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Abstract

Acne vulgaris is a common skin disease in industrialized countries with Western diet characterized by high glycemic load and milk consumption. Accumulating evidence underlines the role of Western diet as a major cause of enhanced nutrient-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling that may over-stimulate sebocyte growth and sebaceous lipogenesis resulting in sebaceous gland hyperplasia, hyperseborrhoea, Propionibacterium acnes overgrowth with biofilm formation and inflammatory follicular reactions. Substantial evidence from translational research suggests that all anti-acne agents operate by a common mechanism: the attenuation of exaggerated mTORC1 signal transduction in the pilosebaceous follicle. Future acne therapy should combine dietary and pharmacological interventions attenuating mTORC1 signaling by a paleolithic-type diet supported with natural or synthetic mTOR inhibitors.
The role of mTORC1 in acne
pathogenesis and treatment
Expert Rev. Dermatol. 8(6), 617–622 (2013)
Bodo C Melnik
Department of Dermatology,
Environmental Medicine and Health
Theory, University of Osnabru
¨ck,
Germany
Tel.: +49 524 198 8060
melnik@t-online.de
Acne vulgaris is a common skin disease in industrialized countries with Western diet characterized
by high glycemic load and milk consumption. Accumulating evidence underlines the role of
Western diet as a major cause of enhanced nutrient-mediated mechanistic target of rapamycin
complex 1 (mTORC1) signaling that may over-stimulate sebocyte growth and sebaceous
lipogenesis resulting in sebaceous gland hyperplasia, hyperseborrhoea, Propionibacterium acnes
overgrowth with biofilm formation and inflammatory follicular reactions. Substantial evidence
from translational research suggests that all anti-acne agents operate by a common mechanism:
the attenuation of exaggerated mTORC1 signal transduction in the pilosebaceous follicle. Future
acne therapy should combine dietary and pharmacological interventions attenuating
mTORC1 signaling by a paleolithic-type diet supported with natural or synthetic mTOR inhibitors.
KEYWORDS:acne • dairy • glycemic load • mechanistic target of rapamycin complex 1 • milk signaling • mTOR
inhibitors • paleolithic diet • treatment • Western diet
Acne is a disease of Western civilization with
prevalence rates in adolescence of over 85% [1,2].
Moderate-to-severe acne affects around 20% of
young people [3]. Western diet, characterized by
high glycemic load and high milk and dairy
protein consumption, has been recognized to be
a fundamental nutritional factor promoting
acne [48]. The placebo-controlled randomized
study of Smith et al. [6] and the case-control
study of Kwon et al. [7] provided evidence for
the improvement of acne by a low glycemic
load diet. The case control study of Di
Landro et al. [8] supported the role of milk con-
sumption as well as increased body mass index
(BMI) as aggravating factors of acne. Remark-
ably, acne is absent in populations consuming
less insulinotropic paleolithic diets [1,9], which
exclude grains, milk and dairy products and
thus exhibit much lower insulin/insulin-like
growth factor (IGF-1)/mTORC1 signaling [4,9].
Recent evidence points to a link between acne,
increased BMI and insulin resistance [911],
explained by exaggerated nutrient-stimulated
mTORC1 signaling [10].
mTORC1: the cellular sensor of nutrient
signaling
At the cellular level, nutrients (glucose, essential
amino acids), cellular energy (adenosine triphos-
phate (ATP)) as well as growth factors (insulin,
IGF-1, FGFs) are sensed by the nutrient-
sensitive kinase mechanistic target of rapamycin
complex 1 (mTORC1), the central cellular regu-
lator promoting protein-, lipid- and nucleotide
synthesis, cell growth and proliferation [12,13].
Recent evidence underlines that anabolic
mTORC1 signaling is the pivotal regulatory
pathway of lipogenesis and adipogenesis [1416],
linking enhanced mTORC1 signaling to ana-
bolic states of metabolism resulting in increased
body and fat mass, frequently associated with
the development of insulin resistance. From all
branched-chain amino acids (BCAAs) leucine
plays a crucial role for mTORC1 activation [17].
Notably, milk proteins provide highest amounts
of leucine in comparison to all other animal pro-
teins to optimize mTORC1 activation for post-
natal growth [18]. Several recent metabolomics
studies underline the relationship between high
plasma BCAA profiles, increased BMI and insu-
lin resistance [19]. In fact, accumulating evidence
supports the association of acne with increased
mTORC1 activation, increased BMI and insulin
resistance [8,11,20]. Thus, acne appears to feature
over-activated mTORC1 signaling over-
stimulating the sebaceous follicle by nutrient sig-
nals derived from Western diet [6,21].
Acne pathogenesis: mTORC1 up
High glycemic load and dairy protein consump-
tion both increase insulin/IGF-1 signaling that
is superimposed on elevated IGF-1 signaling of
Perspective
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puberty [4]. The cells nutritional status is sensed by the forkhead
box transcription factor O1 (FoxO1) and the serine/threonine
kinase mTORC1. Increased insulin/IGF-1 signaling extrudes
FoxO1 into the cytoplasm, whereas nuclear FoxO1 suppresses
hepatic IGF-1 synthesis and thus impairs somatic growth. Fur-
thermore, FoxO1 attenuates androgen signaling, interacts with
regulatory proteins important for sebaceous lipogenesis, regulates
the activity of innate and adaptive immunity and antagonizes oxi-
dative stress [21]. Most importantly, FoxOs function as a rheostat
of mTORC1 (FIGURE 1), the master regulator of cell growth, prolif-
eration and metabolic homeostasis [22]. 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 BMI. Enhanced androgen-,
TNFa- and IGF-1 signaling due to
genetic polymorphisms promoting the risk
of acne are known to increase
mTORC1 activation, an unfavorable
genetic disposition that may be further
enhanced by aberrant nutrient signaling of
Western diet [20].
Acne therapy: mTORC1 down
It has recently been hypothesized that anti-
acne agents either enhance nuclear FoxO
activity or directly inhibit mTORC1
(FIGURE 1) [23]. Benzoyl peroxide (BPO), by
activation of oxidative stress-inducible kin-
ases, increases nuclear FoxO levels promot-
ing Sestrin3-mediated activation of
adenosine monophosphate (AMP)-acti-
vated kinase (AMPK). Furthermore, BPO-
derived reactive oxygen species (ROS) may
activate AMPK via ataxia-telangiectasia
mutated. Isotretinoin and all-trans-retinoic
acid may stimulate FoxO gene expression.
Doxycycline may enhance FoxOs nuclear
retention by inhibiting the expression of
the nuclear export protein exportin-1.
Suppression of TNFasignaling by tetracy-
clines, erythromycin and other macrolides
may attenuate IKKb-TSC1-mediated
activation of mTORC1. Erythromycin
attenuates ERK1/2 activity, thereby
increases TSC2 activity, which inhibits
mTORC1. Azelaic acid may decrease
mTORC1 by inhibiting mitochondrial
respiration, increasing cellular ROS and
nuclear FoxO levels. Anti-androgens may
attenuate mTORC1 by suppressing
mTORC2-mediated Akt/TSC2 signaling.
Thus, the mode of action of all anti-acne
drugs in clinical use can be explained by indirect or direct attenu-
ation of mTORC1 signaling [23].
Potential new anti-acne drugs attenuating
mTORC1 activity
Remarkably, all common anti-acne drugs have been found
empirically without any conclusive strategy for drug develop-
ment. It is thus not surprising that over more than three deca-
des, the development of effective new anti-acne drugs is
missing. However, there is a need for future drug development
as therapeutically effective anti-acne drugs exhibit severe adverse
effects like the teratogenic effect of systemic isotretinoin. Fur-
thermore, recent animal studies pointed out that systemic iso-
tretinoin decreased ovarian reserve in female rats [24],an
Antiandrogen
BPO
AzA
BPO
ATRA
DOXY
IRS
PI3K
Akt
LAT TNFR VDR IR IGF1R AR
TSC1/TSC2
Rheb
mTORC1
AAs
Rag/ragulator
4E-BP-1 S6K1 SREBP-1
Reduced cell growth and lipogenesis
AAs TNFαVitD Insulin IGF-1 Androgen
IKKβDDIT4 mTORC2
AMPK Sestrin3
ATM
AMP
Antiandrogen
Metformin
Metformin
mTORC1-inhibitors
EGCG
Resveratrol
TORkinibs
FoxO
FoxO
EGCG
Lipin-1
Mitochondrial
Mitochondrial
respiration
respiration
Mitochondrial
respiration
ROS
Palaeo diet Palaeo diet AntiandrogenDOXY/AzA VitD
Figure 1. Inhibition of mTORC1 by anti-acne agents. Oral isotretinoin, all-trans-reti-
noic acid (ATRA), doxycycline (DOXY) and BPO increase nuclear FoxO levels, which
increase the expression of Sestrin3. Sestrin3 activates AMPK and augments the inhibitory
function of TSC2 toward Rheb, thus suppresses mTORC1. BPO may stimulate ROS-
mediated activation of ATM, a further stimulator of AMPK-mediated mTORC1 inhibition.
Azelaic acid (AzA) via inhibition of mitochondrial respiration may increase ROS-mediated
up-regulation of FoxOs and FoxO-induced Sestrin3 as well as cellular AMP levels activat-
ing AMPK, like metformin, a well-known activator of AMPK. Furthermore, metformin
inhibits the Rag/Ragulator-mediated amino acid (AA)-dependent activation of mTORC1.
Antiandrogens inhibit mTORC2-dependent activation of Akt, thus increase TSC1/
TSC2-mediated inhibition of Rheb. Antiandrogens suppress the expression of L-type
amino acids transporter (LAT), thus interfere with AA-mediated activation of mTORC1.
Natural mTORC1 inhibitors like resveratrol and epigallocatechin-3-gallate (EGCG) as well
as synthetic mTOR inhibitors inhibit the ATP-dependent kinase activity of mTOR, thereby
directly reducing mTORC1 activity. Vitamin D activates the expression of DNA damage-
inducible transcript 4 (DDIT4), which activates TSC2 inhibitory function towards
mTORC1. Thus, all anti-acne drugs directly or indirectly impair downstream
mTORC1 signaling and attenuate cell growth, proliferation and lipogenesis. A paleolithic
diet (paleo diet), which reduces enhanced insulin/IGF1 signaling of Western diet due to
high glycemic load and dairy consumption thus exerts synergistic effects with pharmaco-
logical agents in the treatment of acne.
Reproduced with permission from [23].
Perspective Melnik
618 Expert Rev. Dermatol. 8(6), (2013)
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adverse effect on fertility that can be explained by isotretinoin´s
induction of FoxO1-mediated apoptosis of follicular granulosa
cells [25].
Plant-derived mTORC1 inhibitors
Resveratrol is a polyphenolic flavonoid that down regulates
mTORC1 signaling [26,27]. Indeed, topical treatment of facial
acne vulgaris in 20 patients with a resveratrol-containing gel
(0.01% weight/volume) significantly reduced the number of
microcomedones, papules and pustules compared with vehicle
control [28]. Furthermore, resveratrol inhibited Propionibacterium
acnes growth and eradicated P. acnes biofilm formation [29,30].
Epigallocatechin-3-gallate (EGCG), the major green tea cate-
chin, is regarded as the active anti-inflammatory and anti-
proliferative compound of green tea extracts. EGCG functions
directly as an ATP-competitive inhibitor of mTORC1 [31].It
has been demonstrated that topical 2% green tea lotion was
effective in the treatment of mild-to-moderate acne vulgaris [32].
After 6 weeks, the mean total lesion count and mean severity
index of acne showed significant reductions of 58 and 39%,
respectively. Furthermore, a 3% green tea emulsion signifi-
cantly reduced sebum production in 10 healthy male volunteers
after 8 weeks of treatment [33]. Most recently, it has been dem-
onstrated that topical application of EGCG to rabbit auricles
reduced the size of sebaceous glands [34]. When applied to cul-
tured human SZ95 sebocytes, EGCG strongly suppressed sebo-
cyte proliferation and lipogenesis [34]. Importantly, EGCG in a
dose-dependent manner decreased IGF-1-stimulated mTOR-
and S6K phosphorylation of SZ95 sebocytes [34]. Thus, direct
experimental evidence underlines that the EGCG attenuates
IGF-1-stimulated mTORC1 activity of sebocytes. As mTORC1
regulates the activity and expression of sterol response element
binding protein 1 (SREBP-1), the most important transcription
factor of lipogenesis [14], it should be expected that EGCG
treatment of sebocytes would reduce sebocyte SREBP-1 expres-
sion. In fact, EGCG has been shown to inhibit SREBP-1 in
SEB-1 sebocytes and improved acne in an 8-week randomized
split-face clinical trial with and without EGCG [35].EGCG-
mediated activation of AMPK is another inhibitory mechanism
attenuating mTORC1-SREBP1 signaling, which explains
EGCG-mediated suppression of sebaceous lipogenesis (FIGURE 1)
[35].
Synthetic mTORC1 inhibitors
Recently, a new generation of mTOR inhibitors, called
mTORkinibs, which compete with ATP in the catalytic site of
mTOR and inhibit both mTORC1 and mTORC2 with a
high degree of selectivity, have been developed [36]. These
inhibitors bind to the ATP binding site of the kinase domain
of mTOR and as a result inhibit the mTOR complexes,
mTORC1 (rapamycin-sensitive) and mTORC2 (rapamycin-
resistant) [37,38]. The small molecular weight mTOR inhibitors
applied in submaximal doses have the potential for the develop-
ment of new synthetic anti-acne drugs attenuating enhanced
mTORC1 signaling up-regulated by Western diet or genetic
polymorphisms converging intoincreaseddownstreammTORC1
signaling [23].
Combination of nutrition therapy and pharmacother-
apy of acne
Increased mTORC1 signaling induced by Western diet appears
to represent the major pathogenic mechanism of diseases of civili-
zation [13]. Accumulating evidence links acne to the family of dis-
eases of civilization [1], characterized by exaggerated
mTORC1 signaling [4]. Thus, the primary focus of causal acne
therapy should eliminate the nutrient-derived stimuli that induce
or aggravate acne [4,5,39]. Nutritional therapy of acne should (1)
normalize total calorie intake, (2) lower glycemic load [57] and
(3) restrict total dairy protein consumption, especially whey pro-
tein abuse [40,41]. The ideal nutrition therapy of acne should favor
a paleolithic-type diet containing less insulinotropic carbohy-
drates and reduced consumption of milk and dairy products to
attenuate mTORC1 activity and should reduce the undesirable
intake of androgen precursors present in milk and dairy prod-
ucts [42]. The paleolithic-type diet offers a higher amount of natu-
ral plant-derived mTORC1 inhibitors (EGCG, resveratrol and
other natural polyphenols) by higher consumption of vegetables,
fruits and green tea. Moreover, a paleolithic-type diet increases
the consumption of fish protein, which exhibits a lower insuli-
naemic index than dairy protein and represents a favorable source
of anti-inflammatory w-3 fatty acids [8,43]. Patients exhibiting an
increased genetic disposition for acne for instance by gene poly-
morphisms of TNFa, IGF1, TLR2, mutated FGFR2 or andro-
gen receptor (AR) polymorphism with shorter CAG repeats may
feature persistently elevated mTORC1 signaling. These individu-
als most likely belong to the group of patients with moderate-
severe acne as well as therapy-resistant acne, which may not be
cured by sole dietary intervention. Certainly, these patients need
prolonged and sufficient pharmacological treatment but may still
benefit from dietary attenuation of mTORC1 signaling by a
paleolithic-type diet.
Conclusion
The appreciation of acne vulgaris as an mTORC1-driven dis-
ease of civilization mediated by Western diet and the recently
proposed concept that the mode of commonly used anti-acne
agents attenuates enhanced mTORC1 signaling allows the
development of new strategies for acne treatment. The primary
causal strategy correcting exaggerated diet-induced mTORC1
signaling in acne should consider a dietary intervention by a
paleolithic-type diet restricting hyperglycemic carbohydrates as
well as high intake of milk and dairy products [44]. The pre-
sented mTORC1 concept of acne pathogenesis and therapy
allows the rational development of new anti-acne agents. Natu-
ral plant-derived topical or systemic mTORC1 inhibitors like
resveratrol and EGCG could be combined with a paleolithic-
type diet. Furthermore, there is the opportunity to develop var-
ious synthetic small molecular weight mTOR kinase inhibitors
(TORkinibs), which may open new avenues for the pharmaco-
logical treatment of acne.
The role of mTORC1 in acne pathogenesis & treatment Perspective
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Five-year view
The recent awareness of acne belonging to the family of ana-
bolic mTORC1-driven metabolic diseases provides the rationale
for mTORC1 down-regulation by nutrition therapy as well as
pharmacological intervention. Two major acne-aggravating or
acne-inducing components of Western diet have been identi-
fied: high glycemic load and milk consumption. Whereas the
adverse effects of high glycemic load on acne have convincingly
been demonstrated, placebo-controlled randomized studies
investigating the effect of milk and various dairy products as
well as studies investigating high glycemic load in combination
with increased milk/dairy consumption still have to be per-
formed in corporation with nutrition science and dermatology.
Future studies should clarify the pathways of milk-driven
mTORC1 signaling. Recently identified exosomal microRNA
in commercial milk may be an important acneigenic stimulus.
Milk-derived microRNA-21 may attenuate the expression of
important cell cycle inhibitors and tumor suppressor proteins
like PTEN, Sprouty and PDCD4, thus further enhancing
mTORC1 signaling promoting the development of acne.
The recent view of acne as an mTORC1-driven disease
allows the implementation of various new pharmaceutical strat-
egies to target increased mTORC1 signaling at various levels. It
should be kept in mind that inflammatory signals and nutrient
signaling are all integrated by mTORC1. In acne patients, not
only sebocytes and acroinfundibular keratinocytes are metabol-
ically over-activated but also immune cells creating the inflam-
matory environment of acne. mTORC1 plays a major role in
the regulation immune responses and inflammation. Due to its
strong immunosuppressive and anti-proliferative effects the
allosteric mTORC1 inhibitor rapamycin is already in use for
immunosuppressive therapy and cancer treatment. Plant-derived
natural mTORC1 inhibitors like resveratrol and EGCG have
already demonstrated promising clinical effects in the treatment
of acne and reduction of sebum synthesis and need be studied
in more detail. Synthetic mTORC1 inhibitors, which have
been recently developed for the treatment of various cancers,
may in a moderate non-lethal concentration be successful for
the topical treatment of acne.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial con-
flict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or
options, expert testimony, grants or patents received or pending, or
royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
Acne is an mTORC1-driven anabolic and inflammatory skin disease.
High glycemic load and milk/dairy consumption as well as pro-inflammatory signals enhance mTORC1 signaling.
Anti-acne agents in clinical use operate by indirect or direct mTORC1 inhibition.
Future anti-acne drugs are either natural or synthetic mTOR-inhibitors.
Future acne therapy should be a combination of nutrition therapy with a paleolithic-type diet supported by pharmacological attenuation
of enhanced mTORC1 signaling.
References
Papers of special note have been highlighted as:
• of interest
•• of special interest
1Cordain L, Lindeberg S, Hurtado M et al.
Acne vulgaris: a disease of Western
civilization. Arch. Dermatol. 38(12),
1584–1590 (2002).
2Collier CN, Harper J C, Cafardi JA et al.The
prevalence of acne in adults 20 years and older.
J. Am. Acad. Dermatol. 58(1), 56–59 (2008).
3Bhate K, Williams HC. Epidemiology of
acne vulgaris. Br. J. Dermatol. 168 (3),
474–485 (2012).
4Melnik B. Dietary intervention in acne:
Attenuation of increased mTORC1 signaling
promoted by Western diet.
Dermatoendocrinol. 4(1), 20–32 (2012).
Explains the role of Western diet in
enhancing mTORC1 signaling.
5Burris J, Rietkerk W, Woolf K. Acne: The
role of medical nutrition therapy. J. Acad.
Nutr. Diet. 113 (3), 416–430 (2013).
6Smith RN, Mann NJ, Braue A et al.The
effect of a high-protein, low glycemic-load
diet versus a conventional, high
glycemic-load diet on biochemical
parameters associated with acne vulgaris:
a randomized, investigator-masked,
controlled trial. J. Am. Acad. Dermatol.
57(2), 247–256 (2007).
•• A valuable randomized, controlled study
demonstrating the beneficial effect of low
glycemic load diet in the treatment of
acne.
7Kwon HH, Youn JY, Hong JS et al.The
clinical and histological effect of low
glycaemic load diet in the treatment of acne
vulgaris in Korean patients: a randomized,
controlled trial. Acta Derm. Venereol. 92(3),
241–246 (2012).
8Di Landro A, Cazzaniga S, Parazzini F et al.
Family history, body mass index, selected
dietary factors, menstrual history, and risk
of moderate to severe acne in adolescents
and young adults. J. Am. Acad. Dermatol.
67(6), 1129–1135 (2012).
•• An important case control study
demonstrating the association of acne and
milk consumption.
9Lindeberg S, Eliasson M, Lindahl B et al.
Low serum insulin in traditional Pacific
Islanders: the Kitava Study. Metabolism
48(10), 1216–1219 (1999).
10 Melnik BC, John SM, Plewig G. Acne: risk
indicator for increased body mass index and
insulin resistance. Acta Derm. Venereol. doi:
10.2340/00015555-1677 (2013) (Epub
ahead of print).
Explains the metabolic relationship
between increased mTORC1 signaling,
increased BMI, insulin resistance and acne.
Perspective Melnik
620 Expert Rev. Dermatol. 8(6), (2013)
Expert Review of Dermatology Downloaded from informahealthcare.com by 79.208.113.223 on 01/12/14
For personal use only.
11 Kumari R, Thappa DM. Role of insulin
resistance and diet in acne. Indian J.
Dermatol. Venereol. Leprol. 79(3), 291–299
(2013).
12 Foster KG, Fingar DC. Mammalian target
of rapamycin (mTOR): conducting the
cellular signaling symphony. J. Biol. Chem.
285(19), 14071–14077 (2010).
13 Zoncu R, Efeyan A, Sabatini DM. mTOR:
from growth signal integration to cancer,
diabetes and ageing. Nat. Rev. Mol. Cell.
Biol. 12(1) 21–35 (2011).
•• An excellent state of the art review on
mTORC1 signaling.
14 Bakan I, Laplante M. Connecting
mTORC1 signalling to SREBP-1 activation.
Curr. Opin. Lipidol. 23(3), 226–234 (2012).
•• A well-written paper showing the pivotal
role of mTORC1 in lipogenesis.
15 Yoon MS, Zhang C, Sun Y et al.
Mechanistic target of rapamycin (mTOR)
controls homeostasis of adipogenesis.
J. Lipid Res. 54(8), 2166–2173 (2013).
16 Laplante M, Sabatini DM. Regulation of
mTORC1 and its impact on gene
expression at a glance. J. Cell Sci. 126(8),
1713–1719.
A most recent update on
mTORC1-mediated gene regulation.
17 Dodd KM, Tee AR. Leucine and
mTORC1: a complex relationship. Am. J.
Physiol. Endocrinol. Metab. 302(11),
E1329–E1342 (2012).
18 Melnik BC, John SM, Schmitz G. Milk is
not just food but most likely a genetic
transfection system activating
mTORC1 signaling for postnatal growth.
Nutr. J. 12, 103 (2013).
•• The first comprehensive review
demonstrating that milk is an endocrine
system of mammalian evolution promoting
mTORC1 signaling.
19 Morris C, O´Grada C, Ryan M et al. The
relationship between BMI and
metabolomics profiles: a focus on amino
acids. Proceed. Nutr. Soc. 71(4), 634–638
(2012).
20 Melnik BC. Diet in acne: further evidence
for the role of nutrient signalling in acne
pathogenesis. Acta Derm. Venerol. 92(3),
228–231 (2012).
21 Melnik BC, Zouboulis CC. Potential role
of FoxO1 and mTORC1 in the
pathogenesis of Western-diet induced acne.
Exp. Dermatol. 22(5), 311–315 (2013).
•• Updated viewpoint providing information
on the interaction of diet, FoxO- and
mTORC1 signaling in the pathogenesis of
acne.
22 Hay N. Interplay between FOXO, TOR,
and Akt. Biochim. Biophys. Acta 1813(11),
1965–1970 (2011).
23 Melnik BC, Schmitz G. Are therapeutic
effects of antiacne agents mediated by
activation of FoxO1 and inhibition of
mTORC1? Exp. Dermatol. 22(7), 502–504
(2013).
•• A viewpoint on acne treatment that shows
for the first time that all anti-acne drugs
have a common mode of action: the
attenuation of mTORC1 signaling.
24 Abali R, Yuksel MA, Aktas C et al.
Decreased ovarian reserve in female
Sprague-Dawley rats induced by isotretinoin
(retinoic acid) exposure. Reprod. Biomed.
Online. 27(2), 184–191 (2013).
Important experimental work
demonstrating that isotretinoin impairs
follicular reserve and thus fertility of
female rats.
25 Melnik BC. Isotretinoin and FoxO1:
A scientific hypothesis. Dermatoendocrinol.
3(3), 141–165 (2011).
Scientific hypothesis suggesting that
isotretinoin up-regulates FoxO expression
and reduces mTORC1 signaling.
26 Fro
¨jdo
¨S, Cozzone D, Vidal H et al.
Resveratrol is a class IA phosphoinositide
3-kinase inhibitor. Biochem. J. 406(3),
511–518 (2007).
27 Melnik BC. Western diet-mediated
mTORC1-signaling in acne, psoriasis,
atopic dermatitis, and related diseases of
civilization: Therapeutic role of
plant-derived natural mTORC1 inhibitors.
In: Bioactive Dietary Factors and Plant
Extracts in Dermatology, Watson RR,
Zibadi S (Eds.). Springer New York
Heidelberg Dordrecht London, chapter 37,
397–419, (2013).
28 Fabbrocini G, Staibano S, De Rosa G et al.
Resveratrol-containing gel for the treatment
of acne vulgaris: a single-blind,
vehicle-controlled, pilot study. Am. J. Clin.
Dermatol. 12(2), 133–141 (2011).
First clinical study that demonstrates
clinical efficacy of reseveratrol in the
treatment of acne.
29 Docherty JJ, McEwen HA, Sweet TJ et al.
Resveratrol inhibition of Propionibacterium
acnes. J. Antimicrob. Chemother. 59(6)
1182–1184 (2007).
30 Coenye T, Brackman G, Rigole P et al.
Eradication of Propionibacterium acnes
biofilms by plant extracts and putative
identification of icariin, resveratrol and
salidroside as active compounds.
Phytomedicine 19(5), 409–412 (2012).
31 Huang CH, Tsai SJ, Wang YJ et al. EGCG
inhibits protein synthesis, lipogenesis, and
cell cycle progression through activation of
AMPK in p53 positive and negative human
hepatoma cells. Mol. Nutr. Food Res. 53(9),
1156–1165 (2009).
32 Elsaie ML, Abdelhamid MF, Elsaaiee LT,
Emam HM. The efficacy of topical 2%
green tea lotion in mild-to-moderate acne
vulgaris. J. Drugs Dermatol. 8(4), 358–364
(2009).
First paper showing beneficial effects of
topical green tea lotion in acne.
33 Mahmood T, Akhtar N, Khan BA et al.
Outcomes of 3% green tea emulsion on
skin sebum production in male volunteers.
Bosn. J. Basic. Med. Sci. 10(3), 260–264
(2010).
34 Im M, Kim SY, Sohn KC et al.
Epigallocatechin-3-gallate suppresses
IGF-I-induced lipogenesis and cytokine
expression in SZ95 sebocytes. J. Invest.
Dermatol. 132(12) 2700–2708 (2012).
•• Important paper which provides evidence
that epigallocatechin-3-gallate suppresses
Akt/mTORC1 signaling in SZ95 sebocytes.
35 Yoon JY, Kwon HH, Min SU et al.
Epigallocatechin-3-gallate improves acne in
humans by modulating intracellular targets
and inhibiting P. acnes. J. Invest. Dermatol.
133(2), 429–440 (2013).
36 Zhou H, Luo Y, Huang S. Updates of
mTOR inhibitors. Anticancer Agents Med.
Chem. 10(7), 571–581 (2010).
37 Feldman ME, Shokat KM. New inhibitors
of the PI3K-Akt-mTOR pathway: insights
into mTOR signaling from a new
generation of Tor kinase domain inhibitors
(TORKinibs). Curr. Top. Microbiol.
Immunol. 347, 241–262 (2010).
38 Liu Q, Kang SA, Thoreen CC et al.
Development of ATP-competitive mTOR
inhibitors. Methods Mol. Biol. 821, 447–460
(2012).
39 Danby FW. Turning acne on/off via
mTORC1. Exp. Dermatol. 22(7), 505–506
(2013).
40 Silverberg NB. Whey protein precipitating
moderate to severe acne flares in 5 teenaged
athlethes. Cutis 90(2), 70–72 (2012).
41 Simonart T. Acne and whey protein
supplementation among bodybuilders.
Dermatology 225(3), 256–258 (2012).
The role of mTORC1 in acne pathogenesis & treatment Perspective
www.expert-reviews.com 621
Expert Review of Dermatology Downloaded from informahealthcare.com by 79.208.113.223 on 01/12/14
For personal use only.
42 Danby FW. Acne, dairy and cancer: the
5alpha-P link. Dermatoendocrinol. 1(1),
12–16 (2009).
Important paper on the potential
acneigenic role of androgen precursors in
commercial milk produced by pregnant
cows.
43 Rubin MG, Kim K, Logan AC. Acne
vulgaris, mental health and omega-3-fatty
acids: a report of cases. Lipids Health Dis 7,
36 (2008).
44 Cordain L. The Dietary Cure for Acne. Paleo
Diet Enterprises, CO, USA (2006).
Perspective Melnik
622 Expert Rev. Dermatol. 8(6), (2013)
Expert Review of Dermatology Downloaded from informahealthcare.com by 79.208.113.223 on 01/12/14
For personal use only.
... 97,98 mTORC1 has recently been recognized to play a major role in diet-induced acne. 47,99,100 FoxO1 activates the transcription of the eukaryotic initiation factor 4 binding protein-1 (4EBP-1), which is a major downstream substrate of mTORC1 and functions as a potent translational inhibitor and growth suppressor. 101,102 Insulin and IGF-1 activate mTORC1, the cell's master regulator orchestrating insulin and IGF-1 signaling, nutrient, glucose, energy, and amino acid availability. ...
Article
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Acne vulgaris, an epidemic inflammatory skin disease of adolescence, is closely related to Western diet. Three major food classes that promote acne are: 1) hyperglycemic carbohydrates, 2) milk and dairy products, 3) saturated fats including trans-fats and deficient ω-3 polyunsaturated fatty acids (PUFAs). Diet-induced insulin/insulin-like growth factor (IGF-1)-signaling is superimposed on elevated IGF-1 levels during puberty, thereby unmasking the impact of aberrant nutrigenomics on sebaceous gland homeostasis. Western diet provides abundant branched-chain amino acids (BCAAs), glutamine, and palmitic acid. Insulin and IGF-1 suppress the activity of the metabolic transcription factor forkhead box O1 (FoxO1). Insulin, IGF-1, BCAAs, glutamine, and palmitate activate the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the key regulator of anabolism and lipogenesis. FoxO1 is a negative coregulator of androgen receptor, peroxisome proliferator-activated receptor-γ (PPARγ), liver X receptor-α, and sterol response element binding protein-1c (SREBP-1c), crucial transcription factors of sebaceous lipogenesis. mTORC1 stimulates the expression of PPARγ and SREBP-1c, promoting sebum production. SREBP-1c upregulates stearoyl-CoA- and Δ6-desaturase, enhancing the proportion of monounsaturated fatty acids in sebum triglycerides. Diet-mediated aberrations in sebum quantity (hyperseborrhea) and composition (dysseborrhea) promote Propionibacterium acnes overgrowth and biofilm formation with overexpression of the virulence factor triglyceride lipase increasing follicular levels of free palmitate and oleate. Free palmitate functions as a "danger signal," stimulating toll-like receptor-2-mediated inflammasome activation with interleukin-1β release, Th17 differentiation, and interleukin-17-mediated keratinocyte proliferation. Oleate stimulates P. acnes adhesion, keratinocyte proliferation, and comedogenesis via interleukin-1α release. Thus, diet-induced metabolomic alterations promote the visible sebofollicular inflammasomopathy acne vulgaris. Nutrition therapy of acne has to increase FoxO1 and to attenuate mTORC1/SREBP-1c signaling. Patients should balance total calorie uptake and restrict refined carbohydrates, milk, dairy protein supplements, saturated fats, and trans-fats. A paleolithic-like diet enriched in vegetables and fish is recommended. Plant-derived mTORC1 inhibitors and ω-3-PUFAs are promising dietary supplements supporting nutrition therapy of acne vulgaris.
... Milk consumption not only enhances adipocyte lipid synthesis but also sebocyte lipid production linking milk consumption to the development of the mTORC1-driven skin disease acne vulgaris [219][220][221][222][223][224][225]. This common and often diet-induced inflammatory skin disease of Western civilization does not exist in populations living under Paleolithic conditions without exposure to milk, dairy and hyperglycemic carbohydrates [226]. ...
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Based on own translational research of the biochemical and hormonal effects of cow's milk consumption in humans, this review presents milk as a signaling system of mammalian evolution that activates the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), the pivotal regulator of translation. Milk, a mammary gland-derived secretory product, is required for species-specific gene-nutrient interactions that promote appropriate growth and development of the newborn mammal. This signaling system is highly conserved and tightly controlled by the lactation genome. Milk is sufficient to activate mTORC1, the crucial regulator of protein, lipid, and nucleotide synthesis orchestrating anabolism, cell growth and proliferation. To fulfill its mTORC1-activating function, milk delivers four key metabolic messengers: (1) essential branched-chain amino acids (BCAAs); (2) glutamine; (3) palmitic acid; and (4) bioactive exosomal microRNAs, which in a synergistical fashion promote mTORC1-dependent translation. In all mammals except Neolithic humans, postnatal activation of mTORC1 by milk intake is restricted to the postnatal lactation period. It is of critical concern that persistent hyperactivation of mTORC1 is associated with aging and the development of age-related disorders such as obesity, type 2 diabetes mellitus, cancer, and neurodegenerative diseases. Persistent mTORC1 activation promotes endoplasmic reticulum (ER) stress and drives an aimless quasi-program, which promotes aging and age-related diseases.
... 16,17 IGF-1 signaling seems to be the major pathway that promotes AV, and it correlates with the clinical course of the disease and the magnitude of sebum production. 23,24 Indeed, patients with Laron syndrome, which is a congenital IGF-1 deficiency caused by a growth hormone receptor mutation, never present with acne unless they are treated. 25 IGF-1 enhances peripheral androgen receptor activation via the nuclear extrusion of FOXO1. ...
Article
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Abstract Objective: Acne vulgaris is a chronic inflammatory disease, and hormonal influences, follicular plugging and follicular hyperkeratinization, increased sebum secretion, Propionibacterium acnes colonization, and inflammation are involved in its pathogenesis. Recently, a significant body of evidence has accumulated that describes the comedolytic properties of vitamin D and its roles as a modulator of the immune system, a regulator of the proliferation and differentiation of sebocytes and keratinocytes, and as an antioxidant. In this study, we aimed to compare serum vitamin D levels in a group of patients with nodulocystic acne with vitamin D levels in a group of control subjects to determine whether there was any relationship between the vitamin D and acne. Methods: Levels of 25-hydroxyvitamin D (25[OH]D) were measured in 43 patients with newly diagnosed nodulocystic acne and in 46 healthy control subjects, and participants were grouped according to their 25[OH]D levels as follows: normal/sufficient (>20 ng/mL) or insufficient/deficient (<20 ng/mL). Serum concentrations of calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and parathyroid hormone (PTH) were measured. Results: Forty-three patients and 46 control individuals, with mean ages of 23.13 (± 5.78) years and 25.23 (± 4.73) years, respectively, were included in this study. There were no significant differences between the groups in relation to their body mass indices and Ca, P, ALP, and PTH levels. However, the patients with nodulocystic acne had significantly lower 25[OH]D levels than the subjects in the control group (P< 0.05). Conclusion: The patients with nodulocystic acne had relatively low serum vitamin D levels compared with the subjects in the control group. The findings from this study suggest that there is a connection between low vitamin D levels and acne. Larger epidemiologic studies are needed to confirm the status of vitamin D levels in patients with acne.
Article
Since the introduction of isotretinoin for the treatment of severe forms acne, it took nearly four decades to understand isotretinoin's mode of action, which is related to the drug's sebum suppressive effect (s1,s2). Isotretinoin-induced sebum reduction depends primarily on sebocyte apoptosis (1,2,s3). Decreased FoxO1 activity in sebocytes of acne patients and increased mechanistic target of rapamycin complex 1 (mTORC1) activity in lesional skin of acne patients promote excessive sebum production and dysseborrhea activating the NLRP3 inflammasome (3-6, s4). This article is protected by copyright. All rights reserved.
Article
In this issue Hellmann-Regen et al. suggested that antiacne effects of erythromycin and tetracyclines may be related to their inhibitory effect of cytochrome P450-mediated degradation of all-trans-retinoic acid (ATRA). We have recently proposed that all antiacne agents function by attenuation of increased mTORC1-signaling. This commentary links the P450-system to mTORC1-regulation in acne. Drug-mediated induction of P450 activity or P450 mutants with increased catabolic activity may reduce cellular ATRA levels and FoxO1 expression, thus reducing FoxO-mediated mTORC1 inhibition. In contrast, agents blocking ATRA degradation like erythromycin and tetracyclines may improve acne by increasing FoxO1 expression with consecutive inhibition of mTORC1-signaling. This article is protected by copyright. All rights reserved.
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Oral isotretinoin (13-cis retinoic acid) is the most effective drug in the treatment of acne and restores all major pathogenetic factors of acne vulgaris. Isotretinoin is regarded as a prodrug which after isomerizisation to all-trans-retinoic acid (ATRA) induces apoptosis in cells cultured from human sebaceous glands, meibomian glands, neuroblastoma cells, hypothalamic cells, hippocampus cells, Dalton´s lymphoma ascites cells, B16F-10 melanoma cells, and neuronal crest cells and others. By means of translational research this paper provides substantial indirect evidence for isotretinoin´s mode of action by upregulation of forkhead box class O (FoxO) transcription factors. FoxOs play a pivotal role in the regulation of androgen receptor transactivation, insulin/insulin like growth factor-1 (IGF-1)-signaling, peroxisome proliferator-activated receptor-γ (PPARγ)- and liver X receptor-α (LXRα)-mediated lipogenesis, β-catenin signaling, cell proliferation, apoptosis, reactive oxygene homeostasis, innate and acquired immunity, stem cell homeostasis, as well as anti-cancer effects. An accumulating body of evidence suggests that the therapeutic, adverse, teratogenic and chemopreventive effecs of isotretinoin are all mediated by upregulation of FoxO-mediated gene transcription. These FoxO-driven transcriptional changes of the second response of retinoic acid receptor (RAR)-mediated signaling counterbalance gene expression of acne due to increased growth factor signaling with downregulated nuclear FoxO proteins. The proposed isotretinoin→ATRA→RAR→FoxO interaction offers intriguing new insights into the mode of isotretinoin action and explains most therapeutic, adverse and teratogenic effects of isotretinoin in the treatment of acne by a common mode of FoxO-mediated transcriptional regulation.
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Acne appears to represent a visible indicator disease of over-activated mTORC1 signalling, an unfavour-able metabolic deviation on the road to serious common Western diseases of civilisation associated with increased body mass index and insulin resistance. Exaggerated mTORC1 signalling by Western diet explains the association of acne with increased body mass index, insulin resistance, and early onset of menarche. Both, a high glycaemic load and increased consumption of milk and milk products, staples of Western diet, aggravate mTORC1 signalling. This review of the literature summarises present evidence for an association between acne, increased body mass index, insulin resistance and Western diet. By dietary intervention with a Palaeolithic-type diet, the dermatologist has the chance to attenuate patients' increased mTORC1 signalling by reducing glycaemic load and milk consumption, which may not only improve acne but may delay the march to more serious mTORC1-driven diseases of civilisation.
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Milk has been recognized to represent a functionally active nutrient system promoting neonatal growth of mammals. Cell growth is regulated by the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1). There is still a lack of information on the mechanisms of mTORC1 up-regulation by milk consumption. This review presents milk as a materno-neonatal relay system functioning by transfer of preferential amino acids, which increase plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), insulin, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) for mTORC1 activation. Importantly, milk exosomes, which regularly contain microRNA-21, most likely represent a genetic transfection system enhancing mTORC1-driven metabolic processes. Whereas human breast milk is the ideal food for infants allowing appropriate postnatal growth and species-specific metabolic programming, persistent high milk signaling during adolescence and adulthood by continued cow s milk consumption may promote mTORC1-driven diseases of civilization.
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Over the past 10 years, the increase in comprehension of the mechanisms behind acne has been truly exponential. Starting with the ethnological work of Cordain, accelerated by the epidemiological work of Adebamowo, supported by the clinical trials of Smith and Mann, Kwon, DiLandro and others, the interface of diet and acne is coming into focus. Melnik now presents an exceptional pair of papers that illustrate for dermatologists what translational research is all about. The Western diet, the role of dairy, FoxO1 and mTORC1, the interplay of agonists and antagonists, therapeutics present and future - the jigsaw puzzle is coming together.
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Acne pathogenesis has recently been linked to decreased nuclear FoxO1 levels and increased mTORC1 activity. This hypothesis postulates that antiacne agents either enhance nuclear FoxO activity or inhibit mTORC1. Benzoyl peroxide (BPO), by activation of oxidative stress-inducible kinases, increases nuclear FoxO levels promoting Sestrin3-mediated AMPK activation. Furthermore, BPO-derived ROS may activate AMPK via ataxia-telangiectasia mutated. Isotretinoin and all-trans retinoic acid may stimulate FoxO gene expression. Doxycycline may enhance FoxOs nuclear retention by inhibiting the expression of exportin 1. Suppression of TNFα signalling by tetracyclines, erythromycin and other macrolides may attenuate IKKβ-TSC1-mediated mTORC1 activation. Erythromycin attenuates ERK1/2 activity and thereby increases TSC2. Azelaic acid may decrease mTORC1 by inhibiting mitochondrial respiration, increasing cellular ROS and nuclear FoxO levels. Antiandrogens may attenuate mTORC1 by suppressing mTORC2-mediated Akt/TSC2 signalling. This hypothesis unmasks a common mode of action of antiacne agents as either FoxO enhancers or mTORC1 inhibitors and thus provides a rational approach for the development of new antiacne agents.
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Signaling mediated by the mechanistic target of rapamycin (mTOR) is believed to play a critical and positive role in adipogenesis, based on pharmacological evidence and genetic manipulation of mTOR regulators and targets. However, there is no direct genetic evidence for an autonomous role of mTOR itself in preadipocyte differentiation. To seek such evidence, we have employed a conditional knockdown approach to deplete mTOR in preadipocytes. Surprisingly, while knockdown of S6K1, a target of mTOR, impairs 3T3-L1 preadipocyte differentiation, reduction of mTOR levels leads to increased differentiation. This enhanced adipogenesis requires the remaining mTOR activity, as mTOR inhibitors abolish differentiation in the mTOR knockdown cells. We also find that mTOR knockdown elevates the levels of C/EBPα and PPARγ. Furthermore, partial reduction of mTOR levels alleviates inhibition of Akt by mTORC1 via IRS1, while at the same time maintaining its positive input through mTORC1 into the adipogenic program. The greater sensitivity of the IRS1-Akt pathway to mTOR levels provides a mechanism that explains the net outcome of enhanced adipogenesis through PPARγ upon mTOR knockdown. Our observations reveal an unexpected role of mTOR in suppressing adipogenesis, and suggest that mTOR governs the homeostasis of the adipogenic process by modulating multiple signaling pathways.
Article
... Moreover, by promoting Akt-mediated glucose uptake, mTORC2 fuels the metabolism of cancer cells. ... loops to counteract the action of rapamycin, dampening its effectiveness in cancer models and ... of rapamycin or its prolonged delivery can block mTORC2 in some cell lines 20 ...
Article
A potent link to dairy seems to exist for three hormone-responsive glands. Acne, breast cancer and prostate cancer have all been linked epidemiologically to dairy intake. Although mechanisms postulated here remain to be accurately defined, the likely link involves Insulin-like Growth Factor-1 as a general stimulant, synergized by the steroid hormones present in milk. The IGF-1 may be either absorbed from milk, or stimulated by its ingestion, or both. The 5α-reduced compound 5α-pregnanedione (5alpha-P) present in milk is a direct precursor of dihydrotestosterone and may act through that pathway in prostate cancer, but 5alpha-P has also recently been shown to be capable of inducing estrogen receptors in breast cancer cells, up-regulating cancer cells' sensitivity to estrogen. The introduction of exogenous hormones and growth factors into tissues that have not evolved defensive feedback inhibition of their corresponding endogenous sources is postulated as a direct stimulatory threat to these organ systems, whether for hyperplasia or neoplasia
Article
Isotretinoin is a retinoid widely used for the treatment of severe nodulocystic acne. Although it has broad side effects, there is no well-designed study about its effects on the ovary. This study investigated possible toxic effects of isotretinoin on female gonads. A total of 30 female rats were randomly divided into three equal groups according to the dose of isotretinoin they were administered: 0 mg/kg/day (group 1), 7.5 mg/kg/day (group 2) or 15 mg/kg/day (group 3). Thirty days after the treatment, the effects of isotretinoin on the ovaries were evaluated with serum anti-Mullerian hormone (AMH) concentrations, apoptosis by TUNEL assay and immunohistochemical observations by proliferating cell nuclear antigen (PCNA). The percentage of atretic follicles was calculated for each stage of folliculogenesis. The serum AMH concentrations were found to be lower in both isotretinoin groups. The percentage of atretic follicles in both isotretinoin groups was higher than the control. The number of PCNA-positive granulosa cells was decreased in the isotretinoin groups. The number of ovarian follicles with apoptotic granulosa cells was increased in the experimental groups. These data are the first to identify that exposure of isotretinoin may be responsible for decreased ovarian reserve and toxic effects on rat ovaries. RBMOnline Crown Copyright