Deletion of Apoptosis Signal-Regulating Kinase 1 (ASK1) Protects Pancreatic Beta-Cells from Stress-Induced Death but Not from Glucose Homeostasis Alterations under Pro-Inflammatory Conditions

Pepin, Émilie; Higa, Arisa; Schuster-Klein, Carole; Bernard, Catherine; Sulpice, Thierry; Guardiola, Béatrice; Chevet, Éric; Alquier, Thierry

doi:10.1371/journal.pone.0112714

Cited by 18 publications

(13 citation statements)

References 45 publications

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“…First, normal diet-fed mice were subjected to a glucose tolerance test (GTT) and an insulin tolerance test (ITT) after an overnight fast or 6 h of fasting, respectively. The results showed that there was no difference in glucose clearance or insulin sensitivity between the two genotypes (S3A-C Figs), which is consistent with a previous study, as evidenced by hyperglycemic clamp and hyperinsulinemic-euglycemic clamp analyses [58]. However, we found that glucose clearance was significantly aggravated in global ASK1KO mice after 10 weeks of HFD exposure (S3D-G Figs).…”

Section: Resultssupporting

confidence: 91%

“…Nonetheless, we observed a significant increase in fasting glucose levels in global ASK1KO mice (S3E and H Figs), but fasting glucose levels did not seem to be altered in hepatocyte-specific ASK1KO mice [65], suggesting that there are other ASK1-dependent regulatory mechanisms for glucose homeostasis. One possibility is a malfunction in insulin secretion, but this is unlikely given the previous results using the hyperglycemic clamp method [58]; however, impaired insulin secretion in fasted HFD-fed ASK1KO mice is possible.…”

Section: Discussionmentioning

confidence: 99%

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β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes

Hattori

Wakatsuki

Sakauchi

et al. 2020

Preprint

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21Boosting energy expenditure by harnessing the activity of brown adipocytes is a promising 22 strategy for combatting the global epidemic of obesity. Many studies have revealed that the β3-adrenergic 23 receptor agonist is a potent activator of brown adipocytes, even in humans, and PKA and p38 MAPK have 24 been demonstrated for regulating the transcription of a wide range of critical genes such as Ucp1. We 25 previously revealed that the PKA-ASK1-p38 axis is activated in immature brown adipocytes and 26 contributes to functional maturation. However, the downstream mechanisms of PKA that initiate the p38 27 MAPK cascade are still mostly unknown in mature brown adipocytes. Here, we identified the ASK family 28 as a crucial signaling molecule bridging PKA and MAPK in mature brown adipocytes. Mechanistically, the 29 phosphorylation of ASK1 at threonine 99 and serine 993 is critical in PKA-dependent ASK1 activation. 30Additionally, PKA also activates ASK2, which contributes to MAPK regulation. These lines of evidence 31 provide new details for tailoring a βAR-dependent brown adipocyte activation strategy. 32 and the approved dose exhibits only limited effects; hence, off-target effects of β3AR agonists and cross-57 activation of β1AR and β2AR should be considered. Clinically, constructing selective methods for activating 58 β3AR on brown and/or beige adipocytes is crucial, but it is of critical importance to understand the signaling 59 mechanisms induced by β3AR agonists in mature brown adipocytes to fully understand the potential side 60 effects of β3AR agonism. However, a limited number of studies have uncovered the involvement of several 61 kinases in β3AR signaling [16][17][18][19]; specifically, the downstream targets of PKA are not fully known. 62Among a wide variety of signaling pathways, the stress-responsive mitogen-activated protein 63 kinase (MAPK) pathway regulates multiple functions such as gene expression and cell death depending on 64 cell types [20,21]. Canonically, three-tiered cascades, MAPK kinase kinase (MAP3K)-MAPK kinase 65 (MAP2K)-MAPK, are the central components of the MAPK pathway, and a tremendous variety of 66 signaling is converged on two exclusive MAPKs, namely, p38s and JNKs [21]. The apoptosis signal- 67regulating kinase (ASK) family, which consists of ASK1, ASK2, and ASK3, is a member of MAP3K and 68 shares similar amino acid sequences throughout the kinase domain but functions differently in many cases 69 [22][23][24]. Additionally, ASKs can form heteromeric complexes and are mutually interactive in some cases 70 [25][26][27][28]. Although the key role of ASK1 is cell death regulation [29][30][31][32][33], we previously reported that ASK1 71 also functions as a differentiation regulator through gene induction in immature brown adipocytes and 72 contributes to functional maturation [9]. However, there have been no reports regarding the functions of 73 the ASK family in mature brown adipocytes. Importantly, cell signaling patterns are incredibly diverse and 74 depend on many parameters,...

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes

Hattori

Wakatsuki

Sakauchi

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…First, normal diet-fed mice were subjected to a glucose tolerance test (GTT) and an insulin tolerance test (ITT) after an overnight fast or 6 h of fasting, respectively. The results showed that there was no difference in glucose clearance or insulin sensitivity between the two genotypes ( S3A–S3C Fig ), which is consistent with a previous study, as evidenced by hyperglycemic clamp and hyperinsulinemic-euglycemic clamp analyses [ 57 ]. However, we found that glucose clearance was significantly aggravated in global ASK1KO mice after 10 weeks of HFD exposure ( S3D–S3G Fig ).…”

Section: Resultsmentioning

confidence: 99%

“…Nonetheless, we observed a significant increase in fasting glucose levels in global ASK1KO mice ( S3E and S3H Fig ), but fasting glucose levels did not seem to be altered in hepatocyte-specific ASK1KO mice [ 64 ], suggesting that there are other ASK1-dependent regulatory mechanisms for glucose homeostasis. One possibility is a malfunction in insulin secretion, but this is unlikely given the previous results using the hyperglycemic clamp method [ 57 ]; however, impaired insulin secretion in fasted HFD-fed ASK1KO mice is possible.…”

Section: Discussionmentioning

confidence: 99%

β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes

et al. 2020

View full text Add to dashboard Cite

Boosting energy expenditure by harnessing the activity of brown adipocytes is a promising strategy for combatting the global epidemic of obesity. Many studies have revealed that the β 3 -adrenergic receptor agonist is a potent activator of brown adipocytes, even in humans, and PKA and p38 MAPK have been demonstrated for regulating the transcription of a wide range of critical genes such as Ucp1 . We previously revealed that the PKA-ASK1-p38 axis is activated in immature brown adipocytes and contributes to functional maturation. However, the downstream mechanisms of PKA that initiate the p38 MAPK cascade are still mostly unknown in mature brown adipocytes. Here, we identified the ASK family as a crucial signaling molecule bridging PKA and MAPK in mature brown adipocytes. Mechanistically, the phosphorylation of ASK1 at threonine 99 and serine 993 is critical in PKA-dependent ASK1 activation. Additionally, PKA also activates ASK2, which contributes to MAPK regulation. These lines of evidence provide new details for tailoring a βAR-dependent brown adipocyte activation strategy.

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“…Insulin secretion was measured in static conditions at 37°C as previously described [ 19 ]. After a 30 min starvation in DMEM without glucose, insulin secretion was measured during 2 h in HEPES-balanced Krebs-Ringer bicarbonate buffer (125 mM NaCl; 5.9 mM KCl; 1.2 mM MgCl 2 ; 1.3 mM CaCl 2 ; 25 mM HEPES, pH 7.4) containing 0.1% BSA and different glucose concentrations (2.5 mM or 20 mM).…”

Section: Methodsmentioning

confidence: 99%

Nr2e1 Deficiency Augments Palmitate‐Induced Oxidative Stress in Beta Cells

Shi

Deng

Dai

et al. 2015

Oxidative Medicine and Cellular Longevity

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Nuclear receptor subfamily 2 group E member 1 (Nr2e1) has been regarded as an essential regulator of the growth of neural stem cells. However, its function elsewhere is unknown. In the present study, we generated Nr2e1 knockdown MIN6 cells and studied whether Nr2e1 knockdown affected basal beta cell functions such as proliferation, cell death, and insulin secretion. We showed that knockdown of Nr2e1 in MIN6 cells resulted in increased sensitivity to lipotoxicity, decreased proliferation, a partial G0/G1 cell-cycle arrest, and higher rates of apoptosis. Moreover, Nr2e1 deficiency exaggerates palmitate-induced impairment in insulin secretion. At the molecular level, Nr2e1 deficiency augments palmitate-induced oxidative stress. Nr2e1 deficiency also resulted in decreases in antioxidant enzymes and expression level of Nrf2. Together, this study indicated a potential protective effect of Nr2e1 on beta cells, which may serve as a target for the development of novel therapies for diabetes.

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Deletion of Apoptosis Signal-Regulating Kinase 1 (ASK1) Protects Pancreatic Beta-Cells from Stress-Induced Death but Not from Glucose Homeostasis Alterations under Pro-Inflammatory Conditions

Cited by 18 publications

References 45 publications

β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes

β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes

β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes

Nr2e1 Deficiency Augments Palmitate‐Induced Oxidative Stress in Beta Cells

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