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Dietary intervention in acne: Attenuation of increased mTORC1 signaling promoted by Western diet

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The purpose of this paper is to highlight the endocrine signaling of Western diet, a fundamental environmental factor involved in the pathogenesis of epidemic acne. Western nutrition is characterized by high calorie uptake, high glycemic load, high fat and meat intake, as well as increased consumption of insulin- and IGF-1-level elevating dairy proteins. Metabolic signals of Western diet are sensed by the nutrient-sensitive kinase, mammalian target of rapamycin complex 1 (mTORC1), which integrates signals of cellular energy, growth factors (insulin, IGF-1) and protein-derived signals, predominantly leucine, provided in high amounts by milk proteins and meat. mTORC1 activates SREBP, the master transcription factor of lipogenesis. Leucine stimulates mTORC1-SREBP signaling and leucine is directly converted by sebocytes into fatty acids and sterols for sebaceous lipid synthesis. Over-activated mTORC1 increases androgen hormone secretion and most likely amplifies 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 downregulate mTORC1 in sebocytes by upregulation of nuclear levels of FoxO1. The role of Western diet in acne can only be fully appreciated when all stimulatory inputs for maximal mTORC1 activation, i.e., glucose, insulin, IGF-1 and leucine, are adequately considered. Epidemic acne has to be recognized as an mTORC1-driven disease of civilization like obesity, type 2 diabetes, cancer and neurodegenerative diseases. These new insights into Western diet-mediated mTORC1-hyperactivity provide a rational basis for dietary intervention in acne by attenuating mTORC1 signaling by reducing (1) total energy intake, (2) hyperglycemic carbohydrates, (3) insulinotropic dairy proteins and (4) leucine-rich meat and dairy proteins. The necessary dietary changes are opposed to the evolution of industrialized food and fast food distribution of Westernized countries. An attenuation of mTORC1 signaling is only possible by increasing the consumption of vegetables and fruit, the major components of vegan or Paleolithic diets. The dermatologist bears a tremendous responsibility for his young acne patients who should be advised to modify their dietary habits in order to reduce activating stimuli of mTORC1, not only to improve acne but to prevent the harmful and expensive march to other mTORC1-related chronic diseases later in life.
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Dietary intervention in acne
Attenuation of increased mTORC1 signaling promoted
by Western diet
Bodo C. Melnik
Department of Dermatology, Environmental Medicine and Health Theory; University of Osnabrück; Osnabrück, Germany
Keywords: acne, androgen, FoxO, IGF-1, insulin, leucine, mTORC1, nutrition, prevention, Western diet
Abbreviations: Akt, Akt kinase (protein kinase B); AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase;
ATP, adenosine triphosphate; ATRA, all-trans-retinoic acid; BCAA, branched-chain amino acid; BCAT2, branched-chain aminotransferase-
2; BPO, benzoyl peroxide; 2DG, 2-desoxyglucose; EGCG, epigallocatechin-3-gallate; FoxO, forkhead box class O transcription factor;
DHT, dihydrotestosterone; 4E-BP, eukaryotic initiation factor (eIF) 4E-binding protein; GH, growth hormone; GHR, growth hormone
receptor; GIP, glucose-dependent insulinotropic polypeptide; GLUT, glucose transporter protein; GR, glucocorticoid receptor;
GDP, guanosine diphosphate; GTP, guanosine triphosphate; IGF, insulin-like growth factor; IGF1R, IGF-1 receptor; IKK, inhibitor of
kappa light chain gene enhancer in B cells; JNK, Jun N-terminus kinase; IL, interleukin; IRS, insulin receptor substrate; KLF, Krüppel-like
factor; LAT, L-typeamino acid transporter; LKB, liver kinase B; mTOR, mammalian target of rapamycin; MST1, STE20-like protein kinase
1; NALA, N-acetylleucine amide; NFkB, nuclear factor kappa B; PCOS, polycystic ovary syndrome; PI3K, phosphoinositol-3 kinase;
Rag, Ras-related GTP-binding protein; Raptor, regulatory associated protein of mTOR; REDD1, regulated in development and DNA
damage responses; Rheb, Ras homolog enriched in brain; Rictor, rapamycin-insensitive companion of mTOR; RSK, ribosomal S6 kinase;
S6K, p70 S6 kinase; SREBP, sterol regulatory element-binding protein; TCR, T cell receptor; TNF, tumor necrosis factor;
TOR, target of rapamycin; TSC, tuberous sclerosis complex; TSC1, hamartin; TSC2, tuberin
The purpose of this paper is to highlight the endocrine signaling
of Western diet, a fundamental environmental factor involved in
the pathogenesis of epidemic acne. Western nutrition is
characterized by high calorie uptake, high glycemic load, high
fat and meat intake, as well as increased consumption of insulin-
and IGF-1-level elevating dairy proteins. Metabolic signals of
Western diet are sensed by the nutrient-sensitive kinase,
mammalian target of rapamycin complex 1 (mTORC1), which
integrates signals of cellular energy, growth factors (insulin,
IGF-1) and protein-derived signals, predominantly leucine,
provided in high amounts by milk proteins and meat. mTORC1
activates SREBP, the master transcription factor of lipogenesis.
Leucine stimulates mTORC1-SREBP signaling and leucine is
directly converted by sebocytes into fatty acids and sterols for
sebaceous lipid synthesis. Over-activated mTORC1 increases
androgen hormone secretion and most likely amplifies
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
downregulate mTORC1 in sebocytes by upregulation of
nuclear levels of FoxO1. The role of Western diet in acne can
only be fully appreciated when all stimulatory inputs for maximal
mTORC1 activation, i.e., glucose, insulin, IGF-1 and leucine, are
adequately considered. Epidemic acne has to be recognized as
an mTORC1-driven disease of civilization like obesity, type 2
diabetes, cancer and neurodegenerative diseases. These new
insights into Western diet-mediated mTORC1-hyperactivity
provide a rational basis for dietary intervention in acne by
attenuating mTORC1 signaling by reducing (1) total energy
intake, (2) hyperglycemic carbohydrates, (3) insulinotropic dairy
proteins and (4) leucine-rich meat and dairy proteins. The
necessary dietary changes are opposed to the evolution of
industrialized food and fast food distribution of Westernized
countries. An attenuation of mTORC1 signaling is only possible
by increasing the consumption of vegetables and fruit, the major
components of vegan or Paleolithic diets. The dermatologist
bears a tremendous responsibility for his young acne patients
who should be advised to modify their dietary habits in order to
reduce activating stimuli of mTORC1, not only to improve acne
but to prevent the harmful and expensive march to other
mTORC1-related chronic diseases later in life.
Introduction
Acne is an epidemic skin disease of industrialized countries,
reaching prevalence rates of over 85% of teenagers.
1
In the United
States, acne nowadays persists after adolescence into the third
decade of life in nearly half of men and women.
2
This demon-
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
Western civilization and has been closely linked to Western
diet.
3
Intriguingly, acne is absent in populations consuming a
Correspondence to: Bodo C. Melnik; Email: melnik@t-online.de
Submitted: 10/30/11; Revised: 12/20/11; Accepted: 02/20/12
http://dx.doi.org/10.4161/derm.19828
Dermato-Endocrinology 4:1, 2032; January/February/March 2012; G2012 Landes Bioscience
20 Dermato-Endocrinology Volume 4 Issue 1
© 2012 Landes Bioscience.
Do not distribute.
Paleolithic diet excluding sugar, grains and dairy protein like the
diet of the Kitava islanders who exhibit low basal insulin levels
compared with age-matched Europeans and do not suffer from
epidemic diseases of civilization.
3,4
Remarkably, a randomized
placebo-controlled Australian trial confirmed that a reduction of
glycemic load improved the clinical symptoms of acne, the rate of
sebum excretion and free androgen index in male acne patients in
the age range of 1525 y.
5-8
Epidemiologic data derived from the Nurses Health Study II and
the Growing Up Today Study in the United States provided
epidemiological evidence for a correlation between milk, and
especially skim milk consumption, and the prevalence of acne.
9-11
Moreover, positive associations between acne and the consump-
tion of other dairy products like instant breakfast drink, sherbet,
cream cheese and cottage cheese have been reported.
9
The
association between acne and food composition has recently been
confirmed in 783 patients with acne and 502 control subjects in
South Korea.
12
The frequency of vegetables and fish intake was
significantly higher in the control group than in the acne group.
Intake of instant noodles, junk food, carbonated drinks, snacks,
processed cheeses, pork, chicken, nuts and seaweed were
significantly higher in acne patients than in the controls.
12
Thus, the food pattern of Western diet composed of high
glycemic load, high fat intake, and high dairy and meat
consumption played an important role in the exacerbation of
acne in South Korea. Nearly half of the male and female acne
patients reported that food intake was an aggravating factor of
their acne. Remarkably, in the group of food-aggravated acne
patients, serum IGF-1 levels (543.9 ± 56.4 ng/mL) were
significantly higher than IGF-1 levels (391.3 ± 118.2 ng/mL) in
the acne group not reporting aggravation by food.
12
Accumulating
evidence derived from epidemiologic and controlled dietary
studies allows the conclusion that especially high glycemic load
diets and increased consumption of dairy proteins are the major
dietary factors of Western diet promoting the development or
exacerbation of acne.
13-20
Although there is overwhelming
evidence for the role of diet in acne, the role of food in acne is
still a controversial issue.
21
The major problem of this uncertainty
is the lack of knowledge on signaling pathways mediated by
nutrients. This paper will help to elucidate major pathways of
nutrient signaling of Western diet involved in the pathogenesis of
acne and highlights the central role of the nutrient-sensitive kinase
mammalian target of rapamycin complex 1 (mTORC1) in
mediating the effects of nutrient-derived signals in the develop-
ment of acne.
mTORC1 Senses and Integrates Nutrient-Derived
Signals
Recent discoveries in the field of molecular biology have
established the key role of the nutrient-sensitive mammalian
target of rapamycin complex 1 (mTORC1) kinase in cell
regulation and cell function. mTORC1 signaling stimulates gene
transcription, translation, ribosome biogenesis, protein synthesis,
cell growth, cell proliferation and lipid synthesis but suppresses
the mechanisms of autophagy.
22-27
mTOR is a multi-domain
protein of approximately 300 kDa exhibiting a protein kinase
domain at its C-terminus related to phosphoinositol-3-kinases
(PI3K). In mammalian cells two functionally different mTOR
complexes exist: mTORC1 and mTORC2. Among other
functional proteins, mTORC1 contains the important partner
protein Raptor, which interacts with substrates for mTORC1-
mediated phosphorylation. mTORC1 controls the G
1
/S trans-
ition and G
2
/M progression of the cell cycle.
24
In contrast to
mTORC2, which contains the partner protein Rictor, only
mTORC1 plays a special role in sensing cellular nutrients, amino
acid and energy (ATP) levels important for cell growth and
proliferation. Liver kinase B1 (LKB1) and AMP-activated protein
kinase (AMPK) are critical regulators of mTORC1.
28
Most
functions of mTORC1 are inhibited by rapamycin, a triene
macrolide antibiotic synthesized by Streptomyces hygroscopicus.
27
mTORC1 has to be regarded as a pivotal convergence point in
cell signaling, because it integrates many intra- and extracellular
signals such as growth factors (insulin, IGF-1), energy-sensing
signals (glucose, the AMP/ATP-ratio regulating AMPK), and
most importantly the availability of sufficient amounts of amino
acids, especially the branched-chain essential amino acid (BCAA)
leucine for mTORC1 activation (Fig. 1).
29
Recent advances in molecular biology have elucidated two
parallel mechanisms of mTORC1 activation: (1) the upstream
activation of the small GTPase Rheb (Ras homolog enriched in
brain) by growth factor signals and high cellular energy levels and
(2) the amino acid-dependent translocation of inactive mTORC1
to active Rheb localized at late endosome or lysosome compart-
ments.
30-32
The activity of Rheb is tightly regulated by the
tuberous sclerosis proteins TSC1 (hamartin) and TSC2 (tuberin),
which form a functional heterodimeric complex. Intriguingly,
loss-of-function mutations of either the TSC1 or TSC2 gene cause
the hamartoma syndrome tuberous sclerosis complex. TSC1
stabilizes TSC2, that possesses a GTPase-activating protein,
which hydrolyses GTP to GDP. The TSC1/TSC2 complex
provides this function to Rheb leading to inactivation of Rheb.
Insulin and IGF-1, which both activate the kinase Akt (protein
kinase B) as well as other growth-related kinases such as ERK and
RSK phosphorylate TSC2, thereby inhibiting the function of the
TSC1/TSC2 complex. This inhibition leads to activation of Rheb
with final activation of mTORC1.
33-35
Besides the important input of growth factor signaling on
mTORC1 activation, AMPK, an essential energy sensor, plays a
key role in energy-dependent mTORC1 regulation. During states
of energy-deficient conditions like glucose deprivation, ATP levels
fall and AMP levels rise, resulting in AMPK activation. AMPK
phosphorylates TSC2 and Raptor, thereby suppressing mTORC1
activity.
36,37
Abundant cellular energy provided by hypercaloric
Western diet with high glycemic load thus reduces AMPK activity
and stimulates mTORC1 signaling.
FoxO Proteins: Rheostats Tuning mTORC1 Activity
Acne pathogenesis has recently been linked to increased insulin/
IGF-1 signaling leading to decreased nuclear levels of FoxO
transcription factors which are extruded into the cytoplasm
REVIEW
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by growth-factor-activated PI3K/Akt-signaling.
38,39
Although experimental direct evidence is still lacking,
indirect evidence from various cell systems supports
the concept that isotretinoin increases 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
FoxO transcription factors, modulate mTORC1 signal-
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,
FoxO4) induce the expression of Sestrin3, which
activates AMPK to inhibit mTORC1 in a TSC2-
dependent manner.
43
Moreover, AMPK has been
shown to phosphorylate FoxO3 and facilitate its
nuclear localization.
44
It has been demonstrated that
Akt-phosphorylated cytoplasmic FoxO1 is able to
Figure 1. mTORC1 signaling of Western diet in acne: Leucine, IGF-1, insulin and glucose synergistically activate mTORC1. Leucine activates mTORC1
by translocation of inactive mTORC1 to Rheb-enriched membrane compartments. High glucose intake increases insulin signaling and elevates cellular
ATP levels resulting in AMPK suppression. mTORC1 activates protein synthesis via S6K1 and 4EBP1 and phosphorylates lipin 1, inducing SREBP-mediated
lipogenesis. DHT increases cellular leucine uptake and directly activates mTORC1.
Figure 2. Attenuation of mTORC1 activity by dietary intervention. Reduction
of animal protein (leucine), hyperglycemic carbohydrates (glucose) and dairy
proteins (insulin/IGF-1) mitigates mTORC1 signaling. Isotretinoin inhibits mTORC1
by upregulation of FoxO-Sestrin3, which stimulates AMPK. Benzoyl peroxide (BPO)
upregulates FoxO-Sestrin3-stimulated AMPK, thereby inhibiting mTORC1. Metformin
inhibits mTORC1 activity by antagonizing leucine signaling and by stimulating AMPK
activity. Plant-derived mTORC1 inhibitors directly downregulate mTORC1
(Abbreviations see text).
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associate with the C terminus of TSC2 thereby dissociating
the TSC1/TSC2 complex leading to activation of mTORC1.
45
From theses data it becomes apparent that FoxOs intimately
interact with mTORC1 and control mTORC1 signaling.
Remarkably, in response to amino acid depletion, mTORC1
activity is rapidly abolished.
46
Amino acid starvation impairs
binding of mTORC1 to Rheb.
47
From all essential amino acids,
leucine exerts the greatest effects on mTORC1 signaling.
24,27,46
Recent evidence has been provided that amino acids and especially
leucine promote the cellular translocation of inactive mTORC1
to lysosomal compartments enriched in activated Rheb.
30,31
This
spatial regulation of inactive mTORC1 by amino acids is
mediated by an active Rag heterodimer and is of utmost biological
importance as it explains the complete mechanism of nutrient
sensing of mTORC1. Thus, mTORC1 integrates not only
growth factor/energy-derived signals to Rheb, but requires parallel
signaling of leucine for final mTORC1 activation by transloca-
tion of inactive mTORC1 to cell compartments enriched in
activated Rheb (Fig. 1 ). These two synergistic major pathways of
mTORC1 activation explain why either insulin/IGF-1 signaling
or amino acid signaling alone is not sufficient to reach maximal
mTORC1 activation. Insulin is not able to activate the mTORC1
pathway when cells are deprived of amino acids.
48
Infact, recent
experimental evidence confirmed that both insulin- and amino
acid-signaling are required for maximal mTORC1 activity in rat
liver.
49
Activated mTORC1 finally phosphorylates important sub-
strates involved in the regulation of the translational machinery,
the S6 kinases (S6Ks), which phosphorylate ribosomal protein S6,
and eukaryotic initiation factor (eIF) 4E-binding proteins (4E-
BPs), which control the activity of the translation factor eIF-4E
that binds to the 5'-cap structure of eukaryotic mRNAs, thereby
facilitating ribosome recruitment. Intriguingly, the downstream
target of mTORC1, S6K1, phosphorylates insulin receptor
substrate protein-1 (IRS-1), mediating an important feed back
mechanism, which downregulates insulin/IGF-1 signaling. This
is a most important mechanism of insulin resistance, a charac-
teristic feature of puberty, obesity, type 2 diabetes and states of
hyperandrogenism.
50
The Link Between Androgen- and mTORC1-Signaling
We are at the very beginning to understand the important
molecular crosstalk between androgens and the mTORC1
pathway. Anabolic effects of testosterone certainly increase protein
synthesis. The mTORC1 pathway is the major regulator of
protein synthesis and cell growth, but the relationship between
testosterone action and mTORC1 has not yet been characterized
in sebaceous glands. Nevertheless, it has been shown in cultured
cardiomyocytes that testosterone induced hypertrophic effects via
mTORC1 signaling. Testosterone increased the phosphorylation
of mTOR and its downstream targets S6K1 and 4E-BP1.
51
S6K1-
phosphorylation induced by testosterone was blocked by the
mTORC1 antagonist rapamycin. This observation is of great
importance for the understanding of insulin resistance in states
of hyperandrogenism like polycystic ovary syndrome (PCOS).
Testosterone-mediated mTORC1-S6K1- IRS-1 signaling pro-
vides a most critical mechanism for the induction of insulin
resistance.
50
On the other hand, metformin treatment of patients
with PCOS reduces androgen levels and improves insulin
resistance. Remarkably, metformin inhibits mTORC1 activity
by antagonizing leucine-mediated mTORC1 activation as well as
AMPK-mediated suppression of mTORC1 activity.
52,53
The
androgen-mTORC1-S6K1 pathway explains the development of
insulin resistance in various syndromes associated with acne and
insulin resistance.
54
In the prostate of mice PI3K levels and mTORC1 activity are
robustly induced by androgens during prostatic development.
PI3K/mTORC1 signaling is necessary for prostatic epithelial
bud invasion of surrounding mesenchyme.
55
The right balance
of PI3K and downstream mTORC1/mTORC2 activity plays a
critical role in the regulation of prostatic epithelial morphogenesis.
Future studies in humans should clarify the role of androgen-
mTORC1-mediated effects on sebaceous gland morphogenesis
and differentiation.
Androgen- and mTORC1-Dependent
Amino Acid Uptake
High intake of BCAAs provided by high dairy protein and meat
consumption may be another important mechanism stimulating
sebaceous lipogenesis. Increased levels of amino acids derived
from meat hydrolysis as well as dairy protein consumption are
known to increase serum levels of IGF-1.
56-59
IGF-1 stimulates the
activity of 5a-reductase, which converts testosterone to the more
potent dihydrotestosterone (DHT).
60
DHT has recently been
shown to stimulate increased uptake of BCAAs in an mTORC1-
dependent process, which could be inhibited by pre-treatment of
muscle cells with the mTORC1 inhibitor rapamycin.
61
It is thus
conceivable that DHT promotes BCAA-uptake by sebaceous
glands, a process that delivers leucine as an important precursor
for sebaceous lipogenesis. In this regard it is of special concern
that male adolescents in the fitness and bodybuilding environ-
ment consume high amounts (6080 g/d) of leucine-rich whey-
or casein-based protein concentrates to gain muscle mass, a
procedure which is often associated with the development of acne
(Table 1).
62,63
Experimental studies are necessary to investigate
the possible role of DHT for leucine uptake of sebaceous glands.
Combined androgen abuse with high dairy protein intake may
operate in a synergistic fashion increasing sebaceous gland growth
Table 1. Leucine-rich proteins (ref. 106)
Protein source Leucine content
(g/100 g protein)
Whey protein concentrate 14%
Cow milk protein (mostly casein) 10%
Egg protein 8.5%
Muscle protein 8%
Soy protein isolate 8%
Wheat protein 7%
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and proliferation. Both increased mTORC1-dependent leucine
uptake for leucine-dependent lipid synthesis as well as androgen-
and leucine-stimulated mTORC1-activation may stimulate
sebocyte growth, proliferation and SREBP-mediated lipid syn-
thesis. Thus, increased consumption of leucine-rich proteins
provided by Western diet appears as a new dietary factor
promoting sebaceous lipogenesis.
The Link Between mTORC1 and Comedogenesis
Comedogenesis is regarded as the primary process in the
pathogenesis of acne and is induced by increased proliferation
and retention of acroinfundibular androgen-dependent keratino-
cytes.
64
Recently, the PI3K/Akt/mTORC1 pathway has been
shown to stimulate keratinocyte proliferation.
65
In keratinocyte
cultures of high cell density, which imitate states of hyperproli-
feration, isotretinoin decreased keratinocyte proliferation.
66
This
finding can now be well explained by FoxO1-mediated inhibition
of mTORC1.
45
Further evidence points to the role of mTORC1
signaling for keratinocyte proliferation because genetic excision of
TSC1 activated mTORC1 signaling in keratinocytes.
65
Loss-of-
function of either the TSC1 (harmatin) or TSC2 (tuberin) gene,
upstream inhibitory regulators of mTORC1, leads to persistent
activation of mTORC1 resulting in the hamartoma syndrome
tuberosus sclerosis complex.
67
Intriguingly, folliculocystic and
collagen hamartoma of tuberous sclerosis complex with multiple
comedones and keratin-containing cysts lined by infundibular
epithelium have recently been described.
68
These findings support
the view that increased mTORC1 signaling of acroinfundibular
keratinocytes may be involved in comedogenesis.
mTORC1: Central Activator of Lipogenesis
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
deductions for sebocyte biology can be drawn. mTORC1
is a crucial regulatory node controlling protein biosyn-
thesis and cell growth and proliferation. However, cell
growth not only affords the synthesis of new proteins but
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-
1.
70,71
It has most recently been demonstrated that
mTORC1 regulates SREBP by controlling the nuclear
entry of lipin 1, a phosphatidic acid phosphatase.
Nutrient-activated, and especially amino acid-activated,
mTORC1 phosphorylates lipin1, which is retained in the cyto-
plasm and allows promotor binding of SREBP in the nucleus
(Fig. 3). However, in the absence of nutrients and amino acids
mTORC1 activity is suppressed. Lipin 1 enters the nucleus and
displaces SREBP from its promoter sites of lipid synthesizing
target genes. SREBP migrates than to the nuclear lamina.
72
Glucose and amino acid deprivation, which inhibits mTORC1
activity, promoted nuclear accumulation of lipin 1 and thus
suppressed SREBP signaling. On the other hand, cytoplasmatic
retention of lipin 1 with increased SREBP activity was positively
promoted by activated mTORC1, which is stimulated by
availability of glucose, insulin, IGF-1 and amino acids, especially
leucine (Fig. 3 ).
72
These new insights clearly underline the rela-
tionship between nutrient- and amino acid-mediated mTORC1
signaling and SREBP-induced lipogenesis which most likely
applies to sebaceous gland lipogenesis.
Leucine: Precursor of Sebaceous Lipids
The Western diet, enriched in meat and dairy proteins, provides
high and persitantly increasing amounts of leucine. From 1950
to 2010, the annual per capita intake of leucine by consumption
of animal-derived proteins has triplicated in Germany. Leucine
not only contributes to the synthesis of muscle proteins but
most importantly can be converted into lipids (fatty acids and
cholesterol) and stored in adipose tissue.
73
Adipose tissue
efficiently converts BCAAs carbon skeletons into newly synthe-
sized fatty acids, a process that is stimulated by insulin.
73
Remarkably, sebaceous glands like adipocytes are able to take
up and convert leucine into their major sebum lipid classes.
74,75
In this regard, the leucine-enriched Western diet may have two
Figure 3. (A) mTORC1-SREBP-mediated lipogenesis. Activated mTORC1 phos-
phorylates lipin1, which resides in the cytoplasm and allows nuclear SREBP binding
to lipogenic target genes resulting in increased lipogenesis. (B) Inactivation
of mTORC1 results in nuclear entry of lipin 1, which disrupts SREBP binding to
target genes, thus suppressing lipogenesis (modified according to Peterson et al.
72
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major effects on sebaceous lipogenesis: (1) to increase leucine-
stimulated mTORC1/SREBP signaling thus driving the genetic
program of sebogenesis and (2) to provide leucine as a structural
lipid precursor for de novo sebaceous lipid synthesis.
Western Diet and mTORC1-Stimulated T Cell Activity
T cell infiltrates are found in early acne lesions, which are
associated with increased synthesis of interleukin-1aof acne-
prone sebaceous follicles.
76
Thus, the question arises whether
Western diet-mediated mTORC1-overactivity affects T-cell
homeostasis and the regulation of inflammatory immune
responses in acne. In fact, mTORC1 signaling has recently been
appreciated to play a fundamental role in the regulation of T-cell
homeostasis and mTORC1 has been linked to T-cell differentia-
tion, function and metabolism.
77
mTORC1 integrates signals in
the immune microenvironment and programs the generation of
CD4
+
effector vs. regulatory T cells, the generation of CD8
+
effector vs. memory cells, T cell trafficking, and T cell activation
vs. anergy. Thus, mTORC1 provides a direct link between T cell
metabolism and T cell function.
78
Remarkably, the tumor
suppressor TSC1 established a quiescence program in naive
T cells by controlling cell size, cell cycle entry and responses to
stimulation of the T cell antigen receptor. TSC1-deficient T cells
exhibited higher mTORC1 activity, which was essential for the
disruption of immune homeostasis.
79
TSC1-dependent control of
mTORC1 is crucial in actively maintaining quiescence of naive
T cells to facilitate adaptive immune functions.
79
Thus,
stimulation of T cell mTORC1 activity by exaggerated insulin/
IGF-1 and leucine signaling of Western diet may disturb T-cell
homeostasis and promote deviations in T cell signaling involved
in the pathogenesis of acne.
mTORC1-Mediated Pro-inflammatory Signaling
of Keratinocytes
Augmented mTORC1 signaling not only activates T cells but also
appears to be involved in pro-inflammatory signaling of
keratinocytes. In primary human keratinocytes treated with
TNFa, mTORC1 activated pro-inflammatory NFkB signaling,
whereas the mTORC1 inhibitor rapamycin inhibited TNFa-
induced IkB degradation, thus reducing the transcriptional
activity of NFkB.
80
In primary human keratinocytes, TNFa-
mediated activation of mTORC1 and pro-inflammatory NFkB
signaling resulted in increased transcription of pro-inflammatory
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-
signaling pathway, has been demonstrated to physically interact
with and phosphorylate TSC1, thereby suppressing TSC1, which
results in mTORC1 activation.
81
TNFa/IKKβ/TSC1/Rheb-
mediated activation of mTORC1 is thus a most conceivable
mechanism for TNFa-mediated keratinocyte proliferation in
autoinflammatory disorders associated with acne and increased
systemic TNFalevels like PAPA syndrome.
54
Indeed, treatment
with TNFa-antagonist showed benefical clinical effects in patients
with PAPA syndrome.
82-84
The Role of Leucine in T Cell Activation
While research of the last decades has primarily focused on the
role of cytokine and hormonal signals in guiding T cell responses,
the fundamental aspect of cellular energy metabolism and
nutrients that regulate T cell function and differentiation has
been neglected.
85
Most recently, the pivotal role of mTORC1 in
T cell metabolism affecting T cell function and differentiation
has been appreciated.
78
The metabolic demands of T cells are
extraordinarily high and an increase in T cell metabolism has
been recognized as a pivotal contribution to T cell activation.
86,87
The transcription factors KLF2 and FoxO have been implicated
in regulating T cell metabolism.
78
Whereas quiescent T cells are
in a resting state of metabolism characterized by catabolism
driven by autophagy, activated T cells have high demands for
adequate amounts of the essential components for protein,
amino acids, lipid, and DNA biosynthesis involving mTORC1
function.
Leucine plays a fundamental role in T cell activation and
function.
88
Notably, the leucine-antagonist N-acetylleucine
amide (NALA) inhibited T cell function and T cell receptor
(TCR) engagement in the presence of NALA and promoted T cell
anergy.
89,90
NALA inhibited leucine-induced S6K phosphoryla-
tion and was capable of inhibiting amino acid-mTORC1
signaling in Jurkat cells, caused cell cycle arrest at G
1
concomitant
with the inhibition of S6K activation and inhibition of p27
degradation.
89
In as much as a lack of leucine inhibits mTORC1
activation, these latter findings are consistent with the observation
that TCR engagement during rapamycin-mediated mTORC1
inhibition promoted anergy.
91
Similarly, the glucose analog
2-deoxyglucose (2DG) inhibited mTORC1 function most likely
via the AMPK pathway and promoted T cell anergy.
92
Furthermore, the AMPK activator AICAR inhibited mTORC1
and T cell function and mitigated experimental autoimmune
encephalomyelitis.
78
Intriguingly, regulatory T cells can inhibit
T cell function by expressing amino acid degrading enzymes that
deplete the environment of essential amino acids, which are
important for mTORC1 function.
93
These observations clearly demonstrate that hyperalimentation
and especially increased consumption of leucine-rich animal
proteins, predominately milk proteins and meat, drive mTORC1-
mediated mechanisms of T cell activation and inflammation
which may all promote the development of acne.
Glucocorticoids Inhibit mTORC1 Signaling
Glucocorticoids are given during initial stages of severe flares of
conglobate acne. Recently, the molecular crosstalk between
glucocorticoid receptor (GR) and mTORC1 signaling has been
elaborated.
94
A well known adverse effect of prolonged systemic
glucocorticoid treatment is muscle atrophy. In skeletal muscle,
direct target genes of the GR signaling involve the protein
REDD1 (regulated in development and DNA damage responses)
and the transcription factor KLF15 (Krüppel-like factor-15).
Both inhibit mTORC1 activity, although via distinct mechan-
isms. The REDD1 gene is activated at the promotor level by
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ligand-bound GR and is transcriptionally induced under stress
conditions like hypoxia (via HIF1a), which appears necessary
for the downregulation of mTORC1 signaling during stress
conditions.
95
REDD1 functions upstream of TSC2 and Rheb
in order to downregulate mTORC1 signaling in response to
glucocorticosteroids.
95-97
KLF15 upregulates gene expression of branched-chain amino-
transferase-2 (BCAT2), a mitochondrial enzyme, catalyzing the
first step in the catabolism of BCAAs.
98
The glucocorticoid-driven
GR-KLF15-BCAT2 axis may negatively modulate the intra-
cellular availability of BCAAs resulting in a negative impact on
mTORC1 function in skeletal muscle. Glucocorticoid-mediated
downregulation of mTORC1 is not only a superb explanation
for glucocorticoid-induced muscle atrophy, but also for skin
atrophy after long-term systemic or topical glucocorticoid use.
However, long-term use of glucocorticoids induces insulin
resistence of adipose tissue and promotes the development of
obesity, which is associated with hyperleucinemia. Under these
conditions high insulin and leucin plasma levels may promote
mTORC1 signaling of the peripheral sebaceous follicles thus
promoting the development of acne.
Western Diet Stimulates All Major mTORC1
Activation Pathways
The Western diet stimulates all three major pathways important
for mTORC1 activation (Fig. 1). The Western diet provides
abundant energy, glucose, and fat to suppress AMPK activity
increasing mTORC1 signaling (Table 2). The high glycemic load
increases glucose availability and stimulates increased glucose-
dependent insulin signaling. High intake of insulinotropic food
has been a matter of concern for more than a decade.
99
Despite of
all efforts in prevention the total yearly consumption of sugar still
increases worldwide. Highly glycemic and insulinemic foods are
ubiquitous elements of the Western diet and comprised 47.7%
of the per capita energy intake in the United States in the year
2002.
100,101
Today, the proportion of insulinotropic food will be
much higher and is further driven by expanding activities of
multiple fast food distributors.
Milk proteins significantly contribute to high insulin/IGF-1
signaling of Western diet. Mammalian milk has to be regarded as
an endocrine signaling system that upregulates mTORC1 activity
by increasing insulin secretion, hepatic IGF-1 secretion, and
mTORC1-mediated β-cell proliferation for neonatal growth
requirements.
102
Milk consumption not only stimulates the
somatotropic axis but also activates incretin signaling by enteral
stimulation of glucose-dependent insulinotropic polypeptide
(GIP).
57,103
Milks excessive insulinotropic activity is characterized
by milks high insulinemic index.
104
Notably, increased daily
intake of milk but not meat significantly raised basal insulin-
and IGF-1 serum levels and increased insulin resistance in 8-y
old boys.
105
Milk-induced insulin resistance can be explained
by increased mTORC1/S6K1-mediated IRS-1 phosphorylation.
50
Epidemiological data in adults clearly confirmed the correlation
between increased dairy protein consumption and raised IGF-1
serum levels.
58,59
Most importantly, to achieve the physiological requirements
for adequate growth, milk proteins provide highest amounts of
leucine, the most effective, essential amino acid required for
mTORC1 activation. Whey proteins have thus to be regarded as
life starter proteins that not surprisingly contain the highest
amount of leucine (14%), followed by casein (10%), the major
protein constituent of cow milk and cheese (Table 1).
106
For
comparison, 100 g of rump steak contains approximately 2.4 g
leucine comparable to 100 g of Gouda cheese (2.4 g), which is in
strong contrast to 100 g white cabbage (0.056 g), or 100 g apple
(0.016 g). To reach the leucine intake provided by 100 g Gouda
cheese or steak, 4.2 kg white cabbage or 100 apples could be
consumed (Tables 3 and 4). These simple calculations exemplify
Table 2. Mechanisms of mTORC1 activation by Western diet
Compound of Western diet Mechanisms
of mTORC1 activation
High total calories ( = high energy) Reduced activity of AMPK
High glycemic load ( = high energy) Reduced activity of AMPK
Increased insulin signaling
High fat intake ( = high energy) Reduced activity of AMPK
High alcohol intake ( = high energy) Reduced activity of AMPK
High dairy protein intake
( = high leucine)
Increased insulin/IGF-1 signaling and
leucine-mediated mTORC1 activation
High meat intake ( = high leucine) Leucine- and IGF-1-mediated
mTORC1 activation
Table 3. Leucine-enriched animal-derived foods
Food Leucine
(mg/100 g food)
Beef (rump steak) 2,369
Gouda cheese (40% fat) 2,359
Coalfish, cooked 1,883
Broiler, cooked 1,806
Curd cheese (20% fat) 1,290
Yoghurt (3.5% fat) 410
Cow milk (1.5% fat) 381
Source: German Nutrient Database, BLS-version 3.01.
Table 4. Plant-derived foods with low leucine content
Food Leucine
(mg/100 g food)
Corn (cooked) 394
Wheat (cooked) 274
Rice (cooked) 219
Broccoli (cooked) 193
Cauliflower (cooked) 185
Potato (cooked) 124
White cabbage (cooked) 56
Tomato 38
Apple 16
Source: German Nutrient Database, BLS-version 3.01.
26 Dermato-Endocrinology Volume 4 Issue 1
© 2012 Landes Bioscience.
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the extreme differences in leucine amounts provided by an animal
meat/dairy protein-based diet in comparison to a vegetarian or
vegan diet. Thus, the increased consumption of meat and dairy
proteins, staples of Western diet, provides abundant amounts of
leucine for mTORC1 activation. In comparison to meat, milk
proteins offer two major signals for mTORC1 activation, insulin/
IGF-1 as well as high leucine.
49
It is most critical that the
mTORC1-activating system milkis frequently combined with
hyperglycemic carbohydrates or pure sugar (milk plus cornflakes,
milk chocolate or milk ice), a combination which potentiates
mTORC1 activation.
Adolescents exhibit the highest protein intake in comparison to
young children or elderly individuals. Dietary survey data of USA
in 2004which will be much higher todaydemonstrated that
protein intake averaged 56 ± 14 g/d in young children, increased
to a high of approximately 91 ± 22 g/d in adults aged 1930 y,
and decreased to approximately 66 ± 17 g/d in the elderly.
107
Adolescents and young adults of Western countries consume the
highest amounts of total protein. These data correlate with acne
prevalence showing a climax during puberty but persisting into
the third decade of life.
2
High intake of glucose, total energy,
insulinotropic and IGF1-raising food and total intake of animal
proteins increasing the availability of leucine will alltogether
maximize mTORC1 signaling (Table 2).
Signaling of Puberty Superimposed
by Signaling of Western Diet
During puberty, nutrient-mediated mTORC-1 activation over-
laps with puberty-driven (IGF-1/androgen)-mTORC1 activation,
thus promoting epidemic acne. It is important to realize that acne
coincides with the growth phase of puberty induced by increased
pituitary secretion of growth hormone (GH) and GH-mediated
hepatic secretion of IGF-1, which is intimately involved in the
pathogenesis of acne.
108
IGF-1 is a strong stimulator of sebaceous
lipogenesis and upregulates the PI3K/Akt and mTORC1 pathway
resulting in increased expression of SREBP-1, the key transcrip-
tion factor of most lipid synthesizing enzymes.
109
IGF-1 mediated
activation of the PI3K/Akt pathway results in nuclear extrusion of
FoxO transcription factors, recently linked to acne pathogen-
esis.
38,39
IGF-1 is also related to increased androgen signaling, as
IGF1- stimulates adrenal and gonadal androgen synthesis and
increases 5a-reductase activity, the responsible enzyme for the
conversion of testosterone to the 10-fold more potent DHT.
60,108
Intriguingly, subjects with Laron syndrome and congenital IGF-1
deficiency due to loss-of-function mutations of GH receptor
exhibit short stature and do not develop acne or clinical signs
of hyperandrogenism, unless substituted with high doses of
recombinant IGF-1.
110
Remarkably, the transcriptional activity
of the androgen receptor itself is also linked to insulin/IGF-1
signaling. IGF-1 stimulates androgen receptor transactivation
by nuclear extrusion of the androgen receptor cosuppressor
FoxO1 from the androgen receptor complex.
111,112
Thus, there
is substantial evidence for the role of insulin/IGF-1 signaling in
the pathogenesis of acne, an IGF-1- and androgen-dependent
disease. Both, IGF1- and androgen-signals are known to activate
mTORC1, which is necessary for growth in puberty. However,
it appears that normal puberty in non-Westernized populations
does not lead to the development of acne. There is no acne in
adolescent Kitava during puberty who live on a Paleolithic diet
and do not consume hyperinsulinemic, IGF-1-raising food like
hyperglycemic carbohydrates and dairy proteins.
3,4
Thus, there
appears to be a threshold for mTORC1-mediated acne which
is clearly exceeded under conditions of Western life style and
nutrition.
Anti-Acne Agents Inhibit Over-Activated
Nutrient-Stimulated mTORC1
Isotretinoin. Oral isotretinoin (13-cis-retinoic acid), the most
powerful sebum suppressive anti-acne agent, is intracellularly
isomerized to all-trans-retinoic acid (ATRA). ATRA/retinoic acid
receptor (RAR) signaling induces in a secondary response
increased expression of FoxO transcription factors.
40
FoxOs have
been recognized as interacting partners of the mTORC1
pathway.
41
FoxO1, FoxO3 and FoxO4 inhibit mTORC1
signaling by increasing the expression of the AMPK activator
Sestrin3 (Fig. 2 ).
41,43-45
Furthermore, isotretinoin has been shown
to reduce serum IGF-1 concentrations.
113
Thus, isotretinoin
inhibits mTORC1 by increased FoxO-Sestrin3-AMPK-signaling
and decreased IGF-1-PI3K/Akt signaling. Isotretinoin promotes
sebaceous gland hypotrophy and inhibits the G
1
/S checkpoint of
the cell cycle.
114
Indirect evidence links isotretinoins mode of
action to FoxO-mediated inhibition of mTORC1, which induces
autophagy leading to sebaceous gland apoptosis or hypotrophy.
Infact, both mTORC1 inhibition and isotretinoin lead to cell
cycle arrest at the G
1
/S transition.
24,114
Moreover, isotretinoin,
downregulated SREBP1 expression in human sebocytes.
109,114
In
accordance, mTORC1 has been linked to SREBP-regulated lipid
metabolism.
69-72
It is thus conceivable that hyperactivated
mTORC1 signaling induced by Western diet is attenuated by
isotretinoin-FoxO1-mediated suppression of mTORC1 resulting
in autophagy and/or apotosis of sebocytes with decreased SREBP
signaling.
Metformin. It should be emphasized that subjects exhibiting
genetic variants featuring increased expression and responsiveness
of certain components of the somatotropic axis (GH, GHR,
IGF-1 and IGF1R) and/or reduced activity of FoxO transcription
factors will show increased susceptibility for acne and mTORC1
activation.
115
Prototypically, obese women with polycystic ovary
syndrome (PCOS) exhibit signs of hyperandrogenism, acne,
insulin resistance and increased insulin and IGF-1 serum levels.
54
Treatment of PCOS with the anti-diabetic drug metformin
improves overweight, reduces insulin resistance and clinical signs
of hyperandrogenism including acne.
116
Metformin is known to
activate AMPK resulting in mTORC1 inhibition.
28,37
Recently, a
second AMPK-independent mechanism of metformin-mediated
mTORC1-inhibition has been identified. Metformin inhibited
leucine-induced translocation of inactive mTORC1 to Rheb-
enriched lysosomal membrane compartments, thereby attenuating
mTORC1 activity (Fig. 2 ).
52
Metformin is thus an effective dual
mTORC1 inhibitor, reduces overweight, insulin resistance (via
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mTORC1/S6K1-driven IRS-phosphorylation) and hyperandro-
genism. Morover, metformin counterbalances the adverse effects
of Western diet mediated by high insulin/IGF-1 as well as
increased leucine signaling. Metformin (C
4
H
11
N
5
; molar mass
129.1) appears to function as a competitive inhibitor of leucine
(C
6
H
13
NO
2
; molar mass 131.2) in the Rag GTPase-dependent
process of mTORC1 activation. Notably, the usual daily dose of
metformin (2 g/d) is in the range of 2 g leucine derived from daily
consumption of 100 g meat or cheese. PCOS is associated with an
increased risk of cancer. Intriguingly, recent evidence points to
cancer-protective effects of metformin treatment.
117-121
Benzoyl peroxide. Benzoyl peroxide (BPO), the classical
external anti-acne agent commonly applied in excessive concen-
trations between 3 and 10% induces high cellular levels of
hydrogen peroxide (H
2
O
2
), which is able to cross membrane
compartments. Across species, high oxidative stress associated
with the generation of reactive oxygen species (ROS) like
hydrogen peroxide is known to activate nuclear FoxO transcrip-
tion factors by stimulation of the oxidative stress inducible
kinases, Jun N-terminus kinase (JNK) and ST20-like protein
kinase 1 (MST1), which phosphorylate specific FoxO sites
resulting in their nuclear accumulation.
41
Intriguingly, FoxO1,
FoxO3 and FoxO4 activated by oxidative stress induce Sestrin3
transcriptionally. Sestrin 3 activates AMPK and thereby inhibits
mTORC1.
41
Thus, topical BPO-treatment may increase FoxO
transcriptional activities, which finally inhibit mTORC1.
Resveratrol. Resveratrol, a polyphenolic flavonoid from grapes
and red wine, downregulates PI3K/Akt/mTORC1 signaling.
122-126
Intriguingly, resveratrol directly inhibits PI3K by targeting the
class IA PI3K ATP-binding site in a competitive and reversible
fashion.
127
PI3K and mTOR belong to the same family of PI3K-
related lipid kinases. Thus, there is convincing evidence for the
role of resveratrol as a direct and indirect inhibitor of mTORC1
(Fig. 2).
These recent insights imply that resveratrol may exert
therapeutic effects in the treatment of acne. Resveratrol has been
shown to inhibit the proliferation of Propionibacterium acnes.
128
Recently, it has been reported that topical treatment of facial acne
vulgaris in 20 patients with a resveratrol-containing gel (0.01%
weight/volume) significantly reduced the number of microcome-
dones, papules and pustules compared with vehicle control.
129
Epigallocatechin-3-gallate. The specific green tea catechin,
epigallocatechin-3-gallate (EGCG), is regarded as the active
anti-inflammatory and anti-proliferative compound of green tea
extracts.
130-133
EGCG inhibited type I collagen expression in
keloid fibroblasts by inhibition of the PI3K/Akt/mTORC1
signaling pathway.
134
EGCG has been proven to function as
an ATP-competitive inhibitor of both PI3K and mTORC1,
respectively (Fig. 2).
135
Topical 2% green tea lotion was effective in the treatment of
mild-to-moderate acne vulgaris.
136
After 6 weeks, the mean total
lesion count and mean severity index of acne showed significant
reductions of 58% and 39%, respectively.
136
Furthermore, a 3%
green tea emulsion significantly reduced sebum production in
10 healthy male volunteers after 8 weeks of treatment.
137
These
data provide preliminary evidence for the effectiveness of natural
plant-derived mTORC1 inhibitors in the treatment of acne
and underline the role of mTORC1 signaling in the pathogenesis
of acne.
Acne and Prostate Cancer Related
to mTORC1 Signaling?
An epidemiologic association between the prevalence of severe
long-lasting acne and increased risk of prostate cancer later in life
has been reported.
138
This association may depend on a life long
over-stimulation of mTORC1-signaling, which may promote
tumorigenesis.
139,140
L-type amino acid transporters such as LAT1
and LAT3 mediate the uptake of essential amino acids. LAT3 is
most effective in leucine transport. Prostate cancer cells coordinate
the expression of LAT1 and LAT3 to maintain sufficient levels of
leucine needed for mTORC1 signaling and cell growth.
Inhibiting LAT function was sufficient to decrease cell growth
and mTORC1 signaling in prostate cancer cells. These cells
maintained levels of amino acid influx through androgen receptor-
mediated regulation of LAT3 expression, and ATF4 regulation of
LAT1 expression after amino acid deprivation.
140
Anti-androgenic
hormone therapy in prostate cancer may thus reduce cellular
leucine uptake and leucine-mediated mTORC1 activation. Anti-
androgens used in acne treatment may exert similar effects on
cellular leucine influx, which should be investigated in future
experimental studies.
Acne: An mTORC1-Driven Disease
of Western Civilization
Accumulating evidence implies that nutrient-activated mTORC1
signaling plays a pivotal role in the pathogenesis of acne.
Moreover, acne should be linked to other mTORC1-driven
diseases of civilization like obesity, type 2 diabetes, metabolic
syndrome, cancer and neurodegenerative diseases ( Fig. 4).
141-148
The common underlying pathogenic factor of these apparently
unrelated diseases appears to be nutrient-mediated over-activation
of mTORC1 leading to increased cellular growth, cell prolifera-
tion, tumorigenic stimulation, endoplasmic reticulum stress and
deranged cell protein homeostasis.
In this regard it is frightening to realize that more than 85% of
adolescents of Western countries exhibit acne, whereas individuals
of non-Western populations like the Kitava are not affected by
this disease and other mTORC1-driven diseases of civiliza-
tion.
3,149
This implies that the majority of our Western popula-
tion is living with over-activated mTORC1 signaling, a major
pathogenic factor, which probably may pave the way for the
development of other serious diseases of civilization (Fig. 4).
Conclusion and Future Perspectives
Epidemic acne of Westernized societies should be considered as a
visible model disease of exaggerated mTORC1 signaling pro-
moted by the Western diet. Dermatologists should not needlessly
waste time with controversial discussions concerning isolated food
components in the pathogenesis of acne but should realize the
28 Dermato-Endocrinology Volume 4 Issue 1
© 2012 Landes Bioscience.
Do not distribute.
emerging whole network of exaggerated mTORC1 signaling
mediated by Western diet. The most important task of preventive
dermatology will be the reduction of mTORC1. All three major
stimulatory pathways of mTORC1 activation have to be
attenuated. Dietary intervention in acne should thus (1) decrease
total energy, glucose and fat intake, (2) diminish insulin/IGF-1
signaling predominantly mediated by high dairy protein
consumption, and (3) should limit the total leucine uptake
predominantly provided by increased animal protein intake
including meat and dairy proteins. This comprehensive dietary
strategy can only be achieved by higher consumption of vegetables
and fruit and reduction of animal-derived food. Indeed, diets
enriched in vegetables and fruits, vegan diet as wells as Paleolithic
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
group than in the acne group consuming more hyperglycemic
carbohydrates, processed meat and dairy products.
12
Paleolithic
diet regimens come close to the goal of attenuated mTORC1
signaling but have to consider that unlimited total protein
intake may overstimulate leucine-mediated mTORC1 activation.
Vegetable-accentuated diets provide less mTORC1 activating
signals and additionally contain natural plant-derived mTORC1-
inhibitors like resveratrol, EGCG, curcumin, genestein, and indole-
3-carbinol monomers, precursors of 3,3'-diindolylmethane.
The dermatologist should take responsibility for dietary
education and intervention of his acne patients and should
initiate first measures in correcting a harmful nutritional pathway
of over-activated mTORC1 signaling with long-term adverse
effects. A deeper understanding of diet-mediated mTORC1
signaling will help to appreciate the statement of Hippocrates of
Kós who said about 2,400 y ago, Your diet should be your
medicine, and your medicine should be your diet.
Note
This article is dedicated to Professor Otto Braun-Falco on the
occasion of his 90th birthday.
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Figure 4. The march of mTORC1-driven diseases of civilization. Persistent
over-activation of mTORC1 promotes chronic diseases of civilization.
Epidemic acne is a visible indicator disease of excessive mTORC1 signaling
increasing the risk for subsequent chronic diseases of civilization.
www.landesbioscience.com Dermato-Endocrinology 29
© 2012 Landes Bioscience.
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32 Dermato-Endocrinology Volume 4 Issue 1
... Leucine stimulates the mTOR pathway, which supposes an increase in lipogenesis of the sebaceous gland [142]. Because leucine activates mTORC1, those who consume meat/dairy-protein-based diets increase that activation, possibly aggravating the inflammation implicated in acne [143]. Likewise, diets rich in animal protein decrease the diversity of the intestinal microbiota, while plantbased diets increase it [144]. ...
Article
Full-text available
The objective of this narrative review was to check the influence of the human microbiota in the pathogenesis of acne and how the treatment with probiotics as adjuvant or alternative therapy affects the evolution of acne vulgaris. Acne is a chronic inflammatory skin disease involving the pilosebaceous units. The pathogenesis of acne is complex and multifactorial involving genetic, metabolic, and hormonal factors in which both skin and gut microbiota are implicated. Numerous studies have shown the bidirectionality between the intestinal microbiota and skin homeostasis, a communication mainly established by modifying the immune system. Increased data on the mechanisms of action regarding the relevance of Cutibacterium acnes, as well as the importance of the gut–skin axis, are becoming known. Diverse and varied in vitro studies have shown the potential beneficial effects of probiotics in this context. Clinical trials with both topical and oral probiotics are scarce, although they have shown positive results, especially with oral probiotics through the modulation of the intestinal microbiota, generating an anti-inflammatory response and restoring intestinal integrity, or through metabolic pathways involving insulin-like growth factor I (IGF-1). Given the aggressiveness of some standard acne treatments, probiotics should continue to be investigated as an alternative or adjuvant therapy.
... The same author proposes an increase in fruit and vegetable consumption, reducing animal derived food and recommends a paleolithic diet. 12 Interestingly, Jung et al have shown a lower incidence of acne in Koreans adhering to a traditional Korean diet, with a low glycemic index and low-fat content and, conversely, a higher incidence in people following a westernized diet. 13 Along with these factors we have hypothesized that the MD could be the most suitable diet for our patients. ...
Article
Full-text available
Acne is a chronic inflammatory disease of the pilosebaceous unit, and its etiology is complex and multifactorial. The role of the diet in its pathogenesis is still debated. The purpose of this study was to assess the association between MD and IGF-1 in acne patients and, as secondary objective, the role of systemic treatment on IGF-1 serum levels, in accordance with the patients’ diet. This study included 35 patients aged 14-30 years affected by acne and treated in line with the EDF guidelines. Patients were divided into 2 groups based on a questionnaire score assessing the adherence to the Mediterranean diet: the Mediterranean Group (score ≥6) and the Western Group (score< 5). IGF-1 serum levels were measured in all patients before and after treatment and then compared to healthy population. IGF-1 levels were higher in patients than in controls and in the Western group than in the Mediterranean group. We speculate that the Mediterranean diet can have a protective role in the pathogenesis of acne by acting on the systemic route of IGF-1.
... лейкинов 1, 6, 8, 12, и матриксных металлопротеиназ. Более того, некоторые авторы связывают высокую активность mTOR с наступлением раннего пубертата и ранним началом акне, персистированием акне, а также других заболеваний -сахарного диабета 2-го типа, инсулинорезистентности, ожирения, некоторых нейродегенеративных заболеваний [24,25]. С другой стороны, соблюдение диеты с низким содержанием углеводов (25% -белок и 45% -углеводы) сопровождается значимым снижением количества высыпаний у пациентов с акне, повышением чувствительности к инсулину, снижением массы тела [26]. ...
Article
The concept of the exposome, formulated more than fifteen years ago, is increasingly discussed in the modern scientific literature. The term “exposome” is understood as a cumulative measure of the impact of environmental factors on an individual throughout his or her life (from the prenatal period to death) and the biological response associated with it. The sum of these factors has a significant impact on the occurrence, course, and treatment efficacy of multifactorial diseases. The skin is a border organ and is constantly exposed to environmental influences, i.e., it is a target for the exposome. The influence of the latter components has been described in skin aging, atopic dermatitis, and malignant skin neoplasms. Acne is one of the most common chronic inflammatory dermatoses. Over the past decade, the worldwide increase in the incidence of acne, its early onset and a prolonged course, affecting adult men and women, has been noted. The review presents an analysis of the data on the effects of the components of the exposome – diet, medications, stress, and pollutants - on the course of acne. Particular attention is paid to the few data on the nature of interaction between the components of the exposome and the skin microbiome, which, on the one hand, is involved in the pathogenesis of dermatoses, including acne, and, on the other hand, is changed under the influence of exposome factors, acting as an intermediary between the environment and the human body. The search for environmental factors has at least two objectives: the discovery of potential pathogenetic links, the strength of their relationship with the clinical manifestations of the disease to develop new therapies aimed at new targets; and the creation and recommendation of a protective regime for factors with a proven effect on the course of the disease, for patients suffering from acne.
... Eine retrospektive Studie mit über 24 000 Akne-Patienten zeigte eine eindrückliche Korrelation zwischen dem klinischen Schweregrad der Erkrankung und dem Verzehr von zuckerhaltigen Speisen und Getränken [37]. Eine Ernährungsumstellung mit Reduktion der GL konnte hingegen zu einer klinischen Verbesserung der Akne führen und sogar eine Reduktion der Pharmakotherapie bedingen [38]. Kwon [44]. ...
Article
Full-text available
Der Einfluss von Ernährung auf die Pathogenese und den klinischen Schweregrad entzündlicher Gesichtsdermatosen wird seit Jahren kontrovers diskutiert. Das zunehmende Gesundheitsbewusstsein in unserer Gesellschaft hat zuletzt dazu beigetragen, dass auch die Wahl der Nahrungsmittel von Patienten bewusster getroffen wird und Behandler aktiv nach diätetischen Empfehlungen gefragt werden. Viele neue Erkenntnisse zum Thema Haut und Ernährung gründen auf dem Verständnis eines diätetisch beeinflussbaren Darm‐, und Hautmikrobioms, dem sogenannten Konzept der Darm‐Haut‐Achse. So können gastrointestinale Beschwerden bei Rosazea‐Patienten auf eine Dysbiose des Darmmikrobioms hindeuten, deren Behandlung auch den Schweregrad der Hautkrankheit verbessert. Spannende Forschungen bei Aknepatienten untersuchen den klinischen Effekt von Omega‐3‐Fettsäuren und Probiotika auf das Hautbild. Im Rahmen eines Behandlungskonzepts sollten neben pharmakologischen daher auch ernährungsmedizinische Empfehlungen gemäß der aktuellen Evidenz bei Patienten mit entzündlichen Gesichtsdermatosen beachtet werden. Während es bei Akne‐ und Rosazea‐Patienten bereits konkrete ernährungsmedizinische Empfehlungen gibt, ist die Studienlage bei seborrhoischem Ekzem und perioraler Dermatitis hingegen noch limitiert. Die aktuellen Entwicklungen und Erkenntnisse geben einen ersten Einblick in den Zusammenhang von Ernährung und entzündlichen Gesichtsdermatosen. Die Vernetzung von Dermatologie und Ernährungsmedizin wird zukünftig sowohl klinisch als auch wissenschaftlich intensiviert werden.
... A retrospective study with more than 24,000 acne patients showed a striking correlation between clinical severity and consumption of sugary foods and drinks [37]. A dietary change with reduction of the GL, on the other hand, led to clinical improvement of acne and even reduction of pharmacotherapy [38]. In a prospective, randomized, blinded interventional study, Kwon et al. investigated the effect of a ten-week dietary intervention with reduced GL (whole-grain products, vegetables, fruit, fish) and showed clinical improvement of acne with significantly reduced expression of SREBP-1 in biopsies from acne lesions [39]. ...
Article
Full-text available
The influence of nutrition on the pathophysiology and clinical severity of inflammat-ory facial dermatoses such as acne, rosacea, seborrheic dermatitis, and perioral der-matitis has been controversially discussed for years. As part of a modern treatment approach, clinicians should provide patients with information on how their choice of diet might impact their dermatologic diagnosis and could potentially enhance therapeutic outcome. Recently, the concept of a gut-skin axis has gained momentum in the understanding of inflammatory dermatoses, with nutrition considered a contributing factor in this context. For example, gastrointestinal symptoms in rosacea patients may indicate a dysbiosis of the gut microbiome, treatment of which may also improve severity of the skin disease. New research efforts were recently made for acne patients addressing the clinical effects of omega-3 fatty acids and probiotics. In contrast, due to the limited data available, no comparable specific dietary recommendations can yet be made for seborrheic or perioral dermatitis. However, there are promising signs that clinical nutrition and dermatology will be more extensively interlinked in the future, both clinically and scientifically.
Article
Acne is a frequently presented dermatological condition brought about by an interplay among inflammation, increased sebum production, hyperkeratinisation, and predominantly Propionibacterium acnes (renamed as Cutibacterium acnes) proliferation, leading to debilitating psychological scars. However, it has been shown that it is the loss of microbial diversity in the skin and the imbalance among C. acnes phylotypes that brings about acne rather than the C. acnes species as a whole. Interestingly, recent evidence suggests that other microorganisms may be implicated, such as the fungi Malassezia and the bacteria Cutibacterium granulosum. A plethora of scientific evidence suggests that the gut microbiome is implicated in the overall health and physiology of the host; studies show that the gut microbiome of acne patients is distinct and depicts less microbial diversity compared to individuals without acne. Herein, using the key terms: acne, C. acnes, IGF-1, sebum, and gut microbiome, we carried out a review of the literature, using Google Scholar and PubMed, and discussed the role of the gut and skin microbiome in relation to acne, as a narrative review. The role of hormones, diet, sebum, and stress in relation to the gut microbiome was also investigated. Therapeutic implications and the use of pre-/postbiotics are also deliberated upon. In this light, future research should investigate the relationship between the gut microbiome and the agreed upon factors of acne pathology, potentially leading to the discovery of novel acne treatments with milder side effects.
Article
Severe forms of acne vulgaris are accompanied by a pronounced decrease in the quality of life and lead to scarring. Early and effective acne therapy is the prevention of the formation of persistent cosmetic defects. Aim. To identify risk factors and predictors for the development of severe forms of acne vulgaris. Materials and methods. Article searches were performed in PubMed, Google Scholar and the Cochrane Central Registry of Controlled Trials over the period from 15 years to 10/25/2021 for the keywords ‘severe acne’, ‘predictors’ and ‘risk factors’. A meta-analysis was prepared using the Review Manager software (RevMan 5.4.1), The Cochrane Collaboration (2020) in line with international guidelines for systematic reviews and meta-analyzes (PRISMA). Results. 38 publications were included in the review. Risk factors for the development of severe forms of acne vulgaris can be divided into nonmodifable (presence of acne in close relatives, male gender, oily skin type, changes in genes) and modifable (increased BMI, consumption of dairy products, Fast digesting carbohydrates, etc.) In the meta-analysis, a statistically signifcant increase in the risk of severe forms of acne vulgaris in the presence of a history of acne in a close family member was found to be 2.54 times (95 % CI [1.63, 3.91]). It was also found that men have a higher risk of developing severe forms than women (1.16 times {95 % CI [1.04, 1.30]}). People with a BMI higher than 25 (2.54 times {95 % CI [1.63, 3.91]}) and those who consume dairy products 1.59 times more often than three times a week (95 % CI [1.37, 1.85]). Conclusion. Understanding the main risk factors for the development of deep forms of acne vulgaris will help to suspect a severe course of the disease in the early stages and to prescribe effective therapy in time. Male gender, family history, elevated BMI, and dairy consumption suggest a high likelihood of early development of severe acne.
Article
In an era of ever-increasing healthcare expenditures, yet simultaneously worsening outcomes, many of our patients choose between traditional medical care or often unproven alternative therapies. While the recognition of lifestyle change in addressing cardiovascular and metabolic disease grows, there is less understanding of the impact of lifestyle change on issues facing women every day. Millions of women around the globe struggle with infertility, cancer, sexual dysfunction, and dermatologic needs. Yet, research on the benefits of lifestyle change on these conditions is scarce, and gaps exist both in our understanding of evidence-based approaches to address these issues, as well as adequate provider education when evidence exists. The Women’s Health Member Interest Group convened medical experts in these areas that affect women’s lives to provide insights and meaningful education applicable not only for our patients, but also in our own lives.
Article
The ever-increasing frequency of metabolic syndrome (MetS) is still a major challenge of the public health care system, worldwide. In recent years, researchers have been drawn to the uncommon (at first look) link between skin illnesses and MetS. Because of the pro-inflammatory mechanisms and insulin resistance (IR) that are upregulated in metabolic syndrome, many skin disorders are correlated to metabolic dysfunctions, including acne vulgaris. A comprehensive understanding of the link between MetS and acne vulgaris may contribute to the development of new treatment strategies. The current review focuses on dietary and therapeutic interventions and assesses the effect of various approaches such as improving diet by avoiding certain food products (i.e., milk and chocolate) or increasing the intake of others (i.e., food products rich in omega-3 fatty acids), metformin administration, therapy with plant extracts, plant essential oils, and probiotic supplementation on the improvement of certain acne vulgaris severity parameters. These therapeutic approaches, when combined with allopathic treatment, can improve the patients' quality of life.
Article
The goal of this study was to compare the efficacy and safety of Azelic (15% gel of azelaic acid), 1% Clindamycin gel and 0.1% Adapalene gel as a complex therapy in patients suffering from mild to moderate acne. Materials and methods. An open-label comparative study involving 40 patients suffering from mild to moderate papulopustular acne. The study was based on the medical history, a questionnaire form, physical examination results, assessment of morphological and functional skin parameters and dynamics of the life quality index (DLQI). Key findings and conclusions. Positive dynamics of the skin process was observed by the end of Week 6 of the treatment depending on the combination treatment type. The administration of Azelic gel resulted in an increased moisture level of the skin and reduced sebometry indices, skin relief intensity and pigmentation level.
Article
Full-text available
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.
Article
Full-text available
Mammalian target of rapamycin (mTOR) is a central regulator of protein synthesis whose activity is modulated by a variety of signals. Energy depletion and hypoxia result in mTOR inhibition. While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known. Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801. Disruption of the TSC1/TSC2 complex through loss of TSC1 or TSC2 blocks the effects of hypoxia on mTOR, as measured by changes in the mTOR targets S6K and 4E-BP1, and results in abnormal accumulation of Hypoxia-inducible factor (HIF). In contrast to energy depletion, mTOR inhibition by hypoxia does not require AMPK or LKB1. Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible REDD1 gene. Disruption of REDD1 abrogates the hypoxia-induced inhibition of mTOR, and REDD1 overexpression is sufficient to down-regulate S6K phosphorylation in a TSC1/TSC2-dependent manner. Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia.
Article
Botanical extracts and single compounds are increasingly used in cosmetics but also in over-the-counter drugs and food supplements. The focus of the present review is on controlled clinical trials with botanicals in the treatment of acne, inflammatory skin diseases, skin infections, UV-induced skin damage, skin cancer, alopecia, vitiligo, and wounds. Studies with botanical cosmetics and drugs are discussed, as well as studies with botanical food supplements. Experimental research on botanicals was considered to a limited extent when it seemed promising for clinical use in the near future. In acne therapy, Mahonia, tea tree oil, and Saccharomyces may have the potential to become standard treatments. Mahonia, Hypericum, Glycyrrhiza and some traditional Chinese medicines appear promising for atopic dermatitis. Some plant-derived substances like dithranol and methoxsalen (8-methoxypsoralen) [in combination with UVA] are already accepted as standard treatments in psoriasis; Mahonia and Capsicum (capsaicin) are the next candidates suggested by present evidence. Oral administration and topical application of antioxidant plant extracts (green and black tea, carotenoids, coffee, and many flavonoids from fruits and vegetables) can protect skin from UV-induced erythema, early aging, and irradiation-induced cancer. Hair loss and vitiligo are also traditional fields of application for botanicals. According to the number and quality of clinical trials with botanicals, the best evidence exists for the treatment of inflammatory skin diseases, i.e. atopic dermatitis and psoriasis. However, many more controlled clinical studies are needed to determine the efficacy and risks of plant-derived products in dermatology. Safety aspects, especially related to sensitization and photodermatitis, have to be taken into account. Therefore, clinicians should not only be informed of the beneficial effects but also the specific adverse effects of botanicals used for dermatologic disorders and cosmetic purposes.
Article
Nutrition science is a highly fractionated, contentious field with rapidly changing viewpoints on both minor and major issues impacting on public health. With an evolutionary perspective as its basis, this exciting book provides a framework by which the discipline can finally be coherently explored. By looking at what we know of human evolution and disease in relation to the diets that humans enjoy now and prehistorically, the book allows the reader to begin to truly understand the link between diet and disease in the Western world and move towards a greater knowledge of what can be defined as the optimal human diet. Written by a leading expert Covers all major diseases, including cancer, heart disease, obesity, stroke and dementia Details the benefits and risks associated with the Palaeolithic diet Draws conclusions on key topics including sustainable nutrition and the question of healthy eating This important book provides an exciting and useful insight into this fascinating subject area and will be of great interest to nutritionists, dietitians and other members of the health professions. Evolutionary biologists and anthropologists will also find much of interest within the book. All university and research establishments where nutritional sciences, medicine, food science and biological sciences are studied and taught should have copies of this title.
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Pyogenic aseptic arthritis, pyoderma gangrenosum, and cystic acne (PAPA) syndrome is an unusual triad that was recently mapped to a chromosome 15q mutation. We describe a patient from this kindred in whom hypogammaglobulinemia and elevated tumor necrosis factor-a serum levels were detected. The patient responded well to intravenous gammaglobulin and intra-articular corticosteroid therapy. Immune abnormalities can be found in PAPA syndrome and could be the consequence of the chromosomal abnormalities affecting candidate genes on this chromosome with subsequent abnormalities in cytokine or chemokine secretion. Rheumatologists should be alert for this syndrome. Correction of the immune abnormalities may be effective in controlling the disease manifestations.
Article
Many of the anabolic effects of growth hormone (GH) are indirect, occurring through GH-stimulated production of insulin-like growth factor-I (IGF-I) by the liver. As well as being regulated by GH, plasma IGF-I concentrations have been demonstrated to depend upon the level of dietary protein intake, with low protein diets being associated with reduced circulatory IGF-I levels. This inhibitory effect cannot be reversed by GH injection, suggesting that liver sensitivity to GH becomes impaired.To investigate the mechanisms through which protein supply affects GH sensitivity, primary cultures of ovine hepatocytes were grown in defined media, containing various proportions (0.2, 1.0 and 5.0) of jugular amino acid concentrations in fed sheep. Production of IGF-I by these cells was measured after 24 and 48 h in culture by radioimmunoassay. In the first 24-h period basal IGF-I production was the same in all defined media, and GH caused an approximately 2-fold increase in IGF-I release in cells grown in 1.0xor 5.0xamino acid media (P<0.01). Although GH appeared to increase IGF-I release in this period for cells grown in 0.2xamino acid media, this effect was not statistically significant. In the period from 24-48 h in defined media, both basal and GH-stimulated IGF-I production was dependent on amino acid availability (P<0.05 and P<0.001 respectively). Factorial analysis of variance demonstrated a strong positive interaction (P<0.001) between the effects of amino acid availability and GH, such that GH increased IGF-I production by more than 2-fold in cells grown in 5.0xamino acid media (P<0.01) but had no effect on production by cells grown in 1.0xor 0.2xamino acid media.Measurement of steady state concentrations of exon 1-derived IGF-I mRNAs using an RNase protection assay demonstrated that the observed effects on IGF-I peptide secretion were strongly associated with parallel effects at the RNA level.Incorporation of (35)S-methionine into cellular proteins over a 4-h period starting 20 h after transfer to defined culture media was not significantly reduced in 1.0xcompared with 5.0x amino acid media, although rates under both of these conditions were significantly higher than those seen in 0.2xamino acid media (P<0.01). The lack of correspondence between the dose-dependent effects of amino acid supply on cellular protein synthesis and those on basal and GH-stimulated IGF-I production, suggests that amino acid supply modulates IGF-I production through selective mechanisms.Steady state levels of the CCAAT/enhancer-binding protein beta (C/EBPbeta) isoforms, liver-enriched activating protein (LAP) and liver-enriched inhibitory protein (LIP) were determined by Western blotting. When levels of LAP were expressed relative to LIP levels in the same extracts, a significant decrease in the LAP:LIP ratio was observed in response to amino acid limitation (P<0.05).These data strengthen earlier arguments that synergistic interaction between the effects of amino acids and GH on hepatic IGF-I gene expression underlie nutrition-dependent changes in circulating IGF-I titres. The association between these effects and altered levels of C/EBPbeta isoforms suggests that CCAAT/enhancer mediated control of IGF-I gene expression may be involved in this phenomenon.
Background: Previous studies suggest possible associations between Western diet and acne. We examined data from the Nurses Health Study II to retrospectively evaluate whether intakes of dairy foods during high school were associated with physician-diagnosed severe teenage acne.