NR3C1/Glucocorticoid receptor activation promotes pancreatic β-cell autophagy overload in response to glucolipotoxicity
Creators: name: Wu, Tijun
name: Shao, Yixue
name: Li, Xirui
name: Wu, Tao
name: Yu, Ling
name: Liang, Jin
name: Zhang, Yaru
name: Wang, Jiahui
name: Sun, Tong
name: Zhu, Yunxia
name: Chang, Xiaoai
name: Wang, Shusen
name: Chen, Fang
name: Han, Xiao
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Physiology
subject: Chemical Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Cancer
subject: Virology

description: Diabetes is a complex and heterogeneous disorder characterized by chronic hyperglycemia. Its core cause is progressively impaired insulin secretion by pancreatic β-cell failures, usually upon a background of preexisting insulin resistance. Recent studies demonstrate that macroautophagy/autophagy is essential to maintain architecture and function of β-cells, whereas excessive autophagy is also involved in β-cell dysfunction and death. It has been poorly understood whether autophagy plays a protective or harmful role in β-cells, while we report here that it is dependent on NR3C1/glucocorticoid receptor activation. We proved that deleterious hyperactive autophagy happened only upon NR3C1 activation in β-cells under glucolipotoxic conditions, which eventually promoted diabetes. The transcriptome and the <i>N6</i>-methyladenosine (m<sup>6</sup>A) methylome revealed that NR3C1-enhancement upregulated the RNA demethylase FTO (fat mass and obesity associated) protein in β-cells, which caused diminished m<sup>6</sup>A modifications on mRNAs of four core <i>Atg</i> (autophagy related) genes (<i>Atg12, Atg5, Atg16l2, Atg9a</i>) and, hence, hyperactive autophagy and defective insulin output; by contrast, FTO inhibition, achieved by the specific FTO inhibitor Dac51, prevented NR3C1-instigated excessive autophagy activation. Importantly, Dac51 effectively alleviated impaired insulin secretion and glucose intolerance in hyperglycemic β-cell specific NR3C1 overexpression mice. Our results determine that the NR3C1-FTO-m<sup>6</sup>A modifications-<i>Atg</i> genes axis acts as a key mediator of balanced autophagic flux in pancreatic β-cells, which offers a novel therapeutic target for the treatment of diabetes. <b>Abbreviations:</b> 3-MA: 3-methyladenine; AAV: adeno-associated virus; Ac: acetylation; Ad: adenovirus; AL: autolysosome; ATG: autophagy related; AUC: area under curve; Baf A1: bafilomycin A<sub>1</sub>; βNR3C1 mice: pancreatic β-cell-specific NR3C1 overexpression mice; cFBS: charcoal-stripped FBS; Ctrl: control; ER: endoplasmic reticulum; FTO: fat mass and obesity associated; GC: glucocorticoid; GRE: glucocorticoid response element; GSIS: glucose-stimulated insulin secretion assay; HFD: high-fat diet; HG: high glucose; HsND: non-diabetic human; HsT2D: type 2 diabetic human; i.p.: intraperitoneal injected; KSIS: potassium-stimulated insulin secretion assay; m<sup>6</sup>A: N6-methyladenosine; MeRIP-seq: methylated RNA immunoprecipitation sequencing; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NR3C1-Enhc.: NR3C1-enhancement; NC: negative control; Palm.: palmitate; RNA-seq: RNA sequencing; T2D: type 2 diabetes; TEM: transmission electron microscopy; UTR: untranslated region; WT: wild-type.