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- Title
Free Radical-derived Oxysterols: Novel Adipokines Modulating Adipogenic Differentiation of Adipose Precursor Cells.
- Authors
Murdolo, Giuseppe; Piroddi, Marta; Tortoioli, Cristina; Bartolini, Desirée; Schmelz, Martin; Luchetti, Francesca; Canonico, Barbara; Papa, Stefano; Zerbinati, Chiara; Iuliano, Luigi; Galli, Francesco
- Abstract
<bold>Context: </bold>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).<bold>Main Outcome Measures: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>Free radical-derived oxysterols accumulate in the "diabetic" fat and may act as novel adipokines modulating the adipogenic potential of undifferentiated adipose precursor cells.
- Subjects
ADIPOSE tissues; CELL culture; CELL physiology; FAT cells; FREE radicals; TYPE 2 diabetes; OBESITY; PEPTIDE hormones; STEM cells; COMORBIDITY
- Publication
Journal of Clinical Endocrinology & Metabolism, 2016, pjc20162918
- ISSN
0021-972X
- Publication type
journal article