Loss of <i>Furin</i> in β-Cells Induces an mTORC1-ATF4 Anabolic Pathway That Leads to β-Cell Dysfunction

Brouwers, Bas; Coppola, Ilaria; Vints, Katlijn; Dislich, Bastian; Jouvet, Nathalie; Lommel, Leentje Van; Segers, Charlotte; Gounko, Natalia V.; Thorrez, Lieven; Schuit, Frans; Lichtenthaler, Stefan F.; Estall, Jennifer L.; Declercq, Jeroen; Ramos‐Molina, Bruno; Creemers, John W.M.

doi:10.2337/db20-0474

Cited by 25 publications

(36 citation statements)

References 43 publications

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“…In addition, fasting blood glucose levels and body weight were unaltered in βIRKO mice (Figure S1E,F). Moreover, a previous study reported that Insr deficiency in mouse islets and β cell lines led to an induction of ATF4-dependent genes (i.e., Trib3) [25], similar to our previous results using the βFurKO [22]. However, we observed a non-significant reduction in the gene expression levels of Trib3, Chop, and Atf4 in isolated islets from the βIRKO mice (Figure 5I).…”

Section: Ir Deficiency In Pancreatic β Cells Does Not Induce Severe Glucose Intolerancesupporting

confidence: 91%

“…As expected, we observed that LFurKO mice remained glucose tolerant both on chow and a HFD (Figure 3C-F) with normal insulin sensitivity on HFD (Figure S1B). In contrast, βFurKO mice were severely glucose intolerant, with significantly higher fasting blood glucose levels on HFD (Figure 3G-H and Figure S1B), even on a chow diet, as we described in a previous study [22]. We also did not observe changes in fasting blood glucose and body weight in LFurKO mice compared to controls (Figure S1C,D).…”

Section: Impact Of Conditional Furin Deletion In Liver and Pancreatic β Cells On Glucose Homeostasissupporting

confidence: 73%

“…Finally, we previously found that FURIN deficiency in pancreatic β cells leads to severe glucose intolerance caused by altered lysosomal acidification and aberrant activation of the mTORC1/ATF4 pathway [22]. Crosstalk between IR signaling and the mTORC1 pathway has been reported in several studies [37,38].…”

Section: Discussionmentioning

confidence: 90%

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Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

Coppola

Brouwers

Meulemans

et al. 2021

IJMS

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The insulin receptor (IR) is critically involved in maintaining glucose homeostasis. It undergoes proteolytic cleavage by proprotein convertases, which is an essential step for its activation. The importance of the insulin receptor in liver is well established, but its role in pancreatic β cells is still controversial. In this study, we investigated the cleavage of the IR by the proprotein convertase FURIN in β cells and hepatocytes, and the contribution of the IR in pancreatic β cells and liver to glucose homeostasis. β-cell-specific Furin knockout (βFurKO) mice were glucose intolerant, but liver-specific Furin knockout (LFurKO) mice were normoglycemic. Processing of the IR was blocked in βFurKO cells, but unaffected in LFurKO mice. Most strikingly, glucose homeostasis in β-cell-specific IR knockout (βIRKO) mice was normal in younger mice (up to 20 weeks), and only mildly affected in older mice (24 weeks). In conclusion, FURIN cleaves the IR non-redundantly in β cells, but redundantly in liver. Furthermore, we demonstrated that the IR in β cells plays a limited role in glucose homeostasis.

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Section: Ir Deficiency In Pancreatic β Cells Does Not Induce Severe Glucose Intolerancesupporting

confidence: 91%

Section: Impact Of Conditional Furin Deletion In Liver and Pancreatic β Cells On Glucose Homeostasissupporting

confidence: 73%

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Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

Coppola

Brouwers

Meulemans

et al. 2021

IJMS

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“…While the mTORC1-ATF4 axis has recently been found to be activated in the pancreatic islets of mice with  cell-specific genetic ablation of the secretory peptidase Furin [60], our findings place ATF4 as a downstream target of mTORC1 in a non-proliferative metabolic tissue activated in response to hormonal cues. Dynamic functional regulation of hepatic mTOR signaling with fasting and feeding was reported in neonatal pigs two decades ago, with protein synthesis as the primary metabolic output [8].…”

Section: Discussionmentioning

confidence: 43%

Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin

Byles

Cormerais

Kalafut

et al. 2021

Preprint

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Objective: The mechanistic target of rapamycin complex 1 (mTORC1) is dynamically regulated by fasting and feeding cycles in the liver to promote protein and lipid synthesis while suppressing autophagy. However, beyond these functions, the metabolic response of the liver to feeding and insulin signaling orchestrated by mTORC1 remains poorly defined. Here, we determine whether ATF4, a stress responsive transcription factor recently found to be independently regulated by mTORC1 signaling in proliferating cells, is responsive to hepatic mTORC1 signaling to alter hepatocyte metabolism. Methods: ATF4 protein levels and expression of canonical gene targets were analyzed in the liver following fasting and physiological feeding in the presence or absence of the mTORC1 inhibitor rapamycin. Primary hepatocytes from wild-type or liver-specific Atf4 knockout (LAtf4KO) mice were used to characterize the effects of insulin-stimulated mTORC1-ATF4 function on hepatocyte gene expression and metabolism. Both unbiased steady-state metabolomics and stable-isotope tracing methods were employed to define mTORC1 and ATF4-dependent metabolic changes. RNA-sequencing was used to determine global changes in feeding-induced transcripts in the livers of wild-type versus LAtf4KO mice. Results: We demonstrate that ATF4 and its metabolic gene targets are stimulated by mTORC1 signaling in the liver in response to feeding and in a hepatocyte-intrinsic manner by insulin. While we demonstrate that de novo purine and pyrimidine synthesis is stimulated by insulin through mTORC1 signaling in primary hepatocytes, this regulation was independent of ATF4. Metabolomics and metabolite tracing studies revealed that insulin-mTORC1-ATF4 signaling stimulates pathways of non-essential amino acid synthesis in primary hepatocytes, including those of alanine, aspartate, methionine, and cysteine, but not serine. Conclusion: The results demonstrate that ATF4 is a novel metabolic effector of mTORC1 in liver, extending the molecular consequences of feeding and insulin-induced mTORC1 signaling in this key metabolic tissue to the control of amino acid metabolism.

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“…30 Testing has also demonstrated that furin mRNA and protein are expressed by human pancreatic islets. 37 Interestingly, combined analysis of islet microarray and RNA sequencing suggested that while ACE2 expression in β cells is lower than that of TMPRSS in islets from nondiabetic donors, ACE2 was upregulated in islets from donors with T2D. 36 In human pluripotent stem cell-derived pancreatic endocrine cells, immunofluorescent staining for ACE2 protein was detected in both in insulin-and glucagon-positive cells.…”

Section: The Case For the Presence Of Machinery Required For Sars-cov-2 Infection Of Human β Cellsmentioning

confidence: 99%

Not so sweet and simple: impacts of SARS-CoV-2 on the β cell

Ibrahim

Monaco

Sims

2021

Islets

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The link between COVID-19 infection and diabetes has been explored in several studies since the start of the pandemic, with associations between comorbid diabetes and poorer prognosis in patients infected with the virus and reports of diabetic ketoacidosis occurring with COVID-19 infection. As such, significant interest has been generated surrounding mechanisms by which the virus may exert effects on the pancreatic β cells. In this review, we consider possible routes by which SARS-CoV-2 may impact β cells. Specifically, we outline data that either support or argue against the idea of direct infection and injury of β cells by SARS-CoV-2. We also discuss β cell damage due to a "bystander" effect in which infection with the virus leads to damage to surrounding tissues that are essential for β cell survival and function, such as the pancreatic microvasculature and exocrine tissue. Studies elucidating the provocation of a cytokine storm following COVID-19 infection and potential impacts of systemic inflammation and increases in insulin resistance on β cells are also reviewed. Finally, we summarize the existing clinical data surrounding diabetes incidence since the start of the COVID-19 pandemic.

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Loss of Furin in β-Cells Induces an mTORC1-ATF4 Anabolic Pathway That Leads to β-Cell Dysfunction

Cited by 25 publications

References 43 publications

Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin

Not so sweet and simple: impacts of SARS-CoV-2 on the β cell

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