Critical Thinking

To endocrinology is further contributed . The endocrine

To maintain
homeostasis in humans, a wide array of extracellular factors is involved to harmonise physiological activities among organs and cell types. These
signalling molecules in the form of hormones, peptides, neurotransmitters,
proteins, ions, and lipids act via specific receptors to elicit cellular
responses. Among all the receptor families, more than 700 G protein-coupled
receptors (GPCRs) form the largest and the most diverse receptor group that
participate in virtually all aspects of human physiology. Their physiological
relevance makes them one of the most popular drug targets, remarkably about
half of all known drugs act through GPRCs or the signaling pathways of GPCRs
(Alberts et al., 2002). The identification of the molecular mechanisms
underlying GPCR signaling has progressed rapidly in recent years (see Eglen,
2005; Katritch et al., 2013; Wacker et al., 2017), and the
understanding of GPCRs in the field of endocrinology is further contributed . The
endocrine diseases related to GPCR mutations clearly reflect their importance
in regulating the endocrine systemWYH1 by the naturally
occurring mutations found in patients
with endocrine diseases  (Vassart and Costagliola, 2011). The classical endocrine system
refers to glands that release hormones into the bloodstream and reaching its
target in a distant part of the body. However, over the past twenty years, it
has become clear that the regulations of hormone secretion, as well as the
physiological responses within the target organs are mediated by more fundamental
communications within the local regionWYH2 . Those communications are known as
paracrine, autocrine, juxtacrine and intracrine interactions (Lodish, 2016). In this review, we will focus on our
current, yet evolving, understanding of the autocrine and paracrine signals regulated
by GPCRs in various physiological systems. Nevertheless, with more knowledge
being established regarding cell-cell interaction mechanisms, it has become obvious
that signals mediated by GPCRs are regulated by a myriad of complex
determinants, and could lead to the crosstalk between different signaling
pathways, culminating in an adjusted regulatory effect on target cells. Consequently, this
review will not only focus on well-established paradigms of GPCRs in
autocrine/paracrine regulations, but will also discuss the role of GPCRs being
used to mediate the physiological responses of endocrine organs in the context
of signaling pathways, which may provide a broader insight for future pharmaceutical development.

 

 

 

GPCRs and the hierarchy of endocrine, autocrine and paracrine signalling

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Although the discovery of
autocrine and paracrine interactions was initially overshadowed by the
characterization of endocrine glands, the concept of cells being able to secrete
regulatory elements has been appreciated more than 200 years ago (see Thompson & Bradshaw, 2003). Now it has become clear that the endocrine glands are
regulated by a plethora of internal and external signals via blood circulation,
and these input signals trigger the release of localized autocrine/paracrine messengers.
The pool of autocrine/paracrine factors contribute to the communications and intricate
feedbacks between different cells within the endocrine gland, resulting in a
coordinated hormonal output
and the corresponding physiological outcome. Noticeably, the same chemical molecule
can be used in multiple contexts of endocrine, paracrine or autocrine
signaling, or even in synaptic signaling. But the function of signaling
molecules can be considered in a hierarchical way for majority
of the endocrine organs (Figure 1):
(1) As a circulatory input that initiate the localized following autocrine/paracrine
interactionsWYH3 LHT4 ; (2) As an autocrine/paracrine messenger that mediate the feedback
network among different cells within the endocrine gland; (3) As a hormonal
output secreted by endocrine cells, which enter the circulation and further
serve as a circulatory input for other organs.

 

Among these
signaling processes, the prevalence of GPCRs make them ineluctable targets for
functional studies and endocrine pharmaceutics. Hence, we
are going to illustrate the roles of GPCRs in mediating endocrine signals in
the following aspects: (1)
From the circulatory input to the endocrine gland, GPCRs mediating mediate
the transition from endocrine and other circulatory signals into
autocrine/paracrine signals; (2) Within the endocrine gland, GPCRs responding
respond to autocrine/paracrine factors
and contributing contribute to the
autocrine/paracrine regulatory network that modulate the
hormonal output of the organ;; (3) Within
a single cell inside the gland, tThe
expression of different GPCRs on different cells in the endocrine glands, helps
to adjust different signaling effects of the messengers, thus
enabling an integrated output from the hormonal output from
the organcell. The examples being discussed in
this review are mainly related to energy homeostasis, as it is a vital
prerequisite for survival by optimizing
nutrient utilization. Yet
the concept of GPCRs in the mediation of autocrine/paracrine responses can be
applied to many other endocrine organs that are not mentioned.

 

 

 

GPCRs in pancreatic islet

 

Pancreatic islet is a peripheral endocrine
gland that plays a key role in maintaining blood glucose level and energy
homeostasis. To adjust the energy fluctuation caused by food intake, circadian
rhythm and physical activities, the islet is sensitive to internal signals which
are governed by the hypothalamus, as well as other circulatory nutrients and
hormones that are influenced by the external environment. Examples of GPCRs
involved in these processes are listed in Table 1.

 

 

For sensing circulatory inputs

 

There are numerous GPCRs that recognize
circulatory nutrients and related hormones. One of the best known incretin
hormones is glucagon-like peptide 1 (GLP1), which is mainly produced and
secreted by intestinal L-cells upon food consumption and then circulates to the islet.
GLP1 receptor (GLP1R) couples to the Gs signaling pathway to control
the secretion of insulin, glucagon, and somatostatin that facilitate glucose
disposal. The activation of GLP1R on ?-cells induces a
robust up-regulation of insulin-like growth factor 1 (IGF1) receptor
expression, and triggers the IGF2/IGF1 receptor autocrine loop associated with
an increase of Akt phosphorylation, which the Akt pathway
is the basis for the anti-apoptotic effect WYH5 (Cornu et al., 2010). GLP1R expressed on ?- and ?-cells can also direct the
paracrine regulations by activating the secretion of insulin and somatostatin
that inhibit glucagon secretion by ?-cells. G astric
inhibitory polypeptide (GIP)WYH6 , another
incretin hormone which signals via GIPR and the Gs signaling
pathway, can also mediate similar routes but is less understood (see
Ahrén
2009). Until
recently it was found that GIP can induce production of IL6 by ? cells, , while another paracrine role of GIPR has been suggestedWYH7 . Activation of GIPR on ?-cells could lead to the production
of IL6, which in turn stimulates the production of GLP1 and
insulin secretion by ?-cell (Timper et al., 2016). Besides,
free fatty acids (FFAs) provide an important energy source as nutrients, and they act as ligands of
several GPCRs including GPR40, GPR41, GPR43, GPR84, GPR119 and GPR120WYH8  (Ichimura
et al., 2009). Among these GPCRs, GPR40 (also known as FFAR1) is
expressed in human islets at levels comparable to those of GLP1R. It has been
demonstrated that palmitate can enhance
the secretion of glucagon and insulin via GPR40 on ?- and ?-cells at fasting
glucose level (Kristinsson et al.,
2017), and this positive regulation is primarily transduced
through the Gq/11 signaling pathway (Briscoe et al., 2003). Another
FFA receptor, GRP119 is expressed predominantly in
?-cells. Binding of long chain FFAs to the GPR119 receptor causes an increase
in intracellular cAMP levels via Gs coupling
to adenylate cyclase (AC). In vitro studies
have indicated a role for GPR119 in promoting glucose-stimulated insulin
secretion (GSIS) (Overton et al., 2008).

 

Apart from
the molecules that are determined by food uptake, the pancreatic islet is also
influenced by signals from the central nervous system (CNS). Multiple studies have demonstrated the metabolic roles
of circadian clocks
in key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle (see Huang et al., 2011). In mammals, the suprachiasmatic
nuclei (SCNWYH9 ) express
a robust circadian rhythm of electrophysiological activity, which is known to
play a key role in circadian rhythm generation (see Gillette and Mitchell 2002; Hannibal 2002). As an
oscillator, the SCN controls the melatonin secretion rhythm by the pineal
gland. The expression of melatonin
receptors MT1 and
MT2 in
the human islets has been evidenced by molecular and immunocytochemical
investigation (Peschke et
al., 2007) and the influence of melatonin on
pancreatic ?-cells is connected with a Gi signaling pathways, which
inhibits AC activity and hence lower the cAMP level and the insulin secretion.
The MT2 receptor is also found to inhibit the insulin secretion by suppressing the guanylate cyclase/cyclic guanosine
monophosphate (GC/cGMP) pathway (Stumpf et al., 2008). Besides, the inhibitory effect of melatonin on somatostatin
secretion has been demonstrated in a human pancreatic ?-cell WYH10 line recently (Zibolka et al., 2015). Classical neurotransmitters such as noradrenaline and adrenaline
can also regulate pancreatic hormone secretion. The ?2-adrenoceptors (?2A, ?2B and ?2C) and
?-adrenoceptors (?1, ?2 and
?3) are widely expressed in the body (Alexander et al., 2017), with their physiological functions extensively studied in animal models. The ?2A-adrenoceptor
on ?-cell is important in Gi/o-mediated inhibition of
insulin secretion. Although it is less studied
in humans, the ?2A-adrenoceptor
agonist can prevent excess insulin release (Fagerholm et al., 2011), and
variants of ?2A-adrenoceptor
are associated with type II diabetes (Talmud et al., 2011). Whereas ?-adrenoceptors that are
coupled to Gs work in the opposite direction
and enhance insulin secretion (Porte, 1967). It has also been
noticed that ?1-/?2-adrenoceptors (?1-/?2ARs)
can increase somatostatin content and transcription in mice via ?-arrestin 1 in
addition to the Gs pathway (Wang et al., 2014).

 

 

For
mediating autocrine/paracrine regulations

 

For
instanceWYH11 , 293
islet GPCRs and 271 different endogenous ligands have been identified in human,
of which at least 131 ligands are present in islet cells (Amisten et al.,
2013). However, the majority of islet GPCRs have unknown effects on pancreatic
hormone secretion. Readers may refer to other reviews for the full list of
islet GPCRs discovered in humans and
their comparative analysis with mouse islet GPCRs (Amisten et al., 2013;
Amisten et al., 2017). Interestingly, among all those endogenous ligands, 119
of them activate more than one receptor in the islet; the redundancy in
signaling suggests that a ligand is able to trigger a variety of GPCRs that are
likely present on multiple cell types, thereby diversifying the signaling event
and inferring a robust paracrine regulatory mechanism.

 

 

 

Upon
receiving various input signals, islet cells in turn secrete
autocrine/paracrine molecules that influence the activity of neighbouring
cells. The paracrine interactions between ?-, ?- and ?-cells have been proposed
for a long time, with the somatostatin-secreting ?-cells provide essential
negative feedback to both insulin and glucagon release, and the
glucagon-secreting ?-cells positively regulating insulin and somatostatin
secretion (Taborsky et al., 1978; Rorsman and Braun, 2013; Caicedo, 2013; Gylfe and Gilon, 2014). There
are five human somatostatin receptor subtypes (SSTR1-5) with only SSTR1, SSTR2, and SSTR5
showing predominant
high WYH12 expression
level in islets. SSTR1 and SSTR2 are
selectively expressed on ?-cells and ?-cells, respectively. SSTR5
is well expressed on both ?-
and ?-cells, and moderately well expressed on all ?-cells (Kumar et al., 1999). All SSTRs are Gi/o-coupled,
SSTR2 and SSTR5 can also signal through Gq/11 G-protein.
As demonstrated in the mice model, the inhibitory effect on insulin and
glucagon secretion is mediated by SSTR5 (Strowski et al., 2003) and
SSTR2, respectively (Strowski et al., 2000). While ?-cells act as a
paracrine repressor, ?-cells work as a positively regulator. Acetylcholine
produced by ?-cells is able to stimulates the insulin secretion by ?-cells
via the muscarinic receptors M3 and M5, and
the somatostatin secretion by ?-cells through
M1 (Molina
et al., 2014). M1, M3
and M5 are all coupled to Gq/11
signaling pathway (Bräuner-Osborne & Brann, 1996).  CB1
is densely located in ?-cells. In vitro experiments revealed that the activation of CB1
receptor can enhance insulin and glucagon secretion, which suggests that CB1 can
mediate both paracrine and autocrine communication (Bermudez-Silva et
al., 2008). Apart
from the paracrine feedback system, the glucagon positive autocrine feedback
loop has been revealed in ?-cells. Glucagon secreted by the ?-cells can
upregulate the expression of its own gene,.
Which the which the process
is signals WYH13 throughmediated
by the glucagon receptor and the Gs-mediated signal
transduction (Leibiger et al., 2012). Since the release of
glucagon is stimulated by lack of glucose, t. WYH14 This kind of positive feedback may
help to optimize the hormonal output response under less favourable energetic
conditions.

 

 

 

GPCRs in brain for regulating
energy homeostasisLHT15 

 

The brain influences the
endocrine system in response to environmental changes. The effect of
circulatory hormones, in turn, can regulate the brain chemistry and structure.
Similar to peripheral endocrine glands, the stimulation of brain by the
circulatory inputs can trigger a sophisticated autocrine/paracrine feedback
network, which generates integrated output signals that regulate the body in
return. But different from the peripheral glands, the autocrine/paracrine
regulation in brain usually involves the synaptic signal transduction, which
enhance the specificity of message delivery, and the physical distance between
message sender and recipient can be longer.

 

 

From circulatory inputs
to neuroendocrine signals

 

In the case of energy
homeostasis, it is important for the brain to sense the level of metabolic
substances so that regulate the energy usage. Inside the CNS, the hypothalamus
is considered as an essential place where the nervous system and the endocrine
system meet. Metabolic signals such as glucose, insulin, cholecystokinin (CCK),
pancreatic polypeptides (PP and PYY) and ghrelin have all been found to
modulate the hypothalamic arcuate nucleus (ARC), altering the food intake and
metabolism (see Abizaid & Horvath, 2008). Examples of GPCRs involved in
receiving metabolic inputs are listed in Table 2. Among these signals, ghrelin
has received a great research interest as it can upregulate food intake while
the majority acts in opposite way (see Abizaid & Horvath, 2008). The
circulatory ghrelin is mainly produced by the gastric X/A-like cells of oxyntic
stomach mucosa under hunger situation (Date et al., 2000). In CNS, ghrelin
receptor type 1a (GHSR1a) is highly expressed in the ARC and ventromendial nucleus
(VMN) of the hypothalamus (Ferrini et al., 2009). By activating the
phospholipase C (PLC) via Gq/11-protein, GHSR1a triggers the release of
NPY that exerts paracrine effects (which will be discussed later). The
heteromerization of GHSR1a with other GPCRs further broadens its downstream
responses. Various studies suggest that GHSR1a specifically
forms dimers with the SST5R (Schellekens et al.,
2013), D1R (Jiang et al., 2006; Schellekens et al., 2012) and D2R
(Kern et al., 2012), MC3R (Schellekens et al.,
2012), and 5-HT2cR (Schellekens et al., 2012). Involvement of heterodimers
of the GHS-R1a with D1R or D2R has been demonstrated in dopaminergic mesolimbic circuits
that are responsible for reward signaling of food (Pradhan et al.,
2013). In contrast, many circulatory signals tends down-regulate the
energy intake. PYY are stimulated during meal intake by the presence of
nutrients in the small intestine, especially fat. Y2
receptor (Y2R), which is coupled to Gi/o-
and Gq/11 proteins, is critical in mediating the effects of PYY3–36
on reducing adiposity and feeding. The expression of Y2R
can be found throughout the CNS, within the nodose ganglion and on vagal
afferents, thus the feeding effects of PYY3-36 is possibly
mediated through central, vagal activation or combinations of both (see Karra
et al., 2009). The pattern of c-fos neuronal activation following peripheral
administration of PYY3–36 further suggests the involvement of Y2Rs
in ARC (Karra et al., 2009).

 

 

Paracrine and
autocrine regulations in hypothalamus for energy homeostasis

 

Within the hypothalamus, ghrelin bound mostly
on presynaptic terminals of NPY neurons and stimulates the activity of arcuate
NPY as evidenced by electrophysiological recordings (Cowley et al., 2003). Further studies
have demonstrated the inhibitory effect of NPY on the release of POMC, thyroid
hormone (THS) and corticotropin releasing hormones (CRH), and stimulate the
secretion of hypocretin/orexin and melanin-concentrating hormone (MCH) from the
lateral hypothalamus (LH), which regulate metabolism through
multiple output pathways that eventually enhance appetite (see Abizaid and Horvath, 2008).

 

In contrast, MCH receptor 1 (MCH1R) knockout mice are leaner,
eat less and have increased metabolism than their wild type littermates (Marsh
et al., 2002)

 

 ARC NPY expression is regulated
in an autocrine manner via presynaptic NPY2 receptors present
in NPY neurons to decrease NPY expression (Acuna-Goycolea & van den Pol,
2005).

 

POMC modulates energy homeostasis principally
through central melanocortin system
which exerts a tonic inhibitory control on food intake and energy storage

 

in particular the ventromedial hypothalamic
nucleus (VMH), was clearly associated with increased food intake, morbid
obesity and insulin resistance, while damage to more lateral hypothalamic
structureswas associated with anorexia and adipsia (Anand & Brobeck, 1951)

 

 

it is widely accepted that the control of food
intake occurs through activation of specific hypothalamic nuclei and the
promotion of neuropeptide Y (NPY) and Agouti related protein (AgRP) expression
4, 5, 103, 142, 145, 148, 157,
the distribution of GHSR in central nervous system (CNS), and the modulation of
neurotransmission in extra-hypothalamic areas suggest broader effects than
originally predicted. This is supported by the fact that, in addition to NPY,
the ARC also contains a second set of neurons that produce ?-melanocyte
stimulating hormone (?-MSH), an anorectic peptide formed fromthe cleavage of
the proopiomelanocortin (POMC) protein 34. This protein acts on melanocortin
receptors types 3 and 4 (MC3/4, respectively) present in various hypothalamic
nuclei to reduce food intake and energy expenditure in a manner similar to
leptin. In addition, NPY neuronsproduce a secondorexigenic peptide, theagouti
relatedpeptide (Agrp), an endogenous antagonist to the MC3/4 receptor 38.This
peptide, likeNPY, increases food intake dramatically, but the increase in
foodintakeproducedby this peptide is longlasting, andeffect that is still
notwell understood 39. Similarly, POMC cells also synthesize a second
anorexic peptide, the cocaine and amphetamine related transcript (CART). The
relative contribution of CART versus ?-MSH in the regulation of food intake and
energy expenditure remains unexplained. What is known is that both NPY/Agrp and
POMC/CART neuronswithin the ARC appear to primarily modulate food intake via
their output

targets

 

because the ARC contains the largest
concentration of cells that

produce NPY and have the densest concentration of
leptin sensitive neurons inthe brain, it is generally acceptedthat this
regionis key to the regulation of energy balance (Fig.1).

 

 

Finally,NPY/Agrp neurons in the ARC appear to
synapse onto neighboring POMC/CARTcells to inhibit themusing GABA as a
neurotransmitter

 

 

 

The ghrelin receptor (GHSR),
which is mainly expressed
on NPY/AGRP producing neurons in the ARC of the hypothalamusb16 ,

 

CCKB primarily
CNS, lesser amounts in the gastrointestinal tract, CCKA primarily GI, less in
CNS

 

 WYH1Re-write.

 WYH2Meaning?

 WYH3This
is confusing. Seems to be similar to (2)

 LHT4Use
figure to illustrate

 WYH5Effect
of GLP1 or IGF?

 WYH6Define.

 WYH7Reference?

 WYH8Reference
or review citation.

 WYH9Define.

 WYH10A
cell or a cell line?

 WYH11Not
a good way to start a paragraph.

 WYH12This
means they are not found elsewhere. Do you mean abundant?

 WYH13Incorrect
grammar.

 WYH14Incomplete
sentence.

 LHT15

 b16Statements
like this will need a citation.

x

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