Dataset Information

Activation of Nrf2 Is Required for Normal and ChREBP?-Augmented Glucose-Stimulated ?-Cell Proliferation.

ABSTRACT: Patients with both major forms of diabetes would benefit from therapies that increase ?-cell mass. Glucose, a natural mitogen, drives adaptive expansion of ?-cell mass by promoting ?-cell proliferation. We previously demonstrated that a carbohydrate response element-binding protein (ChREBP?) is required for glucose-stimulated ?-cell proliferation and that overexpression of ChREBP? amplifies the proliferative effect of glucose. Here we found that ChREBP? reprogrammed anabolic metabolism to promote proliferation. ChREBP? increased mitochondrial biogenesis, oxygen consumption rates, and ATP production. Proliferation augmentation by ChREBP? required the presence of ChREBP?. ChREBP? increased the expression and activity of Nrf2, initiating antioxidant and mitochondrial biogenic programs. The induction of Nrf2 was required for ChREBP?-mediated mitochondrial biogenesis and for glucose-stimulated and ChREBP?-augmented ?-cell proliferation. Overexpression of Nrf2 was sufficient to drive human ?-cell proliferation in vitro; this confirms the importance of this pathway. Our results reveal a novel pathway necessary for ?-cell proliferation that may be exploited for therapeutic ?-cell regeneration.

SUBMITTER: Kumar A

PROVIDER: S-EPMC6054434 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Activation of Nrf2 Is Required for Normal and ChREBPα-Augmented Glucose-Stimulated β-Cell Proliferation.

Kumar Anil A Katz Liora S LS Schulz Anna M AM Kim Misung M Honig Lee B LB Li Lucy L Davenport Bennett B Homann Dirk D Garcia-Ocaña Adolfo A Herman Mark A MA Haynes Cole M CM Chipuk Jerry E JE Scott Donald K DK

Diabetes 20180515 8

Patients with both major forms of diabetes would benefit from therapies that increase β-cell mass. Glucose, a natural mitogen, drives adaptive expansion of β-cell mass by promoting β-cell proliferation. We previously demonstrated that a carbohydrate response element-binding protein (ChREBPα) is required for glucose-stimulated β-cell proliferation and that overexpression of ChREBPα amplifies the proliferative effect of glucose. Here we found that ChREBPα reprogrammed anabolic metabolism to promot ...[more]

PMID: 29764859

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Project description:ObjectiveDefective glucose uptake in adipocytes leads to impaired metabolic homeostasis and insulin resistance, hallmarks of type 2 diabetes. Extracellular ATP-derived nucleotides and nucleosides are important regulators of adipocyte function, but the pathway for controlled ATP release from adipocytes is unknown. Here, we investigated whether Pannexin 1 (Panx1) channels control ATP release from adipocytes and contribute to metabolic homeostasis.MethodsWe assessed Panx1 functionality in cultured 3T3-L1 adipocytes and in adipocytes isolated from murine white adipose tissue by measuring ATP release in response to known activators of Panx1 channels. Glucose uptake in cultured 3T3-L1 adipocytes was measured in the presence of Panx1 pharmacologic inhibitors and in adipocytes isolated from white adipose tissue from wildtype (WT) or adipocyte-specific Panx1 knockout (AdipPanx1 KO) mice generated in our laboratory. We performed in vivo glucose uptake studies in chow fed WT and AdipPanx1 KO mice and assessed insulin resistance in WT and AdipPanx1 KO mice fed a high fat diet for 12 weeks. Panx1 channel function was assessed in response to insulin by performing electrophysiologic recordings in a heterologous expression system. Finally, we measured Panx1 mRNA in human visceral adipose tissue samples by qRT-PCR and compared expression levels with glucose levels and HOMA-IR measurements in patients.ResultsOur data show that adipocytes express functional Pannexin 1 (Panx1) channels that can be activated to release ATP. Pharmacologic inhibition or selective genetic deletion of Panx1 from adipocytes decreased insulin-induced glucose uptake in vitro and in vivo and exacerbated diet-induced insulin resistance in mice. Further, we identify insulin as a novel activator of Panx1 channels. In obese humans Panx1 expression in adipose tissue is increased and correlates with the degree of insulin resistance.ConclusionsWe show that Panx1 channel activity regulates insulin-stimulated glucose uptake in adipocytes and thus contributes to control of metabolic homeostasis.

Dataset Information

Activation of Nrf2 Is Required for Normal and ChREBP?-Augmented Glucose-Stimulated ?-Cell Proliferation.

Publications

Activation of Nrf2 Is Required for Normal and ChREBPα-Augmented Glucose-Stimulated β-Cell Proliferation.

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