Potential role of FoxO1 and mTORC1 in the pathogenesis of Western diet-induced acne.

[IDW2BB]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408989/

Abstract

Acne in adolescents of developed countries is an epidemic skin disease and has currently been linked to the Western diet (WD). It is the intention of this viewpoint to discuss the possible impact of WD-mediated nutrient signalling in the pathogenesis of acne. High glycaemic load and dairy protein consumption both increase insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) that is superimposed on elevated IGF-1 signalling of puberty. The cell's nutritional status is primarily sensed by the forkhead box transcription factor O1 (FoxO1) and the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1). Increased IIS extrudes FoxO1 into the cytoplasm, whereas nuclear FoxO1 suppresses hepatic IGF-1 synthesis and thus impairs somatic growth. FoxO1 attenuates androgen signalling, interacts with regulatory proteins important for sebaceous lipogenesis, regulates the activity of innate and adaptive immunity, antagonizes oxidative stress and most importantly functions as a rheostat of mTORC1, the master regulator of cell growth, proliferation and metabolic homoeostasis. Thus, FoxO1 links nutrient availability to mTORC1-driven processes: increased protein and lipid synthesis, cell proliferation, cell differentiation including hyperproliferation of acroinfundibular keratinocytes, sebaceous gland hyperplasia, increased sebaceous lipogenesis, insulin resistance and increased body mass index. Enhanced androgen, TNF-α and IGF-1 signalling due to genetic polymorphisms promoting the risk of acne all converge in mTORC1 activation, which is further enhanced by nutrient signalling of WD. Deeper insights into the molecular interplay of FoxO1/mTORC1-mediated nutrient signalling are thus of critical importance to understand the impact of WD on the promotion of epidemic acne and more serious mTORC1-driven diseases of civilization.

The Link Between Androgen- and mTORC1-Signaling

We are at the very beginning to understand the important molecular crosstalk between androgens and the mTORC1 pathway. Anabolic effects of testosterone certainly increase protein synthesis. The mTORC1 pathway is the major regulator of protein synthesis and cell growth, but the relationship between testosterone action and mTORC1 has not yet been characterized in sebaceous glands. Nevertheless, it has been shown in cultured cardiomyocytes that testosterone induced hypertrophic effects via mTORC1 signaling. Testosterone increased the phosphorylation of mTOR and its downstream targets S6K1 and 4E-BP1.[SUP]51[/SUP] S6K1-phosphorylation induced by testosterone was blocked by the mTORC1 antagonist rapamycin. This observation is of great importance for the understanding of insulin resistance in states of hyperandrogenism like polycystic ovary syndrome (PCOS). Testosterone-mediated mTORC1-S6K1- IRS-1 signaling provides a most critical mechanism for the induction of insulin resistance.[SUP]50[/SUP] On the other hand, metformin treatment of patients with PCOS reduces androgen levels and improves insulin resistance. Remarkably, metformin inhibits mTORC1 activity by antagonizing leucine-mediated mTORC1 activation as well as AMPK-mediated suppression of mTORC1 activity.[SUP]52[/SUP][SUP],[/SUP][SUP]53[/SUP] The androgen-mTORC1-S6K1 pathway explains the development of insulin resistance in various syndromes associated with acne and insulin resistance.[SUP]54[/SUP]
In the prostate of mice PI3K levels and mTORC1 activity are robustly induced by androgens during prostatic development. PI3K/mTORC1 signaling is necessary for prostatic epithelial bud invasion of surrounding mesenchyme.[SUP]55[/SUP] The right balance of PI3K and downstream mTORC1/mTORC2 activity plays a critical role in the regulation of prostatic epithelial morphogenesis. Future studies in humans should clarify the role of androgen-mTORC1-mediated effects on sebaceous gland morphogenesis and differentiation.