Asprosin impairs insulin secretion in response to glucose and viability through TLR4/JNK-mediated inflammation

• Published in: Molecular and cellular endocrinology Vol. 486; pp. 96 - 104
• Main Authors: Lee, Taeseung, Yun, Subin, Jeong, Ji Hoon, Jung, Tae Woo
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 15.04.2019
• Subjects: adipokines; Animals; Apoptosis; Apoptosis - drug effects; Asprosin; blood serum; Cell Survival - drug effects; cell viability; Cyclic AMP - biosynthesis; dose response; free fatty acids; glucose; Glucose - toxicity; Humans; Inflammation; Inflammation - metabolism; Inflammation - pathology; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; islets of Langerhans; JNK; MAP Kinase Signaling System - drug effects; Mice; Microfilament Proteins - metabolism; MIN6; mitogen-activated protein kinase; noninsulin-dependent diabetes mellitus; Oxidative Stress - drug effects; p38 Mitogen-Activated Protein Kinases - metabolism; palmitates; Palmitates - toxicity; patients; Peptide Fragments - metabolism; Peptide Hormones - metabolism; phosphorylation; Phosphorylation - drug effects; Recombinant Proteins - pharmacology; small interfering RNA; therapeutics; TLR4; Toll-like receptor 4; Toll-Like Receptor 4 - metabolism; transcription factor NF-kappa B; tumor necrosis factors; β-Cell; MIN6; JNK; Inflammation; siRNA; TLR4; Asprosin; Apoptosis; β-Cell
• ISSN: 0303-7207; 1872-8057; 1872-8057
• DOI: 10.1016/j.mce.2019.03.001

Severe inflammation in the islets is observed in obese patients with type 2 diabetes. Inflammation in the islets is caused by obesity-induced serum free fatty acids. Asprosin is a fasting-induced adipokine, which contributes to hepatic glucose production. However, the effects of asprosin on inflammation and cellular dysfunction in pancreatic β-cells remain to be elucidated. Here, we demonstrated that treatment of mouse insulinoma MIN6 cells and human primary islets containing β-cells with palmitate increased asprosin expression and secretion. Treatment of MIN6 cells and human primary islets with palmitate increased phosphorylation of the inflammatory marker nuclear factor-kappa B (NFκB) and the release of pro-inflammatory cytokines including TNF and MCP-1 and decreased glucose-stimulated insulin secretion and cell viability. However, siRNA-mediated suppression of asprosin reversed these changes. Recombinant asprosin treatment of MIN6 cells and human primary islets augmented the inflammation response, cellular dysfunction, and apoptosis in a dose-dependent manner. Asprosin induced toll-like receptor (TLR) 4 expression and JNK phosphorylation. siRNA for TLR4 or JNK mitigated the effects of asprosin on inflammation and cellular dysfunction. These results suggest that palmitate-derived asprosin secretion from β-cells results in their inflammation and dysfunction through a TLR4/JNK-mediated pathway. This report suggests asprosin as a novel therapeutic target for the treatment of type 2 diabetes through preservation of β-cell function. [Display omitted] •Palmitate augments asprosin expression in and palmitate group.•Asprosin promotes inflammation in sion in.•Asprosin induces cellular dysfunction apoptosis in tate gr.•Asprosin binds to TLR4 to stimulate JNK phosphorylation.•TLR4/JNK-mediated pathway plays an important role in asprosin-induced inflammation, cellular dysfunction, and apoptosis in β-cells.