Doi:10.1530/jme-13-024
A WECKMAN and others
Autophagy in the endocrine
Autophagy in the endocrine glands
Andrea Weckman, Antonio Di Ieva, Fabio Rotondo1, Luis V Syro2, Leon D Ortiz3,
Kalman Kovacs1 and Michael D Cusimano
Division of Neurosurgery, Department of Surgery, St Michael's Hospital, University of Toronto, Toronto, Ontario,Canada
1Division of Pathology, Department of Laboratory Medicine, St Michael's Hospital, University of Toronto, Toronto,
should be addressed
2Department of Neurosurgery, Hospital Pablo Tobon Uribe and Clinica Medellin, Medellin, Colombia
3Division of Neurooncology, Instituto de Cancerologia, Clinic Las Americas, Medellin, Colombia
Autophagy is an important cellular process involving the degradation of intracellular
components. Its regulation is complex and while there are many methods available, there is
currently no single effective way of detecting and monitoring autophagy. It has several
" endocrine glands
cellular functions that are conserved throughout the body, as well as a variety of different
physiological roles depending on the context of its occurrence in the body. Autophagy is also
" endocrine diseases
involved in the pathology of a wide range of diseases. Within the endocrine system,
autophagy has both its traditional conserved functions and specific functions. In the
endocrine glands, autophagy plays a critical role in controlling intracellular hormone levels.
In peptide-secreting cells of glands such as the pituitary gland, crinophagy, a specific form
of autophagy, targets the secretory granules to control the levels of stored hormone.
In steroid-secreting cells of glands such as the testes and adrenal gland, autophagy targets
the steroid-producing organelles. The dysregulation of autophagy in the endocrine glands
leads to several different endocrine diseases such as diabetes and infertility. This review aims
to clarify the known roles of autophagy in the physiology of the endocrine system, as well as
Journal of Molecular
in various endocrine diseases.
Endocrinology(2014) 52, R151–R163
Autophagy, self-eating, or self-cannabalism is a genetically
autophagy, such as crinophagy, lipophagy, mitophagy
programmed and evolutionarily conserved intracellular
and zymophagy among others which involve the
catabolic pathway. The word ‘autophagy' derives from
deliberate degradation of specific substrates. Unless
the Greek ‘auto', meaning oneself, and ‘phagy', to eat
otherwise indicated, from this point forward, the term
(Under normal physiological
autophagy will be indicative of macroautophagy.
conditions, autophagy aims to maintain cellular homeo-
Although the existence of autophagy was discovered
stasis via the degradation and recycling of long-lived or
many years ago, it only recently became a rapidly growing
damaged proteins and organelles. The three main types
area of research. Along with its basal physiological roles,
of autophagy, macroautophagy, microautophagy and
autophagy is crucially involved in the development
chaperone-mediated autophagy (have different
and advancement of various diseases such as neurode-
functions and proceed by means of different mechanisms,
generation, cardiac, pulmonary, muscle and liver diseases,
with the common end result of lysosomal degradation
infection, immunity and cancer
(). There are also various specific forms of
, ). Although a large
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A WECKMAN and others
Autophagy in the endocrine
Types of autophagy
Schema of types of autophagy.
amount of research has been done on autophagy, in both
chain 3 (LC3) conjugation systems
physiological and pathological states of the endocrine
Even this ‘core' set is composed of several
system, it has never been consolidated. The present paper
different groups within each subgroup, revealing a
reviews the function and regulation of autophagy, and
complex system of regulation in which each component
its role in the activity of the endocrine glands.
plays a different role vital to the proper functioning ofautophagy as a whole. All of these proteins act down-stream of mammalian target of rapamycin (mTOR) kinase,
Autophagy: regulation and function
the master negative regulator of autophagy, which is itself
The term autophagy denotes the degradation of
regulated by the stimulation of the class 1 PI3-K complex
various cytoplasmic components via lysosomal delivery.
by extracellular activation of growth factor receptors.
Cytoplasmic components include long-lived or damaged
Autophagy is also regulated by AMP-activated protein
organelles and macromolecules, intracellular pathogens
kinase (AMPK) which reacts to energy stress (low energy),
and, acting alongside the ubiquitin-proteosome system,
nuclear and cytosolic p53 tumour suppressor proteins,
build-ups of protein aggregates (
which respond to oncogenic or genotoxic stress, the Bcl2
Autophagy involves several steps beginning with
protein family, eIF2alpha, which is activated under
induction – it is most commonly triggered by nutrient
conditions of nutrient deprivation and endoplasmic
deprivation (– and continuing with the
reticulum (ER) stress, the Ras pathway and several other
engulfment of the aforementioned cytoplasmic consti-
tuents by a double-membraned phagophore or isolation
membrane to form an autophagosome. The auto-
). When the cell has sufficient
phagosome then fuses with the lysosome, exposing its
nutrients, mTOR kinase inhibits the ULK1 protein complex,
contents to lysosomal degradation. The products of
thereby suppressing autophagy. Under conditions of
this breakdown are recycled and reused as nutrients
nutrient starvation, mTOR kinase is inactivated, disinhibit-
to help the cell to survive. There are already extensive
ing ULK1 and activating the intricate, multi-step process of
reviews that explore each of these steps in detail (
autophagy (Although the molecular
players in mammalian autophagy are slowly being clarified
relatively recent discovery of 31 autophagy-related (ATG)
and confirmed, there is still much to be discovered.
genes in yeast, and the subsequent discovery that many
A complete understanding of the external and internal
are evolutionarily conserved between yeast and higher
signalling regulation, as well as the downstream effectors
eukaryotes such as mammals, has led to huge advance-
that are involved in the process of autophagy, has important
ments in the detailed understanding of the molecular
implications for the development of future therapeutic
machinery and mechanisms involved in mammalian
interventions in a variety of pathological conditions.
autophagy ().
Autophagy has numerous physiological functions.
The ‘core' Atg proteins have been divided into
During periods of metabolic stress, such as nutrient
various subgroups: the ULK protein complexes, the
deprivation, hypoxic conditions and/or lack of growth
class III PI3-K/Vps34 complex, the Atg9/mAtg9-WIPI-1
factors, autophagy degrades proteins to provide the amino
transmembrane protein complex and the Atg12 and light
acids necessary for survival. These amino acids are used to
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A WECKMAN and others
Autophagy in the endocrine
synthesiseAUTHOR COPY ONLY
proteins critical for cell adaptation to stress.
monitoring of autophagy, a highly dynamic process,
They can also be used by the tricarboxylic acid cycle (TCA)
remains a challenge in the field. An important distinction
to produce ATP for cellular energy (
must be made between the measurement of number
). Autophagy also serves as a
and volume of autophagic components at a certain point
type of quality control mechanism, clearing the cell of
in the process, vs the measurement of autophagic flux.
damaged or very old proteins and organelles, protein
The former represents a static quantification of a dynamic
aggregates and foreign pathogens
process. For example, the number of autophagosomes is
Recently, it has been proposed that autophagy
often used as a direct quantification of autophagic activity.
acts as a ‘guardian of the genome' (
It is possible, however, that a build-up of autophagosomes,
preventing genomic instability and DNA mutations
instead of representing an increase in autophagic activity,
that eventually lead to tumour development (
could represent a blockage of their fusion with lysosomes,
Along with its basal physiological level of
and thus an inhibition of autophagic activity as a whole.
action, autophagy is involved in specific processes such as
Thus, purely monitoring autophagosomes cannot be used
ageing, where it is proposed to have a potential anti-ageing
as a reliable indicator of autophagic activity. The latter,
effect, cellular differentiation and various aspects of
which involves monitoring the progression of autophagy
developmental progression (
from autophagosome formation through to lysosomal
Focus on autophagy in physiology and pathology has
degradation, represents a dynamic measurement of a
rapidly increased because it became apparent that there
dynamic process and as such provides more precise
are many diseases in which autophagy probably plays
information on the true state of autophagic activity.
an important pathogenic role (
The most long-established method of detecting
autophagy uses the electron microscope to ultrastructu-
Clarifying the pathways and mechanisms
rally detect the presence of autophagic structures in
of autophagy under normal conditions is essential to
both selective and non-selective autophagy. Electron
explaining its dysregulation in the development of
microscopy remains one of the most widely used
disease. Moreover, to uncover the exact mechanisms and
techniques for autophagy detection. It is, however,
pathways of autophagy under normal conditions in a
particularly vulnerable to misinterpretation and bias, and
specific system, first requires knowledge of where and in
its use in concert with other methods has been strongly
what capacity autophagy is acting within that system.
Thus, the present paper aims to provide the foundation for
microscopy is another approach that is often applied to
understanding the complete picture of autophagy in the
assess autophagic activity. Microtubule-associated protein
endocrine glands (Autophagy has been impli-
LC3 is the only known mammalian autophagosome
cated in endocrine conditions such as infertility, and
marker (and it exists within the
endocrine diseases such as diabetes. Providing a basisfor the involvement of autophagy in the normal endo-
cell in a cytosolic form (LC3-I), which is converted into
crine system and under pathological conditions is the first
an autophagosomal membrane-bound form (LC3-II) upon
step in elucidating its specific mechanisms and pathways
induction of autophagy. As LC3-II is concentrated on
in the system. Ultimately, a more systematic approach
the autophagosome membrane, counting the number
to our understanding of autophagy in the endocrine
of GFP-LC3 punctae per cell is a common means of
system will enable efficient development of novel
quantifying autophagosomes in vivo (
therapies for various endocrine diseases.
A third methodof measuring autophagic activation involves the separ-ation and quantification of relative levels of LC3-I and
Methods of monitoring autophagy
LC3-II via western blot. Immunodetection of other ATG
The reliable assessment and study of a phenomenon are
proteins (i.e. BECN1) has also been used as a general
only as good as the techniques used to detect and monitor
indicator of autophagy in the prognosis of various human
it. Thus, in order to fully consider the impact of autophagy
cancers; however, more research is necessary to establish
research, the various techniques for its detection must be
a solid correlation between immunodetection of ATG
briefly discussed. Although there have been several recent
proteins and autophagic activity (
comprehensive reviews on the topic (
Generally, static quantification of LC3 has been deemed
), the proper detection and
to be a useful marker for autophagy; however, these
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A WECKMAN and others
Autophagy in the endocrine
Overview of autophagy in endocrine glands
Autophagya function as currently known
Location: both crinophagy and macroautophagy demonstrated in all secretory cell types of the anterior pituitaryRole: crinophagy is both a mechanism for normal turnover of secretory material and a means to deal with
production of excess secretory material
Regulates/maintains proper intracellular levels of secretory protein
Control: suggested modulation of crinophagy by steroidsRole: macroautophagy appears to be responsible for the turnover of peptide-synthesising machinery
(ER, ribosomes) rather than secretory granules
Note: lack of recent research; mechanism and role remains poorly understood
Location: macroautophagy demonstrated in ovaries of various mammals including humansRole: required for germ cell survival during ovary development, involved also in granulosa cell survival and cell
death, follicular atresia and CL regression
Control: oxLDL-dependent LOX1 autophagic activation in follicular atresia also induced by nutrient deprivation
and cigarette smoke in animal models
Note: thought that macroautophagy may be involved in both obesity-related infertility and age-related infertility
Location: macroautophagy demonstrated in rat Leydig cells, role not known in human testesRole: steroid-producing organelles (mitochondria, smooth endoplasmic reticulum) targeted in autophagosomes,
implying that macroautophagy plays a role in regulation of steroid production in Leydig cells
Control: in Leydig cells, rate of macroautophagic activity fluctuates in tandem with steroid secretion (increased in
inhibited cells and vice versa)
Note: macroautophagic deficiency implicated in reduction of testosterone production in aged rat Leydig cells
Location: macroautophagy demonstrated in both adrenal medulla and adrenal cortexRole: macroautophagic activity demonstrated in adrenal medulla cells; however, no publications on role;
possible role of crinophagy similar to that of other peptide-secreting endocrine cells
Role: macroautophagy in adrenal cortical cells same role as in Leydig cells (control of intracellular steroid levels
via organelle degradation)
Thyroid: limited data on autophagy in thyroid gland under physiological or non-cancerous pathological
Thyroid hormone levels do not appear to be regulated by autophagy
Note: secretory granules containing calcitonin in parafollicular cells of thyroid may be regulated by crinophagy
similarly to other endocrine cells
Parathyroid: in bovine parathyroid, crinophagy functions to eliminate excess hormone; no human data
Location: both macroautophagy and crinophagy demonstrated in pancreatic islet B-cells; endocrine organ most
extensively studied in terms of autophagy
Role: levels of B-granules storing insulin are kept constant by crinophagy; correlation between rates of insulin
synthesis and secretion and rate of crinophagy
Crinophagy activated in islets during periods of hormone overproduction or suppression of hormone secretion;
thus, regulates secretory granule levels
Control: corticosterone and progesterone activity on glucocorticoid receptors modulates crinophagy in pancreatic
islets; prostaglandin level may also be involved in crinophagy regulation
Role: macroautophagy protects B-cells from ER and oxidative stress by eliminating protein aggregates and
digesting damaged mitochondria
Note: Deficient macroautophagy is thought to play a major role in pathophysiology of type 2 diabetes
N.B. macroautophagy vs crinophagy: 1) both macroautophagy and crinophagy appear to regulate intracellular hormone levels in the endocrine system viadifferent mechanisms – the former via degradation of hormone-producing machinery, the latter via direct fusion of secretory granules with lysosomes;2) as steroids are not stored in secretory granules, in steroid-secreting endocrine cells, crinophagy does not exist and macroautophagy is the predominantcontrol mechanism of intracellular hormone levels.
aHere, autophagy refers to autophagy in general; crinophagy and macroautophagy are differentiated within the table.
methods are not perfect and each has specific caveats
the cell is ultimately reduced during prolonged auto-
required to maximise accuracy and reliability.
phagy, the observed decrease in LC3 is inversely correlated
LC3 is also useful in autophagic flux assays. As LC3-II
to autophagic flux and can be measured using flow
itself is degraded in autolysosomes, monitoring LC3-II
cytometry or fluorescence microscopy
turnover gives an idea of autophagic flux. This is
Other cellular components that are selectively
accomplished by using western blot to compare the
taken up by autophagosomes for degradation, such as
amounts of LC3-II in the presence or absence of a
p62 (), can be monitored in a similar
lysosomal inhibitor. The difference in the amounts of
manner. An mRFP–GFP–LC3 construct takes advantage of
LC3-II represents the amount that has been degraded and
the fact that GFP loses its fluorescence in the low pH of the
thus the autophagic flux. Furthermore, as total LC3 within
lysosome to depict autophagic flux (
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Autophagy in the endocrine
cellular components, to the lysosome for degradation,
or anchored to autophagosomes, LC3 will fluoresce
the direct fusion of secretory granule to lysosome
yellow. Autolysosomes containing LC3, however, will be
(crinophagy) presumably spares the granule membrane
labelled red, as GFP is quenched. Thus, the progression
from degradation and allows it to be recycled (
from autophagosome formation to its fusion with a
lysosome can be monitored using this tandem construct.
appears to be a more energy efficient method of autophagy
The classic technique to monitor autophagic flux
for the specific regulation of normal fluctuations in
involves the measurement of long-lived protein degra-
secretory material. The most common method of crino-
dation. Incubating cells with radiolabelled amino acids
phagic detection was, and currently remains, electron
followed by a shorter incubation without radiolabelled
microscopy. Evidence of crinophagy has been uncovered
amino acids allows for the proteosomal degradation of
in most of the endocrine glands, and is generally accepted
labelled short-lived proteins and results in only long-lived
as the main way that peptide-secreting endocrine cells
proteins with radioactive labels. As long-lived proteins
degrade excess secretory material (It
are predominantly degraded via autophagy, the release
has been established that crinophagy is upregulated in
of acid-soluble radioactivity resulting from the degra-
response to an inhibition of secretion or an overproduc-
dation of the proteins is measured to indicate autophagic
tion of secretory material, but the mechanism of
flux. To account for any non-autophagic degradation
induction and regulation remains largely unknown.
of radiolabelled proteins, the results are compared with
Modulation by steroids has been suggested in the
those from a condition in which an autophagic inhibitor
pituitary, where oestrogen positively and progesterone
is applied to the culture
negatively correlated with crinophagy of prolactin
secretory granules (
This brief summary of several techniques for detecting
and the pancreas, where progesterone upregulated
and monitoring autophagy represents only the most
and corticosterone downregulated crinophagy in B-cells
common methods. A more comprehensive look at the
(As progesterone had an opposite
existing techniques and their limitations has been
effect on crinophagy in the pituitary compared with the
described in detail elsewhere
pancreatic islets, there appears to be no universal relation-
). It must be emphasised that each
ship between progesterone and crinophagy. In the
technique has its limitations and the strongest and
pancreatic islet B-cells, changes in crinophagy levels due
most reliable experimental approaches are ones that use
to progesterone and corticosterone were blocked with
several techniques to create a multi-faceted assessment
mifepristone, a receptor antagonist for both corticoster-
of autophagy.
one and progesterone receptors (Furthermore, crinophagy levels positively correlated withincreased production of prostaglandin E2 via progesterone
Autophagy in the endocrine glands
stimulation and its decreased production via corticoster-one stimulation. This suggests that in pancreatic B-cells,
corticosterone and progesterone stimulation may directly
Crinophagy, discovered in pituitary mammotrophs by
modulate crinophagy through their regulation of prosta-
and so named by Christian
glandin E2 ). In the pituitary,
derives from the Greek word ‘crin', which
however, where oestrogen is known to induce the synthesis
means ‘to secrete' It describes the
and secretion of prolactin, the correlation between
process whereby secretory granules containing cell-
oestrogen and crinophagy may be an indirect one; the
specific proteins for secretion from endocrine glands fuse
increase in crinophagy triggered by the overproduction of
directly with lysosomes for degradation
prolactin rather than by oestrogen stimulation directly
It should be noted that as steroids are not stored in
(). More research is required to
granules, crinophagy does not occur in steroid-secreting
confirm the mechanism(s) of steroid-dependent crino-
cells of the endocrine glands. There is a notable
phagy modulation. Inhibition of negative regulators has
functional/structural difference between the elimination
also been suggested as a method of inducing crinophagy
of secretory granules by crinophagy and by macroauto-
and autophagy when hormone secretion is inhibited.
phagy. Whereas autophagy engulfs the secretory granule
In secretory-deficient pancreatic B-cells, LAMP2, a negative
in its entirety and delivers it, along with many other
regulator of autophagy, was significantly downregulated
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Autophagy in the endocrine
in which crinophagy and autophagy had been
Although the complete mechanism and regulation of
upregulated This suggests that the
crinophagy in the pituitary gland remains poorly under-
inability to secrete hormones somehow activates an
stood, as discussed above, several studies have correlated
intracellular signalling cascade that induces crinophagy
rates of crinophagy in mammotrophs to levels of steroid
and autophagic degradation of secretory granules. Regard-
hormones such as oestradiol or progesterone, whereby
less of the mechanism and whether the initiating event is
oestrogen seems to induce crinophagy and progesterone
specific to each cell type, as many other aspects of crino-
seems to decrease it, indicating that crinophagy in the
phagy are conserved between endocrine cells, it is likely
pituitary gland may be modulated by steroids (
that the final downstream effectors are the same in all
peptide-secreting cells. In the remainder of this section, the
In addition to the direct fusion of secretory granules
presently known specifics of crinophagy (and autophagy)
with lysosomes (i.e. crinophagy), autophagic vacuoles
in the context of each endocrine gland will be described.
encompassing protein-synthesising machinery such asrough ER and ribosomes, but rarely secretory granules,were also found in mammotrophs of the anterior pituitary
gland (). Thus, it seems that the
The discovery of autophagy, and more specifically,
autophagic system accounts mainly for the turnover of
crinophagy, in the anterior pituitary gland began with
secretory protein synthesising machinery, rather than
the investigation of mammotrophs, lactotrophs or pro-
the secretory granules themselves After
lactin-secreting cells of the hypophysis. In secretory cells
adrenalectomy, hypersecretion from corticotrophs caused
such as those of the anterior pituitary, crinophagy
a corresponding increase in autophagy of non-granule
functions as both a normal physiological mechanism for
cellular constituents, establishing a logical link between
the regular turnover of secretory material, as well as a
high rates of secretory activity and increased rates of
means of dealing with the induced production of excess
organelle turnover (). Although the volume
secretory material. During the natural oestrous cycle of the
of mammotrophic autophagic vacuoles fluctuated with
rat, if pregnancy does not occur and prolactin is not
the natural oestrous cycle of the rat, remaining low during
required, the excess prolactin granules fuse with lyso-
the proestrous phase, beginning to rise in early oestrous
somes to be degraded and their amino acid components to
and peaking near the end of the oestrous phase (
be recycled (During lactation, mammo-
it was mostly crinophagy that controlled standard
trophs increase the synthesis and secretion of prolactin,
secretory granule levels. Within the oestrous cycle,
which decreases after weaning, while crinophagic bodies
autophagic vacuoles increased as the surface area of the
degrading excess prolactin-filled secretory granules
rough ER and Golgi apparatus decreased, further support-
increase after weaning (Crinophagy
ing the proposition that autophagy is mostly involved
can also be induced. After premature removal of suckling
with controlling hormone synthesising machinery
young from lactating mother rats, the secretory activity
rather than secretory granule levels
of mammotrophs is inhibited, and the resulting excess
In addition, autophagy was found to be most active during
secretory granules are eliminated via crinophagy (
externally induced cellular involution in the mammary
). Although research regarding crino-
phagy in the pituitary gland has predominantly focused
The lack of recent research is a severe limitation to
on mammotrophs, crinophagy has also been confirmed
our understanding of autophagy in the pituitary gland.
in other cell types of the rat pituitary such as cortico-
With modern tools and techniques, the precise role and
troph, somatotroph, gonadotroph and thyrotroph cells
mechanisms of regulation of autophagy and crinophagy
in the pituitary could be more thoroughly elucidated. This
discovered that crinophagy increased in the
lack of research most likely stems from a lack of demand
corticotrophs during states of both hypersecretion due to
for increased knowledge concerning autophagy in the
adrenalectomy and hyposecretion induced by admini-
pituitary gland. As with all scientific endeavours; however,
stration of dexamethasone. Thus, in the pituitary gland,
it must be considered that there remain untouched roles
crinophagy acts in tandem with natural and induced
for autophagy in the normal pituitary, or in its patho-
fluctuations in secretory activity to continuously regulate
logies, that could be revealed using modern technology.
and maintain proper intracellular levels of secretory
These discoveries could help to explain the patho-
physiology of pituitary diseases such as hypo- and
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A WECKMAN and others
Autophagy in the endocrine
hyperpituitarism, or even provide a better understanding
the CL regresses at the end of the menstrual cycle. Electron
of autophagy that could be translatable to other human
microscopic studies revealed the presence of autophago-
endocrine glands and tissues.
somes in many cells during CL regression (At the molecular level, there is a specific endocrinevoltage-activated sodium channel in the human ovary
Ovaries and testes
from which downstream signalling induces autophagy
The discovery of autophagy in the ovaries of a wide range
in CL regression ). Conversely, there is
of animals including Drosophila, fish, quail, nonhuman
increased beclin-1 expression in CL cells during pregnancy
primates, mice and other small mammals, suggests a
as well as in pathological conditions when the CL survives
highly conserved role of autophagy in various ovarian
longer than normal, implicating autophagy in granulosa
processes, such as follicular atresia and corpus luteum (CL)
cell survival as well ). True to the
regression. Autophagy is also an important mechanism in
double-edged reputation of autophagy, these findings
human physiological ovarian function. During develop-
suggest opposing roles for autophagy in CL dynamics.
ment, before the formation of the primordial follicle pool,
This collection of animal and human studies provides
autophagy appears to be required for germ cell survival
convincing evidence for the occurrence and importance of
(). Later, in each menstrual cycle,
autophagy in ovarian function.
ovarian follicles not chosen as the preovulatory follicle
To our knowledge, there are no English-language
undergo follicular atresia. Originally, follicular atresia was
papers exploring the role of autophagy in the human
thought to occur entirely by apoptosis. The discovery of
testes. In rats, however, autophagy occurs more in
granulosa cell death via oxidised LDL (oxLDL)-dependent
normally functioning, testosterone-secreting Leydig cells
lectin-type oxLDL receptor (LOX1)-activated autophagy,
than in many other cell types In Leydig cells,
however, suggests that autophagic forms of programmed
cell death are also involved
producing organelles such as mitochondria and smooth
). As obese women have increased levels of
ER, implying that autophagy has a role in the process of
and consequently a
steroid production. Furthermore, the rate of autophagic
higher incidence of autophagic granulosa cell death, this
activity fluctuates in tandem with steroid secretion –
pathway could account for a higher rate of infertility in
autophagy is increased in inhibited cells and decreased in
obese women (LOX1 stimu-
stimulated cells (This pattern of
lation by oxLDL has also been associated with an increased
activation and inhibition of autophagy closely resembles
level of reactive oxygen species (ROS) leading to oxidative
that of crinophagy in the peptide-secreting cells of the
stress and apoptotic cell death. In younger, normal weight
pituitary. As steroids are not stored in secretory granules
women, reparative autophagy is induced in response to
within the cells, steroid-secreting cells deal with excess
low levels of ROS in order to avoid apoptosis and promote
secretory material via degradation of steroid-producing
cell survival An increase in ROS levels,
organelles (Thus, in rat Leydig cells,
as well as a decline in autophagic markers (LC3-II) in
traditional autophagy appears to be involved in the
human granulosa cells of older women suggests that there
regulation of steroid secretion in a manner analogous to
is a decline in reparative autophagy with age leading
crinophagy in peptide-secreting endocrine cells. This
to granulosa cell apoptosis (,
process is most likely upheld in steroid-producing cells
). This result is in concordance with the
of the ovary and adrenal gland as well.
well-documented, age-related decline in female fertility
Autophagic deficiency was also recently implicated in
the reduction of testosterone production in aged rat Leydig
Various other factors, such as nutrient deprivation
cells. It is generally established that autophagy decreases
and, more recently, cigarette smoke, have also been shown
to induce autophagic programmed cell death in granulosa
case of aged Leydig cells, decreased autophagy, particularly
cells of animal models (These
mitophagy or the selective degradation of damaged
findings offer a promising explanation for the reported
mitochondria, leads to a decrease in the clearance of
correlation between smoking and infertility in female
dysfunctional mitochondria and consequently, an
accumulation of ROS. As ROS are detrimental to Leydig
After ovulation, a progesterone-producing endocrine
cell steroidogenesis
organ, the CL, is formed in the ovary. Without pregnancy,
this accumulation leads to a decrease in testosterone
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Autophagy in the endocrine
ultimately resulting in conditions such as late-onset
regenerating liver (suggested that inhibiting
autophagic degradation is a pro-growth mechanism in
There is evidence of autophagy in Sertoli cells of rat
fast-growing organs such as the regenerating liver and
testes, as well. Increased mitochondrial-mediated germ
ACTH-stimulated adrenal cortex
cell apoptosis has been observed in ethanol-treated rats
A more recent study has mentioned that Atg5K/K mice
(Electron microscopy and immuno-
exhibited ubiquitin-positive protein aggregate formation
histochemistry of autophagy genes (i.e. Lc3) also exposed
in the liver, the anterior pituitary lobe and the adrenal
the presence of autophagy in the Sertoli cells of ethanol-
cortex In contrast, only a small number
exposed rats. Of most importance was the discovery of
of protein aggregates were displayed in the skeletal muscle
increased mitophagy, leading to the hypothesis that
and the heart (This data seems
mitophagy may be acting in an anti-apoptotic capacity
to stress the importance of autophagy in the endocrine
against ethanol toxicity in Sertoli cells by clearing
glands in particular. Perhaps the increased incidence of
damaged mitochondria and preventing their release of
misfolded and aggregated proteins in autophagy-deficient
pro-apoptotic factors
endocrine cells such as pituitary and adrenocortical cells
The collection of research investigating autophagy
is a direct consequence of their increased rate of hormone
in the ovaries and testes of humans and animals reveals,
production and turnover. The connection between
not surprisingly, a diverse set of confirmed and proposed
increased vulnerability to toxic protein aggregation in
functions for autophagy within the reproductive system.
endocrine cells and autophagy certainly merits further
The relative lack of human data, however, leaves the
research, with the potential for shedding light on
impression that much remains to be discovered.
underlying mechanisms in endocrine diseases.
Thyroid and parathyroid glands
In the adrenal medulla, adrenaline and noradrenaline are
Very little research has been performed regarding auto-
stored in secretory granules similar to those of other
phagy in the thyroid gland under physiological or non-
peptide-secreting endocrine cells, and a cytochemical
cancerous pathological conditions. Although the thyroid
study of adrenal medulla cells revealed evidence of
hormone precursor thyroglobulin is proteolytically clea-
autophagy within those cells (
ved into the active thyroid hormones tri-iodothyronine
. Although to our knowledge no
(T3) and thyroxine (T4) by lysosomes, it is stored in the
recent research has been published on autophagy in the
extracellular follicular colloid, rather than in intracellular
adrenal medulla, it is highly probable that the roles of
granules (Thus, thyroid hormone levels do
crinophagy and autophagy in other peptide-secreting
not appear to be regulated by crinophagy or autophagy.
endocrine cells are translatable to the secretory cells of
It is likely, however, that secretory granules containing
the adrenal medulla.
calcitonin in the parafollicular cells of the thyroid gland
As the adrenal cortex is composed of steroid-secreting
are regulated by crinophagy in a similar fashion to the
cells similar to Leydig cells of the testes, it is likely that
majority of endocrine cells.
autophagy has a comparable function in both. In fact, a
Recently, it was discovered that thyroid hormones,
study looking at both Leydig and adrenocortical fascicu-
in particular T3, induce autophagy in in vitro human liver
lata cells in rats showed that autophagy in steroid-
cells and in vivo mouse liver cells (
secreting cells plays a hormone-producing modulatory
In particular, T3 induces selective autophagy of lipids,
role similar to that of crinophagy in peptide-secreting
otherwise called lipophagy, an important mechanism for
endocrine cells (In addition, there is a
lipid homeostasis, metabolism and mobilisation of lipids
unique role for autophagy in the growth regulation of
in hepatic cells (
parenchymal cells in the adrenal zona fasciculate (
Similarly, there is very little to be found about
By measuring autophagic vacuole fractional
autophagy in the parathyroid gland. In the bovine
volume in adrenocortical zona fasciculata cells in rats
parathyroid gland, crinophagy occurs in response to the
exposed to adrenocorticotropic hormone (ACTH),
suppression of parathyroid hormone secretion; in this
showed that autophagy was strongly inhibited
case, secretion is suppressed by high concentrations
during ACTH-induced hyperplasia. This finding, along
with the discovery of the same phenomenon in the
Crinophagy in the bovine parathyroid gland thus
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A WECKMAN and others
Autophagy in the endocrine
functions AUTHOR COPY ONLY
as a means to eliminate excess hormone,
Traditional autophagy also plays its traditional role in
analogous to the mechanism in other endocrine cells.
the functioning of pancreatic B-cells by degrading andrecycling macromolecules and old or damaged organelles(
Pancreatic islets
ER's protein-folding capabilities cannot keep up with the
Autophagy in the endocrine system has been most
demands (e.g. during chronic hyperglycemia), the cell
extensively studied in the pancreas. Pancreatic B-cells are
enters a state of ER stress. ER stress leads to a build-up of
the sole source of insulin in circulation and, as such, are
misfolded proteins, which, if not immediately degraded,
critical for the regulation of blood glucose levels (
become protein aggregates and ultimately result in cellular
Elevated glucose levels stimulate insulin
toxicity and apoptosis ,
secretion from B-cells. Insulin then acts at fat, liver and
It has been suggested that autophagy is generally
muscle cells to induce absorption of glucose from the
required to eliminate protein aggregates, while the
bloodstream or to stop hepatic glucose production. As in
ubiquitin-proteasome system degrades soluble misfolded
other endocrine cells, once insulin is synthesised, it is
proteins that have not yet formed aggregates (
packaged into secretory granules, termed B-granules,
ready for secretion via exocytosis. As B-granules have a
dysfunction caused by stressors such as chronic hyper-
half-life of only 3–5 days, a basal level of crinophagy
glycaemia induces the accumulation of ROS within the
ensures that the number of B-granules stays relatively
cells, resulting in oxidative stress. Autophagy protectsB-cells from oxidative stress by digesting the damaged
constant and the ‘old' B-granules are continuously turned-
mitochondria (Due to the high level of
over Several landmark studies investigated
protein synthesis that occurs in pancreatic B-cells, they are
the relationship between glucose, B-cell stimulation and
especially susceptible to ER and oxidative stress (
intracellular insulin degradation (
. Autophagy plays an
indispensable role in the maintenance of B-cell per-
at varying levels of glucose stimulation, a corresponding
formance during adverse conditions.
imbalance between rates of insulin synthesis and insulin
From a pathological standpoint, type 2 diabetes is the
secretion influenced the rate of crinophagy in isolated
most researched disorder involving pancreatic B-cells and
pancreatic islet cells. It was only at intermediate levels of
autophagy. Type 2 diabetes is characterised by insulin
glucose, where there was sufficient stimulation to increase
resistance in peripheral tissues (i.e. fat, muscle, liver), as
insulin synthesis but not to trigger insulin secretion, that
well as impaired insulin secretion resulting in chronically
B-granules accumulated and crinophagy was upregulated
elevated blood glucose levels, and subsequent death of
(Furthermore, in Rab3AK/K (secretion-
pancreatic B-cells. With the intent of uncovering a
deficient) mice, B-cells responded to insulin overproduc-
definitive role for autophagy in the pancreas, several
tion by increasing both crinophagic and autophagic
studies have focused on a conditional (B-cell specific)
degradative processes to keep B-granule levels stable
knockout of Atg7, an autophagy-related gene, in the
(Thus, similar to the rest of the
pancreatic B-cells of mice
endocrine system, crinophagy is activated in pancreatic
These mice demonstrated the hallmark dysfunc-
islets during periods of hormone overproduction or
tions of type 2 diabetes: defective insulin tolerance,
suppression of hormone secretion, to digest and ulti-
decreased insulin blood levels (and secretion), and decre-
mately recycle excess secretory granules.
ased B-cell mass due to increased cell death and decreased
The specifics of crinophagy induction and modulation
B-cell proliferation. In addition, Atg7-deficient mice
in the pancreas are complex and incompletely known.
exhibited accumulation of ubiquitinated protein aggre-
Along with the ability of glucose to modulate crinophagy
gates and damaged organelles (i.e. mitochondria, ER), the
levels, showed that corticosterone
presence of which most likely caused the increase in cell
and progesterone acting on glucocorticoid receptors
death and resulting decreased B-cell mass (
affected intracellular degradation of insulin, potentially
A human study of type 2 diabetic
by affecting the production of prostaglandins within the
patients revealed an accumulation of autophagosomes in
B-cells. This finding represents the first mention of a
B-cells, most likely due to impaired removal of the
possible downstream molecule that could be involved in
autophagosomes, and a corresponding increase in B-cell
the regulation of crinophagy.
death ). Together, these findings
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A WECKMAN and others
Autophagy in the endocrine
implicate AUTHOR COPY ONLY
deficient autophagy as a major player in the
all peptide-hormone-producing cells, it is likely that
pathophysiology of type 2 diabetes.
crinophagy plays the same role as in the other peptide-
One of the proposed causes for the onset of B-cell
secreting cells discussed above.
deterioration in type 2 diabetes is diet-induced nutrient(free fatty acids (FFA), glucose or both) surplus (
Future implications
For example, chronic glucose overload leads to anunsustainable increase in insulin demand, eventually
The topic of autophagy has garnered increasing attention
resulting in toxic ER and oxidative stress within the
with the discovery of its role in a wide range of
B-cells. Chronic exposure of isolated mouse, rat and
physiopathological processes. In several glands, notably
human pancreatic B-cells to FFAs also impaired insulin
the pituitary, adrenal and thyroid glands, there is a major
lack of recent research about autophagy/crinophagy, or
and induced autophagy,
in the former case, research at all. Although the gold
especially an increase in autophagosome formation (
standard for detecting crinophagy (i.e. electron microscopy)
). If autophagy were dysfunc-
has not changed since its discovery (
tional, as hypothesised in type 2 diabetes, the build-up of
, reassessing these glands based on
misfolded proteins and ER/oxidative stress products
recent research would most likely be enlightening. For
caused by hyperglycemia and lipotoxicity would invari-
example, understanding the basis of crinophagy as a tool
ably lead to B-cell damage and death. As obesity,
to modulate intracellular hormone content, it is plausible
characterised by high levels of FFAs in the circulation, is
to extrapolate that dysfunctional or overactive crinophagy
the primary cause of type 2 diabetes, these findings created
may play a role in those cases of hypo- or hyper-endocrine
a strong link between glucolipotoxicity, type 2 diabetes
activity that have no other visible explanation. Knowing
and autophagy. strengthened this
that autophagy already has a known involvement in
connection using Atg7-deficient mice. Although control
endocrine diseases such as type 2 diabetes and infertility is
mice exposed to a high-fat, diet-induced autophagy in
sufficient evidence to warrant renewed investigation into
the pancreatic B-cells protect themselves from the FFA-
autophagy in the pathologies of the other endocrine glands.
induced B-cell dysfunction, oxidative stress and resulting
For research concerning autophagy and crinophagy to
apoptosis, Atg7-deficient mice exposed to a high-fat diet
progress, the detection techniques must necessarily
could not induce autophagy and experienced extensive
progress as well. As autophagy has been implicated in a
B-cell death, along with other classic features of type 2
wide range of diseases and its potential as a therapeutic
diabetes (Thus, it appears that
target appears extremely promising, the proper inter-
autophagic deficiency in pancreatic B-cells plays an
pretation of autophagic activity is critical to our under-
important role in the pathogenesis of type 2 diabetes.
standing of its involvement and our ability to act
Although various studies have suggested potential mole-
accordingly. Currently, the best approach to monitoring
cular mechanisms to describe the pathway surrounding
autophagy involves the use of several moderately reliable
the contribution of autophagy in B-cells and diabetes
Continued research into the specific players and markers
none have been definitively proven or
of autophagy will allow us to develop increasingly reliable
reproduced. As more evidence concerning the general
detection and monitoring techniques. As autophagy
involvement of autophagic deficiency in type 2 diabetes
has the potential to be both activated and inhibited
accumulates, its precise delineation will be critical in
in different stages of the same disease, being able to
taking advantage of the discovery. The current state of this
accurately monitor its progression is critical in maximis-
research provides the basis for an interesting new avenue
ing the potential for appropriate therapeutic intervention.
of investigation that could focus on therapeutically
Furthermore, there is little or no information on
targeting the molecular mechanisms of pancreatic B-cell
the mechanisms and pathways that lead to the activation
autophagy in patients with type 2 diabetes.
or inhibition of crinophagy specifically. Everything
There has been no research focused on autophagy or
from the extracellular initiating event to the intracellular
crinophagy in the other endocrine cells of the pancreas
signalling cascade currently remains a black box.
(i.e. alpha, delta, gamma or epsilon cells), although
Thus, future research should attempt to uncover this
did show that autophagy in alpha and delta
signalling mechanism and perhaps even attempt to com-
cells was not affected in humans with diabetes. As they are
pare it with what is known about autophagy signalling.
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A WECKMAN and others
Autophagy in the endocrine
considerably more known about the mechanism
the precise molecular mechanisms must be elucidated.
and regulation of autophagy – our understanding is still
There is a large gap in current research on the topic. With
not complete, however, and perhaps there is new
modern technologies and techniques, the scientific com-
information to be gained from further exploring crino-
munity has much to gain from a renewed interest in the
phagy. Another interesting avenue of future research
molecular mechanisms of autophagy in the endocrine
would be to determine how much of the crinophagic
system, especially under pathological conditions.
and autophagic pathways are conserved between eachendocrine gland. As the overall function of both processesis conserved between the glands, it is likely that the
Declaration of interest
intracellular signalling pathways downstream of the initial
The authors declare that there is no conflict of interest that could be
signalling event are also similar. Knowing which aspects
perceived as prejudicing the impartiality of the review.
of crinophagy and autophagy are conserved betweenglands and which aspects are specific would be important
for therapeutically targeting them in gland- or even cell-
This research did not receive any specific grant from any funding agency in
specific diseases such as diabetes.
the public, commercial or not-for-profit sector.
In addition to the traditional role for autophagy in cellular
The authors are grateful to the Jarislowsky and Lloyd Carr-Harris
homeostasis, stress survival and general cellular ‘house-
foundations for their generous support.
keeping', there is a major theme that underlies the roleof autophagy in the endocrine system specifically. In each
gland, autophagy is involved in the regulation of intra-
cellular hormone levels and thus indirectly involved in
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Received in final form 19 December 2013Accepted 8 January 2014
Ñ 2014 Society for Endocrinology
Published by Bioscientifica Ltd.
Printed in Great Britain
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Source: http://idclasamericas.co/Documentos/Investigacion/Publicaciones/Neuro%20Oncologia/JME130241.pdf
Replacing limit learners with equally powerful one-shot query learners Steffen Lange1 and Sandra Zilles2 1 Fachhochschule Darmstadt, FB Informatik, Haardtring 100, 64295 Darmstadt, Germany, 2 Technische Universit¨at Kaiserslautern, FB Informatik, Postfach 3049, 67653 Kaiserslautern, Germany, Abstract. Different formal learning models address different aspectsof human learning. Below we compare Gold-style learning —interpretinglearning as a limiting process in which the learner may change its mindarbitrarily often before converging to a correct hypothesis—to learningvia queries—interpreting learning as a one-shot process in which thelearner is required to identify the target concept with just one hypothesis.Although these two approaches seem rather unrelated at first glance,we provide characterizations of different models of Gold-style learning(learning in the limit, conservative inference, and behaviourally correctlearning) in terms of query learning. Thus we describe the circumstanceswhich are necessary to replace limit learners by equally powerful one-shot learners. Our results are valid in the general context of learningindexable classes of recursive languages.In order to achieve the learning capability of Gold-style learners, thecrucial parameters of the query learning model are the type of queries(membership, restricted superset, or restricted disjointness queries) andthe underlying hypothesis space (uniformly recursive, uniformly r. e., oruniformly 2-r. e. families). The characterizations of Gold-style languagelearning are formulated in dependence of these parameters.
Liver International ISSN 1478-3223 A£atoxin genotoxicity is associated with a defective DNA damageresponse bypassing p53 activation Ozge Gursoy-Yuzugullu1,2, Haluk Yuzugullu1,2, Mustafa Yilmaz2 and Mehmet Ozturk1,2 1 Centre de Recherche INSERM, Institut Albert Bonniot, Universit ´e Joseph Fourier U823, Grenoble, France2 Department of Molecular Biology and Genetics, BilGen Genetics and Biotechnology Research Center, Bilkent University, Ankara, Turkey
