FOX01 and mTORC - What role do they play in acne

The role of hereditary factors whilst involved in the pathogenesis of acne, does not fully account for the increase in acne in Western Society.  After years of debate within the scientific community, finally it is well established with the current research that acne is a disease of the modern diet.  Diet has an influence on genetic expression.  When we eat a cascade of signalling occurs as a result of the release of insulin.  FOX01 and mTORC1 are involved in sensing insuling and deciding what hormones/chemical messengers are released as a result.  When we eat the chemical messengers are sensed by the forkhead box class O1 transcription factor (FoxO1) and the nutrient-sensitive kinase mammalian target of rapamycin complex 1 (mTORC1).

Acne skins have a deficiency in FOX01.  Consumption of high glycaemic foods, milk and animal protein leads to an increase in insuling and IGF1 and a subsequent further depletion of transcription factor FoxO1, which is an activator for acne target genes.  High energy foods like sugar and dairy cause high levels of insulin and IGF-1 hormone. Those hormones activate an enzyme called mTOR, which, in turn, activates different parts of your physiology, including sebum, keratin, and inflammation. The perfect recipe for acne.

 To first understand what is occurring when we eat a high glycaemic index food we must first understand what FOX01 and mTORC are.

What is mTORC?
mTORC1 stands for "the nutrient-sensitive kinase mammalian target of rapamycin complex 1".  mTORC1 is regarded as the conductor of the ‘cellular signalling symphony’ that integrates signals of cellular energy, growth factors and amino acids. Metabolic regulations mediated by FoxO1 and mTORC1 depend on upstream activation of the IIS (insulin/IGF (insulin-like growth factor)-like signalling and this is where diet comes into play.  The foods you eat have a direct influence on the amount of insulin released. 

mTORC1 signalling serves as a ‘growth checkpoint’ surveying the status of the extra- and intracellular milieu of growth factors and nutrients. mTORC1 signalling stimulates gene transcription, translation, ribosome biogenesis, protein synthesis, cell growth, cell proliferation and lipid synthesis but suppresses autophagy. In mammalian cells, two functionally different mTOR complexes exist: mTORC1 and mTORC2. mTORC1 contains the partner protein Raptor that interacts with mTORC1 substrates for their phosphorylation.  The mTORC1 signalling network senses and relays diverse inputs of nutrients, growth factors and cellular energy to a central ‘signalling core’.

The main activator of mTOR is a variety of amino acids and the hormone insulin.  Testosterone also is capable of activating mTOR.

• Protein, especially leucine
• Excess calories
• Excess carbs
• Exercise – activated in brain, muscle and heart….Inhibited in liver and fat cells.
• Orexin
• IGF-1
• Insulin
• Testosterone
• Ghrelin – in hypothalamus
• Leptin – in the hypothalamus
• Thyroid hormone – in the hypothalamus…and other cells
• Oxygen
• Ketamine.  (In the brain – produces antidepressant effect.)
• IL-6  – in muscle and fat

Natural Inhibitors of mTOR

• Protein restriction
• Leucine restriction
• Glutamine restriction
• Methionine restriction
• Lysine restriction
• Arginine restriction
• Threonine restriction
• Isoleucine restriction
• Calorie restriction
• Ketogenic Diets
• Cortisol/Glucocorticoids
• Metformin
• NAC
• Resveratrol
• Aspirin
• Cod liver/ Omega-3
• Extra Virgin Olive Oil
• EGCG/Tea
• Curcumin
• R-Lipoic Acid
• Caffeine
• Apigenin
• Quercetin
• Genistein
• DIM (R)
• Ursolic acid
• Emodin (found in Fo-Ti, Resveratrol, Rhubarb, Aloe,)
• Andrographis/Andrographolide
• Pomegranate/Ellagic acid
• Reishi
• Milk thistle/Silymarin
• Oleanolic acid
• Anthocyanins/Grape Seed Extract
• Rhodiola
• Carnosine

What is FOX01
FOX01 stands for forkhead box class O1 transcription factor.  FoxO1 is an important transcription factor that modulates the expression of genes involved in cell cycle control, DNA damage repair, apoptosis, oxidative stress management, cell differentiation, glucose and lipid metabolism, inflammation, and innate and adaptive immune functions. FoxO1 is expressed in all mammalian tissues including human and plays an important role in the regulation of metabolism. FoxO1 has been proposed to function as a key regulator in the pathogenesis of acne as FoxO1 senses external nutrient and internal growth factor signals and relays these to FoxO1-dependent gene regulation.

High glycemic diet, dairy products and animal protein has been recognized as affecting this expression through activation of IGF-1/insulin, which, in turn, influence mTORC1. Transcriptor factor sterol regulatory element binding protein-1 (SREBP-1) is influenced by mTORC. This pathway leads to pathogenesis in sebaceous glands and more synthesis of free fatty acids, with well known role in acne vulgaris pathogenesis.

But isn't acne genetic?

I have frequently heard Aestheticians say that if a client is having hormonal acne that they should get their hormone levels checked.  Often the therapist is shocked that the client comes back reporting that her levels of hormones are normal and within healthy limits.  The hormone levels of acne clients and non-acne clients are usually normal.  It is not the level of these hormones that is the issue it is how acne-prone skin reacts to them.   Acne skins have increased conversion of testosterone to DHT.

And this is where genes come into play. Because of genetic factors acne patients are deficient in nuclear transcription factor FoxO1. Sebum production and skin cell growth are out of control in acne patients. FoxO1 acts like a break to these processes, and it’s malfunctioning. It reduces sensitivity to androgens by suppressing androgen receptors and regulates cell growth and inflammation. Thus there’s a good reason to believe that the less FoxO1 is present in the skin the more prone to acne it is.

Insulin and IGF-1 can make the situation even worse by further reducing FoxO1 levels.

So how does this work and how does it affect Acne

What you eat can show up on your skin, and one way this happens is through hormones. Studies link acne to Western-style diets (high in sugar and calories), and given what we know this is not a surprise. Eating sugar and refined carbohydrates causes the pancreas to release large amounts of insulin and IGF-1. Over time this type of diet leads to insulin resistance and chronically high levels acne-causing hormones.

Eating minimally processed low glycemic index foods can reverse the situation, and this has been now demonstrated in several studies.  A low glycemic load diet has been shown to improve acne symptoms, and decrease IGF-1 and skin oil production in several studies(1-3).

FoxO1 inhibits lipogenesis

FoxO1 not only suppresses protein synthesis and cell growth, but also lipid metabolism. FoxO1 regulates the key transcription factor of lipid synthesis SREBP-1c.  IGF-1 induced SREBP-1 expression and enhanced lipogenesis in SEB-1 sebocytes via activation of the PI3K/Akt pathway, whereas FoxO1 antagonized the expression of SREBP-1c. Thus, reduced expression of SREBP-1 should be expected from a low glycaemic load diet associated with attenuated IIS. In fact, a 10-week low glycaemic load diet reduced SREBP-1 expression in the skin of acne patients, reduced the size of sebaceous glands, mitigated cutaneous inflammation and improved acne. Furthermore, FoxO1 suppresses the activity of peroxisome proliferator–activated receptor-γ (PPARγ) and LXRα that both costimulate sebaceous gland lipogenesis.

Isotretinoin's sebum-suppressive effect has recently been associated with upregulated FoxO1 expression. Reported reductions in IGF-1 serum levels during isotretinoin treatment.

FoxO1 suppresses androgen signalling

Sebaceous gland growth and acne are androgen dependent. The growth of androgen-responsive tissues is coordinated with general somatic growth. IGF-1 stimulates gonadal and adrenal androgen synthesis as well as intracutaneous intracrine conversion of testosterone to tenfold more active dihydrotestosterone, the most potent androgen receptor (AR) ligand. Enhanced hepatic IGF-1 synthesis by Western Diet may thus increase the availability of potent androgens in the skin.

Intriguingly, FoxO1 functions as an androgen receptor cosuppressor. Nuclear extrusion of FoxO1 by high IIS relieves FoxO1-mediated repression of androgen receptor transactivation. Thus the western diet stimulates androgen receptor-mediated signalling, which explains enhanced peripheral androgen responsiveness.  Both androgen receptors and IIS synergistically increase SREBP-1-mediated lipogenesis and upregulate lipogenic pathways.

FoxO1 reduces oxidative stress

Overnutrition and anabolic states with enhanced mTORC1 activity are associated with increased oxidative stress, which has been observed in acne vulgaris. FoxOs upregulate defense mechanisms against reactive oxygen species (ROS). FoxO1 induces the expression of haeme oxygenase 1 and thereby reduces mitochondrial ROS formation. FoxO1 and FoxO3 mediate the expression of the ROS scavenger sestrin. FoxO3 stimulates the expression of ROS-degrading enzymes manganese superoxide dismutase and catalase. Hence, FoxOs are key players of redox signalling and link western diet to enhanced metabolic oxidative stress in acne vulgaris.

FoxO1 links nutritional status to innate and adaptive immunity

FoxO family members suppress the highly substrate- and energy-dependent process of T-cell activation, whereas FoxO1 deficiency in vivo resulted in spontaneous T-cell activation and effector differentiation. Increased CD4+ T-cell infiltration and enhanced IL-1 activity have been detected in acne-prone skin areas prior to comedo formation.  Thus, FoxO1 links nutrient availability and metabolic conditions to T-cell homoeostasis.
FoxOs control antimicrobial peptide synthesis.

Downregulated FoxO signalling by western diet may thus favour an AMP-deficient follicular microenvironment, which may allow overgrowth of P. acnes.   Western Diet would not only overstimulate sebum production favouring P. acnes growth but may diminish AMP-controlled host responses against P. acnes, which may ultimately stimulate inflammatory TLR-mediated innate immune responses against hypercolonized P. acnes. Upregulated TLR-driven innate immune responses against P. acnes with overexpression of TNF-α may further enhance sebaceous gland lipogenesis via activated proinflammatory mTORC1 signalling.

mTORC1: Convergence point of nutrient signalling in acne

Western diet overactivates mTORC1 by providing an abundance of dairy- and meat-derived essential amino acids, increased IIS induced by dairy protein consumption and high glycaemic load and suppressed AMPK activity by calorie excess. As protein and lipid biosynthesis, cell growth and proliferation are coordinated by mTORC1, it is obvious that mTORC1 plays a key role in acne pathogenesis, characterized by increased proliferation of acroinfundibular keratinocytes, SG hyperplasia and increased SG lipogenesis.

Acne and mTORC1-driven insulin resistance

Nutrient signalling of western diet results in increased activation of downstream substrates of mTORC1. S6K1-mediated phosphorylation of insulin receptor substrate 1 (IRS-1) downregulates IIS and thus induces insulin resistance. Dietary fatty acids directly activate S6K1 independent of mTORC1. Insulin resistance is considered to be a physiological feature of increased growth during puberty. However, pathologically persistent insulin resistance is associated with the metabolic syndrome as well as acne-associated syndromes. Thus, increased mTORC1/S6K1 signalling explains the reported associations between western diet, acne, increased body mass index (BMI) and insulin resistance.

mTORC1 regulates lipid synthesis

Increased sebaceous gland lipid biosynthesis is responsible for seborrhoea and sebaceous gland hyperplasia. Importantly, the key transcription factor of lipid biosynthesis SREBP-1 depends on mTORC1 activation. mTORC1 phosphorylates lipin-1, which controls the access of SREBP-1 to the promoter region of SREBP-1-dependent lipogenic genes in the nucleus.

FoxO1: the rheostat regulating mTORC1

As both mTORC1 and FoxO1 integrate nutrient and growth factor signals, it is conceivable that they interact with each other to coordinate cellular responses to nutrient availability. FoxOs are pivotal inhibitors of mTORC1 and have emerged as important rheostats that modulate the activity of mTORC1. FoxO1, FoxO3 and FoxO4 induce the expression of sestrin3 that activates AMPK, which inhibits mTORC1.  Furthermore, Akt-phosphorylated cytoplasmic FoxO1 binds to TSC2 and thereby dissociates the TSC1/TSC2 complex, which activates mTORC1. Thus, activated Akt inhibits FoxO1, FoxO3 and FoxO4 through direct phosphorylation and indirectly activates mTORC1, which in turn increases protein and lipid synthesis and induces insulin resistance.  In summary, FoxO transcription factors, especially FoxO1, inhibit the activity of mTORC1 at multiple levels of cellular regulation.

Conclusion

References:

Vora, S., Ovhal, A., Jerajani, H., Nair, N. and Chakrabortty, A. (2008), Correlation of facial sebum to serum insulin-like growth factor-1 in patients with acne. British Journal of Dermatology, 159: 990–991.

Melnik, B and Schmitz, G.  Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris.  Exp Dermatol. 2009 Oct;18(10):833-41

Arora, M.; Yadav, A. and Saini, V. Role of Hormones in Acne Vulgaris. Clin Biochem. 2011 Sep;44(13):1035-40.

Cappel, M.; Mauger D. and Thiboutot, D.  Correlation between serum levels of insulin-like growth factor 1, dehydroepiandrosterone sulfate, and dihydrotestosterone and acne lesion counts in adult women.  Arch Dermatol. 2005 Mar;141(3):333-8.

Aizawa, H and Niimura, M.  Elevated serum insulin-like growth factor-1 (IGF-1) levels in women with postadolescent acne. J Dermatol. 1995 Apr;22(4):249-52.

Long, X.; Ortiz-Vega, S.;, Lin, Y and Avruch, J.  Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency.  J Biol Chem. 2005 Jun 24;280(25):23433-6. Epub 2005 May 5.