Nuclear factor-Y mediates pancreatic β-cell compensation by repressing reactive oxygen species-induced apoptosis under metabolic stress.

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.

• Authors: Siyuan He, Xiaoqian Yu, Daxin Cui, Yin Liu, Shanshan Yang, Hongmei Zhang, Wanxin Hu, Zhiguang Su
• Journal: Chinese medical journal (Chin Med J (Engl)) Vol. 136 Issue 8 Pg. 922-932 (04 20 2023) ISSN: 2542-5641 [Electronic] China
• PMID: 37000974 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.

Chemical References

• Reactive Oxygen Species
• Insulin
• Transcription Factors
• Palmitates

Topics

• 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 (metabolism, pharmacology)
• Obesity (metabolism)