Insulin and insulin-like growth factor-1 can modulate the phosphoinositide-3-kinase/Akt/FoxO1 pathway in SZ95 sebocytes in vitro

• Published in: Molecular and cellular endocrinology 2015-11, Vol.415, p.32-44
• Main Authors: Mirdamadi, Yasaman, Thielitz, Anja, Wiede, Antje, Goihl, Alexander, Papakonstantinou, Eleni, Hartig, Roland, Zouboulis, Christos C., Reinhold, Dirk, Simeoni, Luca, Bommhardt, Ursula, Quist, Sven, Gollnick, Harald
• Format: Article
• Language: English
• Subjects: Acne; Acne Vulgaris - genetics; Acne Vulgaris - pathology; Cell Differentiation - drug effects; Cell Line; Cell Proliferation - drug effects; Forkhead Box Protein O1; Forkhead Transcription Factors - genetics; FoxO1; Gene Expression Regulation - drug effects; High glycaemic load diet; Humans; IGF-1; In Vitro Techniques; Insulin; Insulin - pharmacology; Insulin-Like Growth Factor I - pharmacology; Lipogenesis; Models, Biological; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Sebocytes; Signal Transduction - drug effects; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - metabolism
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2015.08.001

A recent hypothesis suggests that a high glycaemic load diet-associated increase of insulin-like growth factor-1 (IGF-1) and insulin may promote acne by reducing nuclear localization of the forkhead box-O1 (FoxO1) transcription factor via activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway. Using SZ95 sebocytes as a model, we investigated the effect of the most important insulinotropic western dietary factors, IGF-1 and insulin on acne. SZ95 sebocytes were stimulated with different concentrations of IGF-1 and insulin (0.001, 0.01, 0.1 and 1 μM) for 15 to 120 min ± PI3K inhibitor LY294002 (50 μM). Cytoplasmic and nuclear protein expression of p-Akt and p-FoxO1 as well as FoxO transcriptional activity was analysed. In addition, the proliferation and differentiation of sebocytes and their TLR2/4 expression were determined. We found that high concentrations of IGF-1 and insulin differentially stimulate the PI3K/Akt/FoxO1 pathway by an early up-regulation of cytoplasmic p-Akt and delayed up-regulation of p-FoxO1 resulting in FoxO1 shift to the cytoplasm and the reduction of FoxO transcriptional activity, physiological serum concentration had no effect. IGF-1 at concentrations of 0.1 and 1 μM significantly reduced proliferation but increased differentiation of sebocytes to a greater extent than insulin (0.1 and 1 μM), but up-regulated TLR2/4 expression to comparable extent. These data provide the first in vitro evidence that FoxO1 principally might be involved in the regulation of growth-factor-stimulatory effects on sebaceous lipogenesis and inflammation in the pathological condition of acne. However, the in vivo significance under physiological conditions remains to be elucidated. •We investigated the role of FoxO1 as a putative regulator in the acne pathogenesis.•IGF-1 and insulin activate PI3K and up-regulate p-Akt and p-FoxO1 in SZ95 sebocytes.•IGF-1 and insulin reduce nuclear FoxO1 and its transcriptional activity.•SZ95 differentiation increases and proliferation decreases via PI3K activation.•IGF-1 and insulin increase expression of pro-inflammatory TLR2/4.