Dietary intervention in acne

13 Pages·2012·1.53 MB·English

Dermato-Endocrinology4:1,20–32;January/February/March2012;G2012LandesBioscience
Dietary intervention in acne
Attenuation of increased mTORC1 signaling promoted
by Western diet
Bodo C. Melnik
DepartmentofDermatology,EnvironmentalMedicineandHealthTheory;UniversityofOsnabrück;Osnabrück,German.y
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Keywords: acne, androgen, FoxO, IGF-1, insulin, leucine, mTORC1, nutrition, preventiocn, Western diet
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Abbreviations:Akt,Aktkinase(proteinkinaseB);AMP,adenosinemonophosphate;AMPeK,AMP-activatedproteinkinase;
ATP,adenosinetriphosphate;ATRA,all-trans-retinoicacid;BCAA,branched-chainaminoaciid;BCAT2,branched-chainaminotransferase-
c
2;BPO,benzoylperoxide;2DG,2-desoxyglucose;EGCG,epigallocatechin-3-gallate;FoxO,forkheadboxclassOtranscriptionfactor;
s
DHT,dihydrotestosterone;4E-BP,eukaryoticinitiationfactor(eIF)4E-bindingprotein;GH,growthhormone;GHR,growthhormone
o
receptor;GIP,glucose-dependentinsulinotropicpolypeptide;GLUT,glucosetransporterprotein;GR,glucocorticoidreceptor;
i
GDP,guanosinediphosphate;GTP,guanosinetriphosphate;IGF,insuBlin-likegrowthfactor;IGF1R,IGF-1receptor;IKK,inhibitorof
kappalightchaingeneenhancerinBcells;JNK,JunN-terminuskinase;IL,interleukin;IRS,insulinrec.eptorsubstrate;KLF,Krüppel-like
s e
factor;LAT,L-typeaminoacidtransporter;LKB,liverkinaseB;mTOR,mammaliantargetofrapamycin;MST1,STE20-likeproteinkinase
1;NALA,N-acetylleucineamide;NFkB,nuclearfactorekappaB;PCOS,polycysticovaryusyntdrome;PI3K,phosphoinositol-3kinase;
d
Rag,Ras-relatedGTP-bindingprotein;Raptor,regulatoryassociatedproteinofmTObR;REDD1,regulatedindevelopmentandDNA
damageresponses;Rheb,Rashomologenrichedninbrain;Rictor,rapamycin-insensitivecompanionofmTOR;RSK,ribosomalS6kinase;
i
S6K,p70S6kinase;SREBP,steroalregulatoryelement-bindingproteinr;TCR,Tcellreceptor;TNF,tumornecrosisfactor;
t
TOR,targetofLrapamycin;TSC,tuberoussclerossiscomplex;TSC1,hamartin;TSC2,tuberin

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Thepurposeofthispaperistohighlighttheendocrinetsignaling diabetes, cancer and neurodegenerative diseases. These new
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ofWesterndiet,afundamentalenvironmentalfactoorinvolvedin insights into Western diet-mediated mTORC1-hyperactivity
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the pathogenesis of epidemic acne. Wesntern nutrition is provide a rational basis for dietary intervention in acne by
©chara cterized by high calorieuptake,ohi gh glycemic load, high attenuating mTORC1 signaling by reducing (1) total energy
fatandmeatintake,aswellasincreasedconsumptionofinsulin- intake,(2)hyperglycemiccarbohydrates,(3)insulinotropicdairy
and IGF-1-level elevating dairyD proteins. Metabolic signals of proteins and (4) leucine-rich meat and dairy proteins. The
Western diet are sensed by the nutrient-sensitive kinase, necessary dietary changes are opposed to the evolution of
mammalian target of rapamycin complex 1 (mTORC1), which industrialized food and fast food distribution of Westernized
integrates signals of cellular energy, growth factors (insulin, countries.AnattenuationofmTORC1signalingisonlypossible
IGF-1) and protein-derived signals, predominantly leucine, byincreasingtheconsumptionofvegetablesandfruit,themajor
providedinhighamountsbymilkproteinsandmeat.mTORC1 components of vegan or Paleolithic diets. The dermatologist
activates SREBP, the master transcription factor of lipogenesis. bears a tremendous responsibility for his young acne patients
Leucine stimulates mTORC1-SREBP signaling and leucine is whoshouldbeadvisedtomodifytheirdietaryhabitsinorderto
directlyconvertedbysebocytesinto fatty acidsandsterolsfor reduceactivatingstimuliofmTORC1,notonlytoimproveacne
sebaceous lipid synthesis. Over-activated mTORC1 increases but to prevent the harmful and expensive march to other
androgen hormone secretion and most likely amplifies mTORC1-relatedchronicdiseaseslaterinlife.
androgen-driven mTORC1 signaling of sebaceous follicles.
Testosterone directly activates mTORC1. Future research
should investigate the effects of isotretinoin on sebocyte
mTORC1 activity. It is conceivable that isotretinoin may Introduction
downregulate mTORC1 in sebocytes by upregulation of
nuclear levels of FoxO1. The role of Western diet in acne can Acne is an epidemic skin disease of industrialized countries,
onlybefullyappreciatedwhenallstimulatoryinputsformaximal reachingprevalenceratesofover85%ofteenagers.1IntheUnited
mTORC1 activation, i.e., glucose, insulin, IGF-1 and leucine, are
States, acne nowadays persists after adolescence into the third
adequatelyconsidered.Epidemicacnehastoberecognizedas
decade of life in nearly half of men and women.2 This demon-
an mTORC1-driven disease of civilization like obesity, type 2
strates that the environmental acne-promoting mechanisms
persist after puberty and are independent of endocrine signaling
of puberty. Acne has been clearly identified as a disease of
Correspondenceto:BodoC.Melnik;Email:[email protected]
Western civilization and has been closely linked to Western
Submitted:10/30/11;Revised:12/20/11;Accepted:02/20/12
http://dx.doi.org/10.4161/derm.19828 diet.3 Intriguingly, acne is absent in populations consuming a
20 Dermato-Endocrinology Volume4Issue1
REVIEW
Paleolithic diet excluding sugar, grains and dairy protein like the protein of approximately 300 kDa exhibiting a protein kinase
diet of the Kitava islanders who exhibit low basal insulin levels domain at its C-terminus related to phosphoinositol-3-kinases
compared with age-matched Europeans and do not suffer from (PI3K). In mammalian cells two functionally different mTOR
epidemic diseases of civilization.3,4 Remarkably, a randomized complexes exist: mTORC1 and mTORC2. Among other
placebo-controlled Australian trial confirmed that a reduction of functional proteins, mTORC1 contains the important partner
glycemicloadimprovedtheclinicalsymptomsofacne,therateof protein Raptor, which interacts with substrates for mTORC1-
sebumexcretionandfreeandrogenindexinmaleacnepatientsin mediated phosphorylation. mTORC1 controls the G /S trans-
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the age range of 15–25 y.5-8 ition and G /M progression of the cell cycle.24 In contrast to
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EpidemiologicdataderivedfromtheNursesHealthStudyIIand mTORC2, which contains the partner protein Rictor, only
the Growing Up Today Study in the United States provided mTORC1playsaspecialroleinsensingcel.lularnutrients,amino
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epidemiological evidence for a correlation between milk, and acid and energy (ATP) levels important for cell growth and
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especiallyskimmilkconsumption,andtheprevalenceofacne.9-11 proliferation.LiverkinaseB1(LKB1)andAMP-activatedprotein
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Moreover, positive associations between acne and the consump- kinase (AMPK) are critical regulators of mTORC1.28 Most
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tion of other dairy products like instant breakfast drink, sherbet, functions of mTORC1 are inhibited by rapamycin, a triene
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cream cheese and cottage cheese have been reported.9 The macrolide antibiotcic synthesized by Streptomyces hygroscopicus.27
associationbetweenacneandfoodcompositionhasrecentlybeen mTORC1shastoberegardedasapivotalconvergencepointin
confirmed in 783 patients with acne and 502 control subjects in cell signaoling, because it integrates many intra- and extracellular
South Korea.12 The frequency of vegetables and fish intake was signials such as growth factors (insulin, IGF-1), energy-sensing
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significantly higher in the control group than in the acne group. signals (glucose, the AMP/ATP-ratio regulating AMPK), and
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Intake of instant noodles, junk food, carbonated drinks, snasck s, most importantly the availabeility of sufficient amounts of amino
processed cheeses, pork, chicken, nuts and seaweeed were acids, especially the brantched-chain essential amino acid (BCAA)
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significantly higher in acne patients than in thde controls.12 leucine for mTORC1 activation (Fig.1).29
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Thus, the food pattern of Western diet cnomposed of high Recent advances in molecular biology have elucidated two
glycemic load, high fat intake, and high dairy and meat parallel miechanisms of mTORC1 activation: (1) the upstream
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consumption played an important role in the exacerbation of activtation of the small GTPase Rheb (Ras homolog enriched in
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acne in South Korea. Nearly half of the male and female acne brain)bygrowthfactorsignalsandhighcellularenergylevelsand

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patients reported that food intake was an aggravating factord of (2)theaminoacid-dependenttranslocationofinactivemTORC1
their acne. Remarkably1, in the group of food-aggrava ted acne to active Rheb localized at late endosome or lysosome compart-
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patients, serum 0IGF-1 levels (543.9 ± 56.4 ng/mL) were ments.30-32 The activity of Rheb is tightly regulated by the
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significantly2higher than IGF-1 levels (391.3 ± 118.2 ng/mL) in tuberoussclerosisproteinsTSC1(hamartin)andTSC2(tuberin),
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theacn egroupnotreportingaggravationbyfood.12Accumulating which form a functional heterodimeric complex. Intriguingly,
ev©idence derived from epidemiologioc and controlled dietary loss-of-functionmutationsofeithertheTSC1orTSC2genecause
studies allows the conclusion thDat especially high glycemic load the hamartoma syndrome tuberous sclerosis complex. TSC1
diets and increased consumption of dairy proteins are the major stabilizes TSC2, that possesses a GTPase-activating protein,
dietary factors of Western diet promoting the development or which hydrolyses GTP to GDP. The TSC1/TSC2 complex
exacerbation of acne.13-20 Although there is overwhelming provides this function to Rheb leading to inactivation of Rheb.
evidence for the role of diet in acne, the role of food in acne is Insulin and IGF-1, which both activate the kinase Akt (protein
stillacontroversialissue.21Themajorproblemofthisuncertainty kinaseB)aswellasothergrowth-relatedkinasessuchasERKand
is the lack of knowledge on signaling pathways mediated by RSKphosphorylate TSC2, thereby inhibiting the function of the
nutrients. This paper will help to elucidate major pathways of TSC1/TSC2complex.ThisinhibitionleadstoactivationofRheb
nutrientsignalingofWesterndietinvolvedinthepathogenesisof with final activation of mTORC1.33-35
acneandhighlightsthecentralroleofthenutrient-sensitivekinase Besides the important input of growth factor signaling on
mammalian target of rapamycin complex 1 (mTORC1) in mTORC1 activation, AMPK, an essential energy sensor, plays a
mediating the effects of nutrient-derived signals in the develop- keyroleinenergy-dependentmTORC1regulation.Duringstates
ment of acne. ofenergy-deficientconditionslikeglucosedeprivation,ATPlevels
fall and AMP levels rise, resulting in AMPK activation. AMPK
mTORC1 Senses and Integrates Nutrient-Derived phosphorylatesTSC2andRaptor,therebysuppressingmTORC1
Signals activity.36,37 Abundant cellular energy provided by hypercaloric
WesterndietwithhighglycemicloadthusreducesAMPKactivity
Recent discoveries in the field of molecular biology have and stimulates mTORC1 signaling.
established the key role of the nutrient-sensitive mammalian
target of rapamycin complex 1 (mTORC1) kinase in cell FoxO Proteins: Rheostats Tuning mTORC1 Activity
regulation and cell function. mTORC1 signaling stimulates gene
transcription, translation, ribosome biogenesis, protein synthesis, Acne pathogenesis has recently been linked to increased insulin/
cell growth, cell proliferation and lipid synthesis but suppresses IGF-1 signaling leading to decreased nuclear levels of FoxO
the mechanisms of autophagy.22-27 mTOR is a multi-domain transcription factors which are extruded into the cytoplasm
www.landesbioscience.com Dermato-Endocrinology 21
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Figure1.mTORC1signalingofWesterndietinacne:Leucine,IGF-1,insulinandgtlucosesynergisticallyactivatemTORC1.LeucineactivatesmTORC1
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bytranslocationofinactivemTORC1toRheb-enrichedmembranecompartmesnts.Highglucoseintakeincreasesinsulinsignalingandelevatescellular

ATPlevelsresultinginAMPKsup2pression.mTORC1activatesproteinsynthiesisviaS6K1and4EBP1andphosphorylateslipin1,inducingSREBP-mediated
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lipogenesis.DHTincreasescellularleucineuptakeanddirectlyactivatesmTORC1.
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by growth2-factor-activated PI3K/Akt-signaling.38,39
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Although experimental direct evidence is still lacking,

in©direct evidence from various cell soys tems supports
the concept that isotretinoin inDcreases nuclear levels
of FoxO1, which explains the therapeutic mechanism
and the adverse effects of isotretinoin treatment.40
There is convincing evidence that other important
nutrient- and growth factor-sensors, especially the
FoxOtranscriptionfactors,modulatemTORC1signal-
ing (Fig.2).41 Increased insulin/IGF-1 signaling and
activation of the PI3K/Akt-pathway results in Akt-
mediated nuclear phosphorylation of FoxO proteins,
thereby promoting their extrusion from the nucleus
into the cytoplasm. This FoxO shuttling mechanism
functions as a molecular switch for FoxO-mediated
gene regulation. Like mTORC1, FoxOs are involved
in the regulation of cell proliferation, apoptosis, anti-
oxidative stress responses and regulation of metabo-
lism.42 Intriguingly, FoxOs have emerged as important
rheostats that coordinate the activity of Akt and
mTORC1.41 Activated FoxOs (FoxO1 and FoxO3, Figure2.AttenuationofmTORC1activitybydietaryintervention.Reduction
ofanimalprotein(leucine),hyperglycemiccarbohydrates(glucose)anddairy
FoxO4) induce the expression of Sestrin3, which
proteins(insulin/IGF-1)mitigatesmTORC1signaling.IsotretinoininhibitsmTORC1
activates AMPK to inhibit mTORC1 in a TSC2-
byupregulationofFoxO-Sestrin3,whichstimulatesAMPK.Benzoylperoxide(BPO)
dependent manner.43 Moreover, AMPK has been upregulatesFoxO-Sestrin3-stimulatedAMPK,therebyinhibitingmTORC1.Metformin
shown to phosphorylate FoxO3 and facilitate its inhibitsmTORC1activitybyantagonizingleucinesignalingandbystimulatingAMPK
nuclear localization.44 It has been demonstrated that activity.Plant-derivedmTORC1inhibitorsdirectlydownregulatemTORC1
(Abbreviationsseetext).
Akt-phosphorylated cytoplasmic FoxO1 is able to
22 Dermato-Endocrinology Volume4Issue1
associate with the C terminus of TSC2 thereby dissociating Testosterone-mediated mTORC1-S6K1- IRS-1 signaling pro-
the TSC1/TSC2 complex leading to activation of mTORC1.45 vides a most critical mechanism for the induction of insulin
From theses data it becomes apparent that FoxOs intimately resistance.50 On the other hand, metformin treatment of patients
interact with mTORC1 and control mTORC1 signaling. with PCOS reduces androgen levels and improves insulin
Remarkably, in response to amino acid depletion, mTORC1 resistance. Remarkably, metformin inhibits mTORC1 activity
activity is rapidly abolished.46 Amino acid starvation impairs by antagonizing leucine-mediated mTORC1 activation as well as
binding of mTORC1 to Rheb.47 From all essential amino acids, AMPK-mediated suppression of mTORC1 activity.52,53 The
leucine exerts the greatest effects on mTORC1 signaling.24,27,46 androgen-mTORC1-S6K1 pathway explains the development of
Recentevidencehasbeenprovidedthataminoacidsandespecially insulin resistance in various syndromes associated with acne and
leucine promote the cellular translocation of inactive mTORC1 insulin resistance.54 .
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to lysosomal compartments enriched in activated Rheb.30,31 This In the prostate of mice PI3K levels and mTORC1 activity are
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spatial regulation of inactive mTORC1 by amino acids is robustly induced by androgens during prostatic development.
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mediatedbyanactiveRagheterodimerandisofutmostbiological PI3K/mTORC1 signaling is necessary for prostatic epithelial
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importance as it explains the complete mechanism of nutrient bud invasion of surrounding mesenchyme.55 The right balance
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sensing of mTORC1. Thus, mTORC1 integrates not only of PI3K and dowcnstream mTORC1/mTORC2 activity plays a
growthfactor/energy-derivedsignalstoRheb,butrequiresparallel criticalroleinstheregulationofprostaticepithelialmorphogenesis.
signaling of leucine for final mTORC1 activation by transloca- Future stoudies in humans should clarify the role of androgen-
tion of inactive mTORC1 to cell compartments enriched in mTiORC1-mediated effects on sebaceous gland morphogenesis
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activated Rheb (Fig.1). These two synergistic major pathways of and differentiation.
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mTORC1 activation explain why either insulin/IGF-1 signaslin g e
or amino acid signaling alone is not sufficient to reachemaximal Androgen- tand mTORC1-Dependent
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mTORC1activation.InsulinisnotabletoactivatetdhemTORC1 Amino Acid Uptake
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pathway when cells are deprived of amino acinds.48 Infact, recent
experimental evidence confirmed that both insulin- and amino High intakie of BCAAs provided by high dairy protein and meat
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acid-signaling are required for maximal mTORC1 activity in rat constumption may be another important mechanism stimulating
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liver.49 sebaceous lipogenesis. Increased levels of amino acids derived

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Activated mTORC1 finally phosphorylates important sdub- from meat hydrolysis as well as dairy protein consumption are
strates involved in the 1regulation of the translational ma chinery, knowntoincreaseserumlevelsofIGF-1.56-59IGF-1stimulatesthe
theS6kinases(S60Ks),whichphosphorylateribosomaltproteinS6, activity of 5a-reductase, which converts testosterone to the more
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and eukaryo2tic initiation factor (eIF) 4E-binding proteins (4E- potent dihydrotestosterone (DHT).60 DHT has recently been
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BPs), w hich control the activity of the translation factor eIF-4E shown to stimulate increased uptake of BCAAs in an mTORC1-
th©at binds to the 5'-cap structure of eouk aryotic mRNAs, thereby dependent process, which could be inhibited by pre-treatment of
facilitating ribosome recruitmentD. Intriguingly, the downstream muscle cells with the mTORC1 inhibitor rapamycin.61 It is thus
target of mTORC1, S6K1, phosphorylates insulin receptor conceivable that DHT promotes BCAA-uptake by sebaceous
substrate protein-1 (IRS-1), mediating an important feed back glands, a process that delivers leucine as an important precursor
mechanism, which downregulates insulin/IGF-1 signaling. This for sebaceous lipogenesis. In this regard it is of special concern
is a most important mechanism of insulin resistance, a charac- that male adolescents in the fitness and bodybuilding environ-
teristic feature of puberty, obesity, type 2 diabetes and states of ment consume high amounts (60–80 g/d) of leucine-rich whey-
hyperandrogenism.50 or casein-based protein concentrates to gain muscle mass, a
procedurewhichisoftenassociatedwiththedevelopmentofacne
The Link Between Androgen- and mTORC1-Signaling (Table 1).62,63 Experimental studies are necessary to investigate
the possible role of DHT for leucine uptake of sebaceous glands.
We are at the very beginning to understand the important Combined androgen abuse with high dairy protein intake may
molecular crosstalk between androgens and the mTORC1 operateinasynergisticfashionincreasingsebaceousglandgrowth
pathway.Anaboliceffectsoftestosteronecertainlyincreaseprotein
synthesis. The mTORC1 pathway is the major regulator of
Table1.Leucine-richproteins(ref.106)
protein synthesis and cell growth, but the relationship between
testosterone action and mTORC1 has not yet been characterized Proteinsource Leucinecontent
(g/100gprotein)
in sebaceous glands. Nevertheless, it has been shown in cultured
cardiomyocytes that testosterone induced hypertrophic effects via Wheyproteinconcentrate 14%
mTORC1 signaling. Testosterone increased the phosphorylation Cowmilkprotein(mostlycasein) 10%
ofmTORanditsdownstreamtargetsS6K1and4E-BP1.51S6K1- Eggprotein 8.5%
phosphorylation induced by testosterone was blocked by the
Muscleprotein 8%
mTORC1 antagonist rapamycin. This observation is of great
Soyproteinisolate 8%
importance for the understanding of insulin resistance in states
Wheatprotein 7%
of hyperandrogenism like polycystic ovary syndrome (PCOS).
www.landesbioscience.com Dermato-Endocrinology 23
and proliferation. Both increased mTORC1-dependent leucine mTORC1 phosphorylates lipin1, which is retained in the cyto-
uptake for leucine-dependent lipid synthesis as well as androgen- plasm and allows promotor binding of SREBP in the nucleus
and leucine-stimulated mTORC1-activation may stimulate (Fig.3). However, in the absence of nutrients and amino acids
sebocyte growth, proliferation and SREBP-mediated lipid syn- mTORC1 activity is suppressed. Lipin 1 enters the nucleus and
thesis. Thus, increased consumption of leucine-rich proteins displaces SREBP from its promoter sites of lipid synthesizing
provided by Western diet appears as a new dietary factor target genes. SREBP migrates than to the nuclear lamina.72
promoting sebaceous lipogenesis. Glucose and amino acid deprivation, which inhibits mTORC1
activity, promoted nuclear accumulation of lipin 1 and thus
The Link Between mTORC1 and Comedogenesis suppressed SREBP signaling. On the other hand, cytoplasmatic
retention of lipin 1 with increased SREBP.activity was positively
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Comedogenesis is regarded as the primary process in the promoted by activated mTORC1, which is stimulated by
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pathogenesis of acne and is induced by increased proliferation availability of glucose, insulin, IGF-1 and amino acids, especially
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and retention of acroinfundibular androgen-dependent keratino- leucine (Fig.3).72 These new insights clearly underline the rela-
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cytes.64 Recently, the PI3K/Akt/mTORC1 pathway has been tionship between nutrient- and amino acid-mediated mTORC1
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shown to stimulate keratinocyte proliferation.65 In keratinocyte signaling and SRcEBP-induced lipogenesis which most likely
cultures of high cell density, which imitate states of hyperproli- applies to sebsaceous gland lipogenesis.
feration, isotretinoin decreased keratinocyte proliferation.66 This o
findingcannowbewellexplainedbyFoxO1-mediatedinhibition i Leucine: Precursor of Sebaceous Lipids
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of mTORC1.45 Further evidence points to the role of mTORC1
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signalingforkeratinocyteproliferationbecausegeneticexcisiosn of The Western diet, enriched ien meat and dairy proteins, provides
TSC1 activated mTORC1 signaling in keratinocytes.65eLoss-of- high and persitantly inctreasing amounts of leucine. From 1950
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function of either the TSC1 (harmatin) or TSC2 (tduberin) gene, to 2010, the annual per capita intake of leucine by consumption
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upstream inhibitory regulators of mTORC1,nleads to persistent of animal-derived proteins has triplicated in Germany. Leucine
activation of mTORC1 resulting in the hamartoma syndrome not only icontributes to the synthesis of muscle proteins but
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tuberosus sclerosis complex.67 Intriguingly, folliculocystic and mosttimportantly can be converted into lipids (fatty acids and
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collagen hamartoma of tuberous sclerosis complex with multiple cholesterol) and stored in adipose tissue.73 Adipose tissue

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comedones and keratin-containing cysts lined by infundibudlar efficiently converts BCAAs carbon skeletons into newly synthe-
epitheliumhaverecently1 beendescribed.68Thesefindings support sized fatty acids, a process that is stimulated by insulin.73
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the view that incr0eased mTORC1 signaling of acroinfundibular Remarkably, sebaceous glands like adipocytes are able to take
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keratinocytes2 may be involved in comedogenesis. up and convert leucine into their major sebum lipid classes.74,75
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In this regard, the leucine-enriched Western diet may have two
©mTORC1: Central Activator ofo L ipogenesis
D
Although mTORC1 mediates central pathways in cell
metabolism of all mammalian cells, studies investigating
mTORC1 signaling in sebocytes are not yet available.
However, by means of translational research important
deductionsforsebocytebiologycanbedrawn.mTORC1
is a crucial regulatory node controlling protein biosyn-
thesis and cell growth and proliferation. However, cell
growthnotonlyaffordsthesynthesisofnewproteinsbut
also requires substantial amounts of lipids for the
maintenance of membrane compartments absolutely
necessary for appropriate cell function. It is thus not
surprising that mTORC1 signaling has been linked to
lipid biosynthesis.69 The key master transcription factor
of most lipid synthesizing enzymes for fatty acid and
sterol biosynthesis is the transcription factor SREBP
(sterol regulatory element-binding factor). The SREBP
family is comprised of three isoforms: SREBP-1a,
SREBP-1c, and SREBP-2. Previous work shows that
mTORC1 positively regulates the activity of SREBP- Figure3.(A)mTORC1-SREBP-mediatedlipogenesis.ActivatedmTORC1phos-
1.70,71 It has most recently been demonstrated that phorylateslipin1,whichresidesinthecytoplasmandallowsnuclearSREBPbinding
mTORC1 regulates SREBP by controlling the nuclear tolipogenictargetgenesresultinginincreasedlipogenesis.(B)Inactivation
ofmTORC1resultsinnuclearentryoflipin1,whichdisruptsSREBPbindingto
entry of lipin 1, a phosphatidic acid phosphatase.
targetgenes,thussuppressinglipogenesis(modifiedaccordingtoPetersonetal.72
Nutrient-activated, and especially amino acid-activated,
24 Dermato-Endocrinology Volume4Issue1
major effects on sebaceous lipogenesis: (1) to increase leucine- The Role of Leucine in T Cell Activation
stimulated mTORC1/SREBP signaling thus driving the genetic
program of sebogenesis and (2) to provide leucine as a structural While research of the last decades has primarily focused on the
lipid precursor for de novo sebaceous lipid synthesis. roleofcytokineandhormonalsignalsinguidingTcellresponses,
the fundamental aspect of cellular energy metabolism and
Western Diet and mTORC1-Stimulated T Cell Activity nutrients that regulate T cell function and differentiation has
been neglected.85 Most recently, the pivotal role of mTORC1 in
T cell infiltrates are found in early acne lesions, which are T cell metabolism affecting T cell function and differentiation
associated with increased synthesis of interleukin-1a of acne- has been appreciated.78 The metabolic demands of T cells are
prone sebaceous follicles.76 Thus, the question arises whether extraordinarily high and an increase in T.cell metabolism has
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Western diet-mediated mTORC1-overactivity affects T-cell been recognized as a pivotal contribution to T cell activation.86,87
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homeostasis and the regulation of inflammatory immune The transcription factors KLF2 and FoxO have been implicated
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responses in acne. In fact, mTORC1 signaling has recently been in regulating T cell metabolism.78 Whereas quiescent T cells are
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appreciated toplay a fundamental role in the regulation of T-cell in a resting state of metabolism characterized by catabolism
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homeostasis and mTORC1 has been linked to T-cell differentia- driven by autophcagy, activated T cells have high demands for
tion, function and metabolism.77 mTORC1 integrates signals in adequate amosunts of the essential components for protein,
the immune microenvironment and programs the generation of amino acoids, lipid, and DNA biosynthesis involving mTORC1
CD4+ effector vs. regulatory T cells, the generation of CD8+ funcition.
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effector vs. memory cells, T cell trafficking, and T cell activation Leucine plays a fundamental role in T cell activation and
.
vs.anergy.Thus,mTORC1providesadirectlinkbetweenTsce ll function.88 Notably, the eleucine-antagonist N-acetylleucine
metabolism and T cell function.78 Remarkably, thee tumor amide (NALA) inhibitetd T cell function and T cell receptor
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suppressor TSC1 established a quiescence progrdam in naive (TCR)engagementinthepresenceofNALAandpromotedTcell
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T cells by controlling cell size, cell cycle entrny and responses to anergy.89,90 NALA inhibited leucine-induced S6K phosphoryla-
stimulation oftheTcellantigenreceptor. TSC1-deficient Tcells tion andiwas capable of inhibiting amino acid-mTORC1
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exhibited higher mTORC1 activity, which was essential for the signatlinginJurkatcells,causedcellcyclearrestatG concomitant
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disruptionofimmunehomeostasis.79TSC1-dependentcontrolof with the inhibition of S6K activation and inhibition of p27

mTORC1 is crucial in activ2ely maintaining quiescence of nadiveidegradation.89 In as much as a lack of leucine inhibits mTORC1
T cells to facilitate1 adaptive immune functions.7 9 Thus, activation,theselatterfindingsareconsistentwiththeobservation
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stimulation of T0cell mTORC1 activity by exaggerated insulin/ that TCR engagement during rapamycin-mediated mTORC1
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IGF-1 and l2eucine signaling of Western diet may disturb T-cell inhibition promoted anergy.91 Similarly, the glucose analog
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homeo stasis and promote deviations in T cell signaling involved 2-deoxyglucose (2DG) inhibited mTORC1 function most likely
in©the pathogenesis of acne. o via the AMPK pathway and promoted T cell anergy.92
D Furthermore, the AMPK activator AICAR inhibited mTORC1
mTORC1-Mediated Pro-inflammatory Signaling and T cell function and mitigated experimental autoimmune
of Keratinocytes encephalomyelitis.78 Intriguingly, regulatory T cells can inhibit
T cell function by expressing amino acid degrading enzymes that
AugmentedmTORC1signalingnotonlyactivatesTcellsbutalso deplete the environment of essential amino acids, which are
appears to be involved in pro-inflammatory signaling of important for mTORC1 function.93
keratinocytes. In primary human keratinocytes treated with These observations clearly demonstrate that hyperalimentation
TNFa, mTORC1 activated pro-inflammatory NFkB signaling, and especially increased consumption of leucine-rich animal
whereas the mTORC1 inhibitor rapamycin inhibited TNFa- proteins,predominatelymilkproteinsandmeat,drivemTORC1-
induced IkB degradation, thus reducing the transcriptional mediated mechanisms of T cell activation and inflammation
activity of NFkB.80 In primary human keratinocytes, TNFa- which may all promote the development of acne.
mediated activation of mTORC1 and pro-inflammatory NFkB
signaling resulted in increased transcription of pro-inflammatory Glucocorticoids Inhibit mTORC1 Signaling
cytokines TNFa, IL-6, IL-8 IL-17, IL-20, IL-22 and IL-23.80
Intriguingly, IKKβ, a major downstream kinase in the TNFa- Glucocorticoids are given during initial stages of severe flares of
signaling pathway, has been demonstrated to physically interact conglobate acne. Recently, the molecular crosstalk between
withandphosphorylateTSC1,therebysuppressingTSC1,which glucocorticoid receptor (GR) and mTORC1 signaling has been
results in mTORC1 activation.81 TNFa/IKKβ/TSC1/Rheb- elaborated.94 A well known adverse effect of prolonged systemic
mediated activation of mTORC1 is thus a most conceivable glucocorticoid treatment is muscle atrophy. In skeletal muscle,
mechanism for TNFa-mediated keratinocyte proliferation in direct target genes of the GR signaling involve the protein
autoinflammatory disorders associated with acne and increased REDD1 (regulated in development and DNA damage responses)
systemic TNFa levels like PAPA syndrome.54 Indeed, treatment and the transcription factor KLF15 (Krüppel-like factor-15).
withTNFa-antagonistshowedbeneficalclinicaleffectsinpatients Both inhibit mTORC1 activity, although via distinct mechan-
with PAPA syndrome.82-84 isms. The REDD1 gene is activated at the promotor level by
www.landesbioscience.com Dermato-Endocrinology 25
ligand-bound GR and is transcriptionally induced under stress Most importantly, to achieve the physiological requirements
conditions like hypoxia (via HIF1a), which appears necessary for adequate growth, milk proteins provide highest amounts of
for the downregulation of mTORC1 signaling during stress leucine, the most effective, essential amino acid required for
conditions.95 REDD1 functions upstream of TSC2 and Rheb mTORC1 activation. Whey proteins have thus to be regarded as
in order to downregulate mTORC1 signaling in response to life starter proteins that not surprisingly contain the highest
glucocorticosteroids.95-97 amount of leucine (14%), followed by casein (10%), the major
KLF15 upregulates gene expression of branched-chain amino- protein constituent of cow milk and cheese (Table 1).106 For
transferase-2 (BCAT2), a mitochondrial enzyme, catalyzing the comparison, 100 g of rump steak contains approximately 2.4 g
firststepinthecatabolismofBCAAs.98Theglucocorticoid-driven leucinecomparableto100gofGoudacheese(2.4g),whichisin
GR-KLF15-BCAT2 axis may negatively modulate the intra- strong contrast to 100 g white cabbage (0.0.56 g), or 100 g apple
e
cellular availability of BCAAs resulting in a negative impact on (0.016 g). To reach the leucine intake provided by 100 g Gouda
c
mTORC1 function in skeletal muscle. Glucocorticoid-mediated cheese or steak, 4.2 kg white cabbage or 100 apples could be
n
downregulation of mTORC1 is not only a superb explanation consumed (Tables 3 and 4). These simple calculations exemplify
e
for glucocorticoid-induced muscle atrophy, but also for skin
i
atrophy after long-term systemic or topical glucocorticoid use. c
Table2.MechanismsofmTORC1activationbyWesterndiet
However, long-term use of glucocorticoids induces insulin s
resistence of adipose tissue and promotes the development of CompooundofWesterndiet Mechanisms
ofmTORC1activation
obesity, which is associated with hyperleucinemia. Under these i
B
conditions high insulin and leucin plasma levels may promote Hightotalcalories(=highenergy) ReducedactivityofAMPK
.
mTORC1 signaling of the peripheral sebaceous follicles tshu s Highglycemicload(=higheneergy) ReducedactivityofAMPK
promoting the development of acne. e t Increasedinsulinsignaling
u
d Highfatintake(=highenergy) ReducedactivityofAMPK
b
Western Diet Stimulates All Majonr mTORC1 Highalcoholintake(=highenergy) ReducedactivityofAMPK
Activation Pathways i
a Hirghdairyproteinintake Increasedinsulin/IGF-1signalingand
L t (=highleucine) leucine-mediatedmTORC1activation
s
The Western diet stimulates all three major pathways important
Highmeatintake(=highleucine) Leucine-andIGF-1-mediated
2 i
for mTORC1 activation (Fig.1). The Western diet providdes mTORC1activation
abundant energy, gluco1se, and fat to suppress AMPK activity
t
increasingmTOR0C1signaling(Table2).Thehighglycemicload Table3.Leucine-enrichedanimal-derivedfoods
o
increases glu2cose availability and stimulatesnincreased glucose- Food Leucine
depend ent insulin signaling. High intake of insulinotropic food (mg/100gfood)
ha©sbeenamatterofconcernformoreoth anadecade.99Despiteof Beef(rumpsteak) 2,369
alleffortsinpreventionthetotalDyearlyconsumptionofsugarstill
Goudacheese(40%fat) 2,359
increases worldwide. Highly glycemic and insulinemic foods are
Coalfish,cooked 1,883
ubiquitous elements of the Western diet and comprised 47.7%
of the per capita energy intake in the United States in the year Broiler,cooked 1,806
2002.100,101 Today, the proportion of insulinotropic food will be Curdcheese(20%fat) 1,290
much higher and is further driven by expanding activities of Yoghurt(3.5%fat) 410
multiple fast food distributors. Cowmilk(1.5%fat) 381
Milk proteins significantly contribute to high insulin/IGF-1
Source:GermanNutrientDatabase,BLS-version3.01.
signalingofWesterndiet.Mammalianmilkhastoberegardedas
anendocrinesignalingsystemthatupregulatesmTORC1activity Table4.Plant-derivedfoodswithlowleucinecontent
by increasing insulin secretion, hepatic IGF-1 secretion, and
Food Leucine
mTORC1-mediated β-cell proliferation for neonatal growth
(mg/100gfood)
requirements.102 Milk consumption not only stimulates the
Corn(cooked) 394
somatotropic axis but also activates incretin signaling by enteral
Wheat(cooked) 274
stimulation of glucose-dependent insulinotropic polypeptide
(GIP).57,103Milk’sexcessiveinsulinotropicactivityischaracterized Rice(cooked) 219
by milk’s high insulinemic index.104 Notably, increased daily Broccoli(cooked) 193
intake of milk but not meat significantly raised basal insulin- Cauliflower(cooked) 185
and IGF-1 serum levels and increased insulin resistance in 8-y
Potato(cooked) 124
old boys.105 Milk-induced insulin resistance can be explained
Whitecabbage(cooked) 56
byincreasedmTORC1/S6K1-mediatedIRS-1phosphorylation.50
Tomato 38
Epidemiological data in adults clearly confirmed the correlation
between increased dairy protein consumption and raised IGF-1 Apple 16
serum levels.58,59 Source:GermanNutrientDatabase,BLS-version3.01.
26 Dermato-Endocrinology Volume4Issue1
theextremedifferencesinleucineamountsprovidedbyananimal mTORC1, which is necessary for growth in puberty. However,
meat/dairy protein-based diet in comparison to a vegetarian or it appears that normal puberty in non-Westernized populations
vegan diet. Thus, the increased consumption of meat and dairy does not lead to the development of acne. There is no acne in
proteins, staples of Western diet, provides abundant amounts of adolescent Kitava during puberty who live on a Paleolithic diet
leucine for mTORC1 activation. In comparison to meat, milk and do not consume hyperinsulinemic, IGF-1-raising food like
proteinsoffertwomajorsignalsformTORC1activation,insulin/ hyperglycemic carbohydrates and dairy proteins.3,4 Thus, there
IGF-1 as well as high leucine.49 It is most critical that the appears to be a threshold for mTORC1-mediated acne which
mTORC1-activating “system milk” is frequently combined with is clearly exceeded under conditions of Western life style and
hyperglycemic carbohydrates or pure sugar (milk plus cornflakes, nutrition.
milk chocolate or milk ice), a combination which potentiates .
e
mTORC1 activation. Anti-Acne Agents Inhibit Over-Activated
c
Adolescentsexhibitthehighestproteinintakeincomparisonto Nutrient-Stimulated mTORC1
n
youngchildrenorelderlyindividuals.DietarysurveydataofUSA
in 2004—which will be much higher today—demonstrated that Isotretinoin. Oral isotreteinoin (13-cis-retinoic acid), the most
i
protein intake averaged 56 ± 14 g/d in young children, increased powerful sebum csuppressive anti-acne agent, is intracellularly
to a high of approximately 91 ± 22 g/d in adults aged 19–30 y, isomerized tosall-trans-retinoic acid (ATRA). ATRA/retinoic acid
and decreased to approximately 66 ± 17 g/d in the elderly.107 receptoro(RAR) signaling induces in a secondary response
Adolescents and young adults of Western countries consume the incrieased expression of FoxO transcription factors.40 FoxOs have
B
highest amounts of total protein. These data correlate with acne been recognized as interacting partners of the mTORC1
.
prevalence showing a climax during puberty but persisting sint o pathway.41 FoxO1, FoxO3e and FoxO4 inhibit mTORC1
the third decade of life.2 High intake of glucose, totaleenergy, signaling by increasingtthe expression of the AMPK activator
u
insulinotropic and IGF1-raising food and total intadke of animal Sestrin3(Fig.2).41,43-45Furthermore,isotretinoinhasbeenshown
b
proteins increasing the availability of leucinne will alltogether to reduce serum IGF-1 concentrations.113 Thus, isotretinoin
maximize mTORC1 signaling (Table 2). inhibits miTORC1 by increased FoxO-Sestrin3-AMPK-signaling
a r
andtdecreased IGF-1-PI3K/Akt signaling. Isotretinoin promotes
L
s
Signaling of Puberty Superimposed sebaceous gland hypotrophy and inhibits the G /S checkpoint of
1
by Signalin2g of Western Diet d ithe cell cycle.114 Indirect evidence links isotretinoin’s mode of
1 actiontoFoxO-mediatedinhibitionofmTORC1,whichinduces
t
During puberty, 0nutrient-mediated mTORC-1 activation over- autophagy leading to sebaceous gland apoptosis or hypotrophy.
o
lapswithpu2berty-driven(IGF-1/androgen)-mTORC1activation, Infact, both mTORC1 inhibition and isotretinoin lead to cell
n
tcho©uinscpidr oesmwoittihngthepeigdreomwitchapcnhea.seItoifspimuobpeo rrttyanintdtoucreedalibzyeitnhcarteaacsnede cdyocwlenraergrueslatteadt tShReEGBP1/1Setxrparnessistiioonn.2in4,11h4umMaonresoevbeorc,yitseost.r1e09t,i1n14oiInn,
pituitary secretion of growth horDmone (GH) and GH-mediated accordance, mTORC1 has been linked to SREBP-regulated lipid
hepatic secretion of IGF-1, which is intimately involved in the metabolism.69-72 It is thus conceivable that hyperactivated
pathogenesisofacne.108IGF-1isastrongstimulatorofsebaceous mTORC1 signaling induced by Western diet is attenuated by
lipogenesisandupregulatesthePI3K/AktandmTORC1pathway isotretinoin-FoxO1-mediated suppression of mTORC1 resulting
resulting in increased expression of SREBP-1, the key transcrip- in autophagy and/or apotosis of sebocytes with decreased SREBP
tionfactorofmostlipidsynthesizingenzymes.109IGF-1mediated signaling.
activationofthePI3K/Aktpathwayresultsinnuclearextrusionof Metformin. It should be emphasized that subjects exhibiting
FoxO transcription factors, recently linked to acne pathogen- genetic variants featuring increased expression and responsiveness
esis.38,39 IGF-1 is also related to increased androgen signaling, as of certain components of the somatotropic axis (GH, GHR,
IGF1- stimulates adrenal and gonadal androgen synthesis and IGF-1andIGF1R)and/orreducedactivityofFoxOtranscription
increases 5a-reductase activity, the responsible enzyme for the factors will show increased susceptibility for acne and mTORC1
conversionoftestosteronetothe10-foldmorepotentDHT.60,108 activation.115 Prototypically, obese women with polycystic ovary
Intriguingly,subjectswithLaronsyndromeandcongenitalIGF-1 syndrome (PCOS) exhibit signs of hyperandrogenism, acne,
deficiency due to loss-of-function mutations of GH receptor insulin resistance and increased insulin and IGF-1 serum levels.54
exhibit short stature and do not develop acne or clinical signs Treatment of PCOS with the anti-diabetic drug metformin
of hyperandrogenism, unless substituted with high doses of improves overweight, reduces insulin resistance and clinical signs
recombinant IGF-1.110 Remarkably, the transcriptional activity of hyperandrogenism including acne.116 Metformin is known to
of the androgen receptor itself is also linked to insulin/IGF-1 activateAMPKresultinginmTORC1inhibition.28,37Recently,a
signaling. IGF-1 stimulates androgen receptor transactivation second AMPK-independent mechanism of metformin-mediated
by nuclear extrusion of the androgen receptor cosuppressor mTORC1-inhibition has been identified. Metformin inhibited
FoxO1 from the androgen receptor complex.111,112 Thus, there leucine-induced translocation of inactive mTORC1 to Rheb-
is substantial evidence for the role of insulin/IGF-1 signaling in enrichedlysosomalmembranecompartments,therebyattenuating
the pathogenesis of acne, an IGF-1- and androgen-dependent mTORC1 activity (Fig.2).52 Metformin is thus an effective dual
disease. Both, IGF1- and androgen-signals are known to activate mTORC1 inhibitor, reduces overweight, insulin resistance (via
www.landesbioscience.com Dermato-Endocrinology 27
mTORC1/S6K1-driven IRS-phosphorylation) and hyperandro- plant-derived mTORC1 inhibitors in the treatment of acne
genism. Morover, metformin counterbalances the adverse effects andunderlinetheroleofmTORC1signalinginthepathogenesis
of Western diet mediated by high insulin/IGF-1 as well as of acne.
increased leucine signaling. Metformin (C H N ; molar mass
4 11 5
129.1) appears to function as a competitive inhibitor of leucine Acne and Prostate Cancer Related
(C H NO ; molar mass 131.2) in the Rag GTPase-dependent to mTORC1 Signaling?
6 13 2
process of mTORC1 activation. Notably, the usual daily dose of
metformin(2g/d)isintherangeof2gleucinederivedfromdaily An epidemiologic association between the prevalence of severe
consumptionof100gmeatorcheese.PCOSisassociatedwithan long-lasting acne and increased risk of prostate cancerlater inlife
increased risk of cancer. Intriguingly, recent evidence points to has been reported.138 This association may.depend on a life long
e
cancer-protective effects of metformin treatment.117-121 over-stimulation of mTORC1-signaling, which may promote
c
Benzoyl peroxide. Benzoyl peroxide (BPO), the classical tumorigenesis.139,140L-typeaminoacidtransporterssuchasLAT1
n
external anti-acne agent commonly applied in excessive concen- and LAT3 mediate the uptake of essential amino acids. LAT3 is
e
trations between 3 and 10% induces high cellular levels of mosteffectiveinleucinetransport.Prostatecancercellscoordinate
i
hydrogen peroxide (H O ), which is able to cross membrane theexpressionofLcAT1andLAT3tomaintainsufficientlevelsof
2 2
compartments. Across species, high oxidative stress associated leucine needsed for mTORC1 signaling and cell growth.
with the generation of reactive oxygen species (ROS) like Inhibitinog LAT function was sufficient to decrease cell growth
hydrogen peroxide is known to activate nuclear FoxO transcrip- andimTORC1 signaling in prostate cancer cells. These cells
B
tion factors by stimulation of the oxidative stress inducible maintainedlevelsofaminoacidinfluxthroughandrogenreceptor-
.
kinases, Jun N-terminus kinase (JNK) and ST20-like prostei n mediatedregulationofLAT3eexpression,andATF4regulationof
kinase 1 (MST1), which phosphorylate specific FoxeO sites LAT1expressionafteramtinoaciddeprivation.140Anti-androgenic
u
resulting in their nuclear accumulation.41 Intriguidngly, FoxO1, hormone therapy in prostate cancer may thus reduce cellular
b
FoxO3 and FoxO4 activated by oxidative strenss induce Sestrin3 leucine uptake and leucine-mediated mTORC1 activation. Anti-
transcriptionally. Sestrin 3 activates AMPK and thereby inhibits androgensiused in acne treatment may exert similar effects on
a r
mTORC1.41 Thus, topical BPO-treatment may increase FoxO cellutlar leucine influx, which should be investigated in future
L
s
transcriptional activities, which finally inhibit mTORC1. experimental studies.

2 i
Resveratrol. Resveratrol, a polyphenolic flavonoid from gradpes
andredwine,downregu1latesPI3K/Akt/mTORC1signali ng.122-126 Acne: An mTORC1-Driven Disease
t
Intriguingly, resve0ratrol directly inhibits PI3K by targeting the of Western Civilization
o
class IA PI32K ATP-binding site in a competitive and reversible
n
fashion .127 PI3K and mTOR belong to the same family of PI3K- Accumulating evidence implies that nutrient-activated mTORC1
rel©ated lipid kinases. Thus, there is coon vincing evidence for the signaling plays a pivotal role in the pathogenesis of acne.
role of resveratrol as a direct andD indirect inhibitor of mTORC1 Moreover, acne should be linked to other mTORC1-driven
(Fig.2). diseases of civilization like obesity, type 2 diabetes, metabolic
These recent insights imply that resveratrol may exert syndrome, cancer and neurodegenerative diseases (Fig.4).141-148
therapeutic effects in the treatment of acne. Resveratrol has been The common underlying pathogenic factor of these apparently
shown to inhibit the proliferation of Propionibacterium acnes.128 unrelateddiseasesappearstobenutrient-mediatedover-activation
Recently,ithasbeenreportedthattopicaltreatmentoffacialacne of mTORC1 leading to increased cellular growth, cell prolifera-
vulgaris in 20 patients with a resveratrol-containing gel (0.01% tion, tumorigenic stimulation, endoplasmic reticulum stress and
weight/volume) significantly reduced the number of microcome- deranged cell protein homeostasis.
dones, papules and pustules compared with vehicle control.129 Inthisregarditisfrighteningtorealizethatmorethan85%of
Epigallocatechin-3-gallate. The specific green tea catechin, adolescentsofWesterncountriesexhibitacne,whereasindividuals
epigallocatechin-3-gallate (EGCG), is regarded as the active of non-Western populations like the Kitava are not affected by
anti-inflammatory and anti-proliferative compound of green tea this disease and other mTORC1-driven diseases of civiliza-
extracts.130-133 EGCG inhibited type I collagen expression in tion.3,149 This implies that the majority of our Western popula-
keloid fibroblasts by inhibition of the PI3K/Akt/mTORC1 tion is living with over-activated mTORC1 signaling, a major
signaling pathway.134 EGCG has been proven to function as pathogenic factor, which probably may pave the way for the
an ATP-competitive inhibitor of both PI3K and mTORC1, development of other serious diseases of civilization (Fig.4).
respectively (Fig.2).135
Topical 2% green tea lotion was effective in the treatment of Conclusion and Future Perspectives
mild-to-moderate acne vulgaris.136 After 6 weeks, the mean total
lesion count and mean severity index of acne showed significant EpidemicacneofWesternizedsocietiesshouldbeconsideredasa
reductions of 58% and 39%, respectively.136 Furthermore, a 3% visible model disease of exaggerated mTORC1 signaling pro-
green tea emulsion significantly reduced sebum production in motedbytheWesterndiet.Dermatologistsshouldnotneedlessly
10 healthy male volunteers after 8 weeks of treatment.137 These wastetimewithcontroversialdiscussionsconcerningisolatedfood
data provide preliminary evidence for the effectiveness of natural components in the pathogenesis of acne but should realize the
28 Dermato-Endocrinology Volume4Issue1
including meat and dairy proteins. This comprehensive dietary
strategycanonlybeachievedbyhigherconsumptionofvegetables
and fruit and reduction of animal-derived food. Indeed, diets
enrichedinvegetablesandfruits,vegandietaswellsasPaleolithic
diet (excluding sugar, hyperglycemic grains and dairy) have all
been demonstrated to improve insulin sensitivity in type 2
diabetes, and metabolic syndrome and showed preventive effects
in the development of Alzheimer disease.120,147,150-155 According
to the recent Korean acne diet study, the frequency of vegetables
and fish intake was significantly higher in.the acne-free control
e
group than in the acne group consuming more hyperglycemic
c
carbohydrates, processed meat and dairy products.12 Paleolithic
n
diet regimens come close to the goal of attenuated mTORC1
e
signaling but have to consider that unlimited total protein
i
intake may oversticmulate leucine-mediated mTORC1 activation.
Vegetable-accesntuated diets provide less mTORC1 activating
signals anod additionally contain natural plant-derived mTORC1-
Figure4.ThemarchofmTORC1-drivendiseasesofcivilization.Persistent inhiibitorslikeresveratrol,EGCG,curcumin,genestein,andindole-
over-activationofmTORC1promoteschronicdiseasesofcivilization. B
3-carbinolmonomers,precursorsof3,3'-diindolylmethane.
EpidemicacneisavisibleindicatordiseaseofexcessivemTORC1signaling .
increasingtheriskforsubsequentchronicdiseasesofcivilization. s The dermatologist shouled take responsibility for dietary
e education and interventtion of his acne patients and should
u
d initiatefirstmeasuresincorrectingaharmfulnutritionalpathway
b
emerging whole network of exaggerated mnTORC1 signaling of over-activated mTORC1 signaling with long-term adverse
mediatedbyWesterndiet.Themostimportanttaskofpreventive effects. Aideeper understanding of diet-mediated mTORC1
a r
dermatology will be the reduction of mTORC1. All three major signatling will help to appreciate the statement of Hippocrates of
L
stimulatory pathways of mTORC1 activation have to be Ksós who said about 2,400 y ago, “Your diet should be your

attenuated. Dietary intervent2ion in acne should thus (1) decredaseimedicine, and your medicine should be your diet.”
total energy, glucose an1d fat intake, (2) diminish insuli n/IGF-1
signaling predom0inantly mediated by high dairty protein Note
o
consumption2, and (3) should limit the total leucine uptake This article is dedicated to Professor Otto Braun-Falco on the
n
predom inantly provided by increased animal protein intake occasion of his 90th birthday.
© o
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www.landesbioscience.com Dermato-Endocrinology 29