Western diet has been linked to the pathogenesis of acne vulgaris that is associated with high intake of hyperglycaemic carbohydrates, milk and saturated fats (1-3, s1). In 2010, I have proposed that nutrient signalling in acne may reduce the nuclear activity of the metabolic transcription factor FoxO1 4. In 2012, I have suggested that acne may be linked to increased activity of the nutrient‐ and growth factor sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1) (s1, 5). mTORC1 orchestrates protein and lipid biogenesis, cell growth and proliferation (s2–s4). Mirdamadi et al. 6 showed that insulin/IGF‐1 signalling downregulates nuclear FoxO1 levels in SZ95 sebocytes. In this issue, Monfrecola et al. 7 provide direct evidence that mTOR expression and mTORC1‐S6K1 signalling are upregulated in the skin of acne patients.

FoxO1 and mTORC1: pivotal players of acne metabolomics Both FoxO1 and mTORC1 are pivotal nutrient‐ and growth factor‐dependent regulators of metabolism. Nuclear FoxO1 suppresses the transcriptional activity of androgen receptor (AR), liver X receptor‐α (LXRα), sterol response element‐binding protein‐1c (SREBP‐1c) and peroxisome proliferator‐activated receptor‐γ (PPARγ) 7, whereas mTORC1 controls gene expression and protein levels of SREBP‐1c and PPARγ (s4), crucial transcription factors of sebaceous lipogenesis (s5, 8) (Fig. 1). Figure 1 Open in figure viewer PowerPoint mTORC1‐centred model of NLRP3 inflammasome activation proposing the nutrigenomic pathogenesis of acne vulgaris. Nutrient signalling of Western diet via downregulation of FoxO1 and hyperactivation of mTORC1 modifies sebum quantity and composition that activate the NLRP3 inflammasome. AR, androgen receptor; BCAAs, branched‐chain amino acids; C16:0, palmitic acid; C18:1, oleic acid; Δ6D, Δ6‐desaturase; FLG, filaggrin; FoxO1, forkhead box class O1; Gln, glutamine; HIF1α, hypoxia‐inducible factor‐1α; HK1, hexokinase 1; IGF‐1, insulin‐like growth factor‐1; IL‐1α, interleukin‐1α; IL‐1β, interleukin‐1β; IL‐17, interleukin‐17; LTA, lipoteichoic acid; LXRα, liver X receptor‐α; mTORC1, mechanistic target of rapamycin complex 1; NLRP3, Nod‐like receptor family, pyrin domain‐containing 3 inflammasome; P. acnes, Propionibacterium acnes; PPARγ, peroxisome proliferator‐activated receptor‐γ; SCD, stearoyl‐CoA desaturase; S6K1, ribosomal protein S6 kinase, 70‐KD, 1; 1; SREBP1c, sterol response element‐binding protein‐1c; TG, triglyceride; TGL, triglyceride lipase; TLR2, toll‐like receptor 2; Th17, Th17 T cell. Sebocyte SREBP‐1c activity not only controls the total amount of synthesized sebum triglycerides (s5) but via expression of Δ6‐desaturase‐ and stearoyl‐CoA desaturase increases the concentration of sebum monounsaturated fatty acids (s6, s7). In fact, an association between the synthesis of total sebum triglycerides and triglyceride levels of monounsaturated fatty acid such as sapienic acid (16:1) and oleic acid (18:1) has been reported (s8). mTORC1 activity is negatively controlled by FoxO transcription factors (s9, s10) but activated by insulin, IGF‐1, testosterone, essential branched‐chain amino acids (BCAAs), glutamine and palmitic acid (s2–s4, s11–s13). High glycemic load diet‐stimulated insulin secretion increases PI3K/Akt/mTORC1/SREBP1 signalling in acne (s5, s14–s16), whereas a low glycemic load diet reduces SREBP expression in the skin of acne patients (s16). Milk has been identified as mammal's post‐natal endocrine system promoting mTORC1‐dependent translation 9. Thus, the main components of Western diet ‘milk & sugar’ exaggerate the magnitude of mTORC1 signalling that apparently affects metabolic homoeostasis of sebaceous follicles (s1,5). The kinase S6K1, a major downstream target of mTORC1, plays a central role for activation of SREBP‐1. mTORC1 inactivates the negative SREBP‐1 regulator lipin 1 (s17), promotes gene expression of SREBP‐1c (s4) and via activation of S6K1 promotes SREBP‐1c cleavage into its active form (s18). Thus, the nutrigenomic regulators FoxO1 and mTORC1 control the activity of SREBP‐1, the key transcription factor of sebaceous lipogenesis (s5) (Fig. 1).

The impact of acne metabolomics on the sebofollicular microbiome Overstimulated SREBP‐1 expression has two critical effects on sebaceous gland homoeostasis by (i) increasing the total amount of sebum triglycerides (s16) and (ii) by enhancing the relative amount of monounsaturated fatty acids in sebum triglycerides (s5, s6). Quantitative and qualitative changes of sebum are intimately involved in Propionibacterium acnes colonization and biofilm formation (s19‐s21). Free oleic acid (C18:1) enhances P. acnes adherence (s22, s23) and increases P. acnes growth (s24). Notably, free oleic acid increases biofilm formation in S. aureus (s25). Propionibacterium acnes in biofilm produce more virulence factors such as exogenous triglyceride lipase (TGL) (s26‐s28), which perpetuates the release of more free fatty acids into sebum (s26). In keratinocytes, free oleic acid stimulates the production interleukin‐1α (IL‐1α) (s29), a cytokine that is critically involved in keratinocyte proliferation, differentiation and comedogenesis (s30‐s33).

Increased mTORC1 signalling promotes inflammation Toll‐like receptor 2 (TLR‐2) and TLR‐4 expression are increased in the epidermis of acne lesions (s34). Importantly, saturated free fatty acids are ‘danger signals’ that activate the NLRP3 inflammasome via TLR signalling and enhance innate immunity (s35). Free palmitic acid and stearic acid activate the NLRP3 inflammasome either via enhancing TLR2/TLR1 dimerization or via lysosome destabilization (s36‐s41) (Fig. 1). Remarkably, the lysosome is the critical organelle for activating mTORC1 and the NLRP3 inflammasome, respectively (s39, s42, s43). The lysosome integrates metabolic‐inflammatory crosstalk resulting in macrophage inflammasome activation (s40). Free fatty acids promote lipotoxicity by lysosomal destabilization (s44). Palmitic acid via disrupting lysosome integrity plays a key role in NLRP3 inflammasome activation (s39). The NLRP3 inflammasome is regarded as a sensor for metabolic danger (s45) and epidemic acne vulgaris apparently features a visible diet‐induced danger response of the sebaceous follicle during the period of puberty, which is characterized by increased magnitudes of IGF‐1/mTORC1 signalling. Activation of the NRLP3 inflammasome promotes interleukin‐1β (IL‐1β) release resulting in Th17 cell differentiation. In fact, TLR2 activation by P. acnes in monocyte–macrophages and sebocytes mediates NLRP3 inflammasome‐mediated release IL‐1β resulting in Th17 differentiation (s46‐s49). Thus, two interconnected pathways activate the TLR‐NRLP3 inflammasome in acne (s50): (i) the release of sebum free saturated fatty acids, which function as metabolic danger signals activating TLR2‐ and TLR4 signalling (s36‐s42, s53‐s54) and (ii) P. acnes‐derived lipoteichoic acid (LTA) (s55) that activates TLR2‐mediated NLRP3 inflammasome activation (s56). Western diet via mTORC1 thus stimulates NLRP3 activation promoting the Th17/IL‐17 pathway in acne (s48). Remarkably, mTORC1 activation increases the expression of leptin (s57), a recently identified sebocyte‐derived adipokine (s58) that is involved in pro‐inflammatory signalling in acne (s59). Leptin is apparently another connecting piece between metabolisms, innate as well as adaptive immunity (s60, s61). mTORC1‐driven leptin signalling further enhances Th17 differentiation (s62). Ductal hypoxia due to excess sebum production, comedo formation and P. acnes overgrowth may upregulate hypoxia‐inducible factor‐1α (HIF‐1α), which further promotes leptin expression (s63). In a vicious cycle, hyperactivated mTORC1, a known inducer of HIF‐1α (s64), may promote sebocyte‐derived leptin synthesis augmenting Th17‐IL‐17 signalling in acne (s48, s62).

Glutaminolysis and glycolysis activate mTORC1 Human sebaceous glands engage in aerobic glycolysis and glutaminolysis (s65). Glutamine is a highly enriched amino acid of milk that activates the glutaminolysis pathway activating mTORC1 8. Glucose is the major hexose provided by hyperglycaemic diets. Moon et al. (s66) recently demonstrated that hexokinase 1‐dependent glycolysis is regulated via mTORC1 and represents a critical metabolic pathway activating the NLRP3 inflammasome. Thus, Western diet‐activated mTORC1 signalling may play a fundamental role in acne pathogenesis (s65).

Acne therapy attenuates mTORC1 signalling We have recently hypothesized that acne therapy either increases FoxO1 signalling and/or reduces mTORC1 activity (s67) and showed that the antidiabetic drug metformin operates as a multifunctional inhibitor of mTORC1 (s68). In accordance, Fabbrocini et al. (s69) demonstrated that a low glycemic diet combined with metformin treatment was effective in male subjects with acne resistant to common treatments.

Acne vulgaris: a diet‐induced sebofollicular inflammasomopathy Taken together, overactivated mTORC1 signalling induced by Western diet, superimposed on high IGF‐1/mTORC1 signalling during puberty, generates a metabolic danger response of the sebaceous follicle. Aberrant mTORC1 signalling by Western diet apparently initiates a sequence of sebolipotoxic alterations that disturb sebaceous metabolomics, change the follicular microbiome, enhance innate and adaptive immunity finally generating the visible inflammasomopathy acne vulgaris 8.

Conflict of interest The author has declared no conflicting interests.

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