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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 [4–8]. 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 [9–11],
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 [14–16],
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 cell’s 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 [5–7] 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
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