Deletion of the Akt/mTORC1 Repressor REDD1 Prevents Visual Dysfunction in a Rodent Model of Type 1 Diabetes

Miller, William P.; Chen, Yang; Mihăilescu, M; Moore, Joshua; Dai, Weiwei; Barber, Alistair J.; Dennis, Michael D.

doi:10.2337/db17-0728

Cited by 42 publications

(54 citation statements)

References 38 publications

(62 reference statements)

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“…Also, the hyperactive basal FOXO1/3A phosphorylation in REDD1 KO skeletal muscle reported herein were consistent with the findings of the Dennis Laboratory (Miller et al. ), showing that FOXO1 phosphorylation is elevated in REDD1 CRISPR R28 knockout retinal cells versus WT retinal cells. Given the lack of change in FOXO phosphorylation following insulin treatment in the REDD1 KO when compared to the WT group, it may suggest that there is limited capacity to further enhance FOXO activation.…”

Section: Discussionsupporting

confidence: 91%

Acute treadmill exercise discriminately improves the skeletal muscle insulin-stimulated growth signaling responses in mice lacking REDD1

2019

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A loss of the re gulated in d evelopment and D NA damage 1 ( REDD 1) hyperactivates mechanistic Target of Rapamycin Complex 1 ( mTORC 1) reducing insulin‐stimulated insulin signaling, which could provide insight into mechanisms of insulin resistance. Although aerobic exercise acutely inhibits mTORC 1 signaling, improvements in insulin‐stimulated signaling are exhibited. The goal of this study was to determine if a single bout of treadmill exercise was sufficient to improve insulin signaling in mice lacking REDD 1. REDD 1 wildtype ( WT ) and REDD 1 knockout ( KO ) mice were acutely exercised on a treadmill (30 min, 20 m/min, 5% grade). A within animal noninsulin‐to‐insulin‐stimulated percent change in skeletal muscle insulin‐stimulated kinases ( IRS ‐1, ERK 1/2, Akt), growth signaling activation (4E‐ BP 1, S6K1), and markers of growth repression ( REDD 1, AMPK , FOXO 1/3A) was examined, following no exercise control or an acute bout of exercise. Unlike REDD 1 KO mice, REDD 1 WT mice exhibited an increase ( P < 0.05) in REDD 1 following treadmill exercise. However, both REDD 1 WT and KO mice exhibited an increase ( P < 0.05) A MPK phosphorylation, and a subsequent reduction ( P < 0.05) in mTORC 1 signaling after the exercise bout versus nonexercising WT or KO mice. Exercise increased ( P < 0.05) the noninsulin‐to‐insulin‐stimulated percent change phosphorylation of mTORC 1, ERK 1/2, IRS ‐1, and Akt on S473 in REDD 1 KO mice when compared to nonexercised KO mice. However, there was no change in the noninsulin‐to‐insulin‐stimulated percent change activation of Akt on T308 and FOXO 1/3A in the KO when compared to WT or KO mouse muscle after exercise. Our data show that a bout of treadmill exercise discriminately improves insulin‐stimulated signaling in the absence of REDD1.

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Section: Discussionsupporting

confidence: 91%

Acute treadmill exercise discriminately improves the skeletal muscle insulin-stimulated growth signaling responses in mice lacking REDD1

2019

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“…Our laboratory has previously demonstrated a role for REDD1 in PP2A-dependent dephosphorylation of Akt (18), and other studies support increased REDD1 expression in the muscle of rodents fed a diet high in saturated fats (19,20). Moreover, we recently demonstrated a critical role for hyperglycemia-induced REDD1 in streptozotocin-induced retinal cell death and visual dysfunction (21). Indeed, REDD1 expression was elevated in the retina of mice fed a Western diet and in cells exposed to Cer.…”

supporting

confidence: 58%

Deletion of the stress‐response protein REDD1 promotes ceramide‐induced retinal cell death and JNK activation

et al. 2018

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The role of dyslipidemia in the development of retinal dysfunction remains poorly understood. Using an animal model of diet-induced obesity/pre-type 2 diabetes, we investigated molecular defects in the retina arising from consumption of a diet high in saturated fats and sugars ( i.e., a Western diet). We found that feeding mice a Western diet increased the abundance of retinal sphingolipids, attenuated protein kinase B (Akt) phosphorylation, enhanced JNK activation, and increased retinal cell death. When we used palmitate or C6-ceramide (Cer) to assess sphingolipid-mediated signaling in cultured murine and human cells, we observed similar effects on Akt, JNK, and cell death. Furthermore, both Western diet and C6-Cer exposure enhanced expression of the stress-response protein regulated in development and DNA damage response 1 (REDD1) and loss of REDD1 increased C6-Cer-induced JNK activation and cell death. Exogenous REDD1 expression repressed JNK-mediated phosphorylation in cultured cells. We found that thioredoxin-interacting protein (TXNIP) expression was elevated in REDD1-deficient cell lines and C6-Cer promoted TXNIP expression in both wild-type and REDD1-deficient cells. Likewise, TXNIP knockdown attenuated JNK activation and caspase 3 cleavage after either C6-Cer exposure or REDD1 deletion. The results support a model wherein Cer-induced REDD1 expression attenuates TXNIP-dependent JNK activation and retinal cell death.-Dai, W., Miller, W. P., Toro, A. L., Black, A. J., Dierschke, S. K., Feehan, R. P., Kimball, S. R., Dennis, M. D. Deletion of the stress-response protein REDD1 promotes ceramide-induced retinal cell death and JNK activation.

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“…In rodent models, visual behavior is more difficult to assess, but many investigators use the optokinetic reflex response, where animals only respond to stimuli that have sufficient contrast or size so that they can distinguish moving bars. Using these measures in rats and mice, contrast sensitivity and visual acuity have been shown to be reduced only 4 weeks after diabetes induction (Kirwin et al, 2011;Aung et al, 2013;Aung et al, 2014;Miller et al, 2018). Together, all of these studies suggest important functional changes in inner retinal activity and visual behavior early in diabetes.…”

Section: Changes In In Vivo Inner Retinal Activity Before the Developmentioning

confidence: 88%

The effects of early diabetes on inner retinal neurons

Eggers

Carreon

2020

Vis Neurosci

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Diabetic retinopathy is now well understood as a neurovascular disease. Significant deficits early in diabetes are found in the inner retina that consists of bipolar cells that receive inputs from rod and cone photoreceptors, ganglion cells that receive inputs from bipolar cells, and amacrine cells that modulate these connections. These functional deficits can be measured in vivo in diabetic humans and animal models using the electroretinogram (ERG) and behavioral visual testing. Early effects of diabetes on both the human and animal model ERGs are changes to the oscillatory potentials that suggest dysfunctional communication between amacrine cells and bipolar cells as well as ERG measures that suggest ganglion cell dysfunction. These are coupled with changes in contrast sensitivity that suggest inner retinal changes. Mechanistic in vitro neuronal studies have suggested that these inner retinal changes are due to decreased inhibition in the retina, potentially due to decreased gamma aminobutyric acid (GABA) release, increased glutamate release, and increased excitation of retinal ganglion cells. Inner retinal deficits in dopamine levels have also been observed that can be reversed to limit inner retinal damage. Inner retinal targets present a promising new avenue for therapies for early-stage diabetic eye disease.

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Deletion of the Akt/mTORC1 Repressor REDD1 Prevents Visual Dysfunction in a Rodent Model of Type 1 Diabetes

Cited by 42 publications

References 38 publications

Acute treadmill exercise discriminately improves the skeletal muscle insulin-stimulated growth signaling responses in mice lacking REDD1

Acute treadmill exercise discriminately improves the skeletal muscle insulin-stimulated growth signaling responses in mice lacking REDD1

Deletion of the stress‐response protein REDD1 promotes ceramide‐induced retinal cell death and JNK activation

The effects of early diabetes on inner retinal neurons

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