Free Radical-derived Oxysterols: Novel Adipokines Modulating Adipogenic Differentiation of Adipose Precursor Cells

• Published in: The journal of clinical endocrinology and metabolism Vol. 101; no. 12; pp. 4974 - 4983
• Main Authors: Murdolo, Giuseppe, Piroddi, Marta, Tortoioli, Cristina, Bartolini, Desirée, Schmelz, Martin, Luchetti, Francesca, Canonico, Barbara, Papa, Stefano, Zerbinati, Chiara, Iuliano, Luigi, Galli, Francesco
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.12.2016; Copyright by The Endocrine Society
• Subjects: Adipocytes; Adipocytes - metabolism; Adipogenesis; Adipokines - metabolism; Adipose tissue; Adipose Tissue - metabolism; Adult; Biopsy; Body fat; Cell differentiation; Cell size; Cell viability; Cells, Cultured; Comorbidity; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - metabolism; Extracellular signal-regulated kinase; Female; Free radicals; Free Radicals - metabolism; Gas chromatography; Humans; Insulin resistance; Lipids; Male; MAP kinase; Mass spectroscopy; Middle Aged; Obesity; Obesity - epidemiology; Obesity - metabolism; Oxidative stress; Oxysterols - metabolism; Signal transduction; Stem Cells - metabolism; Wnt protein; β-Catenin
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2016-2918

Context:Increased oxidative stress in adipose tissue emerges as an inducer of obesity-linked insulin resistance. Here we tested whether free-radical derived oxysterols are formed by, and accumulate in, human adipocytes. Moreover, we asked whether increased accumulation of oxysterols characterizes the adipose cells of obese patients with type 2 diabetes (T2D) (OBT2D) compared with lean, nondiabetic controls (CTRLs). Finally, we studied the effects of the free radical–derived oxysterols on adipogenic differentiation of adipose-derived stem cells (ASCs).Main Outcome Measures:Adipocytes and ASCs were isolated from sc abdominal adipose tissue biopsy in four OBT2D and four CTRL subjects. Oxysterols in adipocytes were detected by gas chromatography/mass spectrometry. The cellular and molecular effects of oxysterols were then evaluated on primary cultures of ASCs focusing on cell viability, adipogenic differentiation, and “canonical” WNT and MAPK signaling pathways.Results:7-ketocholesterol (7κ-C) and 7β-hydroxycholesterol were unambiguously detected in adipocytes, which showed higher oxysterol accumulation (P < .01) in OBT2D, as compared with CTRL individuals. Notably, the accumulation of oxysterols in adipocytes was predicted by the adipose cell size of the donor (R2 = 0.582; P < .01). Challenging ASCs with free radical–derived type I (7κ-C) and type II (5,6-Secosterol) oxysterols led to a time- and concentration-dependent decrease of cell viability. Meaningfully, at a non-toxic concentration (1μM), these bioactive lipids hampered adipogenic differentiation of ASCs by sequential activation of WNT/β-catenin, p38-MAPK, ERK1/2, and JNK signaling pathways.Conclusion:Free radical–derived oxysterols accumulate in the “diabetic” fat and may act as novel adipokines modulating the adipogenic potential of undifferentiated adipose precursor cells.