for treatment

Accili

Kitamoto

et al. 2022

Diabetol Int

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“…In contrast to Akr1c19, we did not observe HNF1a-induced promoter activation of Akr1c12 and 13 in HEK293 cells ( S1 Fig ). In previous work, we have shown that the three FoxO genes (1, 3a, and 4) are required to maintain the MODY-related gene network [ 10 , 28 ]. Therefore, to investigate the involvement of FoxO1 in the regulation of Akr1c19 by HNF1a, we co-expressed HNF1a and a dominant negative FoxO1 D256, a truncated mutant lacking the transactivation domain [ 23 ], in HEK293 cells.…”

Section: Resultsmentioning

confidence: 99%

Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets

et al. 2021

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Beta cell failure is a critical feature of diabetes. It includes defects of insulin production, secretion, and altered numbers of hormone-producing cells. In previous work, we have shown that beta cell failure is mechanistically linked to loss of Foxo1 function. This loss of function likely results from increased Foxo1 protein degradation, due to hyperacetylation of Foxo1 from increased nutrient turnover. To understand the mechanisms of Foxo1-related beta cell failure, we performed genome-wide analyses of its target genes, and identified putative mediators of sub-phenotypes of cellular dysfunction. Chromatin immunoprecipitation analyses demonstrated a striking pattern of Foxo1 binding to the promoters of a cluster of aldo-ketoreductases on chromosome 13: Akr1c12, Akr1c13, Akr1c19. Of these, Akr1c19 has been reported as a marker of Pdx1-positive endodermal progenitor cells. Here we show that Akr1c19 expression is dramatically decreased in db/db islets. Thus, we investigated whether Akr1c19 is involved in beta cell function. We performed gain- and loss-of-function experiments in cultured beta cells and generated Akr1c19 knockout mice. We show that Foxo1 and HNF1a cooperatively regulate Akr1c19 expression. Nonetheless, functional characterization of Akr1c19 both using islets and knockout mice did not reveal abnormalities on glucose homeostasis. We conclude that reduced expression of Akr1c19 is not sufficient to affect islet function.

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“…Furthermore, loss of β-cell identity leads to increased glycolysis by disrupting key β-cell metabolic genes including Slc2a2 , Gck , Hk1 , Hk2 , and Ldha [ 42 , 71 ]. Recent evidence demonstrates that FoxO1 suppresses glycolytic genes and thereby protects β cells from excess glycolysis and dysfunction [ [72] , [73] , [74] ]. These studies further support the hypothesis that attenuation of hyperactive glycolysis prevents the impairment of β-cell function and identity.…”

Section: Discussionmentioning

confidence: 99%

Increased glycolysis affects β-cell function and identity in aging and diabetes

Murao

Yokoi

Takahashi

et al. 2022

Molecular Metabolism

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Objective Age is a risk factor for type 2 diabetes (T2D). We aimed to elucidate whether β-cell glucose metabolism is altered with aging and contributes to T2D. Methods We used senescence-accelerated mice (SAM), C57BL/6J (B6) mice, and ob / ob mice as aging models. As a diabetes model, we used db / db mice. The glucose responsiveness of insulin secretion and the [U- 13 C]-glucose metabolic flux were examined in isolated islets. We analyzed the expression of β-cell-specific genes in isolated islets and pancreatic sections as molecular signatures of β-cell identity. β cells defective in the malate-aspartate (MA) shuttle were previously generated from MIN6-K8 cells by the knockout of Got1 , a component of the shuttle. We analyzed Got1 KO β cells as a model of increased glycolysis. Results We identified hyperresponsiveness to glucose and compromised cellular identity as dysfunctional phenotypes shared in common between aged and diabetic mouse β cells. We also observed a metabolic commonality between aged and diabetic β cells: hyperactive glycolysis through the increased expression of nicotinamide mononucleotide adenylyl transferase 2 ( Nmnat2 ), a cytosolic nicotinamide adenine dinucleotide (NAD)-synthesizing enzyme. Got1 KO β cells showed increased glycolysis, β-cell dysfunction, and impaired cellular identity, phenocopying aging and diabetes. Using Got1 KO β cells, we show that attenuation of glycolysis or Nmnat2 activity can restore β-cell function and identity. Conclusions Our study demonstrates that hyperactive glycolysis is a metabolic signature of aged and diabetic β cells, which may underlie age-related β-cell dysfunction and loss of cellular identity. We suggest Nmnat2 suppression as an approach to counteract age-related T2D.

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Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function

Cited by 5 publications

References 49 publications

Reflections on the state of diabetes research and prospects for treatment

Reflections on the state of diabetes research and prospects for treatment

Aldo-ketoreductase 1c19 ablation does not affect insulin secretion in murine islets

Increased glycolysis affects β-cell function and identity in aging and diabetes

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