Nuclear factor-Y mediates pancreatic β-cell compensation by repressing reactive oxygen species-induced apoptosis under metabolic stress.
10.1097/CM9.0000000000002645
- Author:
Siyuan HE
1
;
Xiaoqian YU
2
;
Daxin CUI
1
;
Yin LIU
1
;
Shanshan YANG
1
;
Hongmei ZHANG
1
;
Wanxin HU
1
;
Zhiguang SU
1
Author Information
1. Molecular Medicine Research Center and National Clinical Research Center for Geriatrics, West China Hospital, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, China.
2. Clinical Translational Innovation Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
- Publication Type:Journal Article
- MeSH:
Rats;
Mice;
Animals;
Reactive Oxygen Species/metabolism*;
Diabetes Mellitus, Type 2/metabolism*;
Insulin Resistance;
Insulin;
Insulin-Secreting Cells/metabolism*;
Apoptosis;
Stress, Physiological;
Transcription Factors/metabolism*;
Palmitates/pharmacology*;
Obesity/metabolism*
- From:
Chinese Medical Journal
2023;136(8):922-932
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:Pancreatic β-cells elevate insulin production and secretion through a compensatory mechanism to override insulin resistance under metabolic stress conditions. Deficits in β-cell compensatory capacity result in hyperglycemia and type 2 diabetes (T2D). However, the mechanism in the regulation of β-cell compensative capacity remains elusive. Nuclear factor-Y (NF-Y) is critical for pancreatic islets' homeostasis under physiological conditions, but its role in β-cell compensatory response to insulin resistance in obesity is unclear.
METHODS:In this study, using obese ( ob/ob ) mice with an absence of NF-Y subunit A (NF-YA) in β-cells ( ob , Nf-ya βKO) as well as rat insulinoma cell line (INS1)-based models, we determined whether NF-Y-mediated apoptosis makes an essential contribution to β-cell compensation upon metabolic stress.
RESULTS:Obese animals had markedly augmented NF-Y expression in pancreatic islets. Deletion of β-cell Nf-ya in obese mice worsened glucose intolerance and resulted in β-cell dysfunction, which was attributable to augmented β-cell apoptosis and reactive oxygen species (ROS). Furthermore, primary pancreatic islets from Nf-ya βKO mice were sensitive to palmitate-induced β-cell apoptosis due to mitochondrial impairment and the attenuated antioxidant response, which resulted in the aggravation of phosphorylated c-Jun N-terminal kinase (JNK) and cleaved caspase-3. These detrimental effects were completely relieved by ROS scavenger. Ultimately, forced overexpression of NF-Y in INS1 β-cell line could rescue palmitate-induced β-cell apoptosis, dysfunction, and mitochondrial impairment.
CONCLUSION:Pancreatic NF-Y might be an essential regulator of β-cell compensation under metabolic stress.
