# Hexarelin Signaling to PPARγ in Metabolic Diseases

Authors: Annie Demers; Amélie Rodrigue-Way; André Tremblay
Journal: PPAR Research
 (2008)

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## Abstract

Investigating the metabolic functions of the nuclear receptor peroxisome proliferator-activated receptorγ (PPARγ) has been extremely rewarding over the past years.
Uncovering the biologic roles of PPARγ and its mechanism of action has greatly advanced our understanding of the transcriptional control of lipid and glucose metabolism, and compounds such as thiazolidinediones which directly regulate PPARγ have proven to exhibit potent insulin-sensitizer effects in the treatment of diabetes. We review here recent advances on the emerging role of growth hormone releasing peptides in regulating PPARγ through interaction with scavenger receptor CD36 and ghrelin GHS-R1a receptor. With the impact that these peptides exert on the metabolic pathways involved in lipid metabolism and energy homeostasis, it is hoped that the development of novel approaches in the regulation of PPAR functions will bring additional therapeutic possibilities to face problems related to metabolic diseases.


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## Body

## 1. Introduction

Vascular diseases impose the greatest burden upon health care
systems and are predicted to remain the leading cause of death and disability
in industrialized countries. The identification of excess body weight as a
major risk factor, the epidemic of obesity and diabetes in Western societies
and their increasing prevalence in children indicate that pathologies
associated to the metabolic syndrome will continue to impact the health of
individuals. Insulin resistance is a recurrent trait associated with increased
adiposity, and despite the amplitude of health problems related to metabolic
disorders, the mechanisms underlying excessive fat storage by adipocytes remain
largely undefined.The
adipocyte is the major site of fatty acid storage in the body and plays a
critical role in maintaining normal glucose and lipid homeostasis. If the
capacity of the adipocyte to store lipids is exceeded, it can no longer
regulate normally the release of fatty acids into the circulation, which
ultimately leads to the abnormal accumulation of lipids in fat tissues and
nonadipose depots. Such buildup of lipids in fat, liver, pancreatic islets, and
muscle cells is associated to metabolic dysregulation of these tissues,
resulting in many pathologic states of the metabolic syndrome, such as central obesity,
atherosclerosis, type 2 diabetes, and insulin resistance
[1, 2]. Over the
recent years, with the unveiling of their ability to behave as master
regulators of an array of genes that coordinate numerous pathways in lipid,
glucose, and energy metabolism, the
peroxisome proliferator-activated receptors (PPAR) have been considered
important targets in the therapeutic management of metabolic disorders.


## 2. The PPARs, Fatty Acid Sensors

The PPARs
consist of three isoforms, PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3), all of which
are bona fide members of the nuclear receptor family. Upon ligand
activation, the PPARs act as transcription factors by directly binding DNA as
obligate heterodimers with retinoid X receptor RXR (NR2B) to a peroxisome
proliferator response element (PPRE) contained in the promoters of target
genes. With identified ligands such as mono- and polyunsaturated fatty acids,
and derivatives such as eicosanoids, the PPARs have been recognized as
physiologic sensors for fatty acids that control the transcription of many
genes governing lipid metabolism [3–5].PPARα
is predominantly expressed in the liver, where it activates a broad range of
genes involved in fatty acid uptake, glycerol metabolism, β-
and ω-oxidation
of unsaturated fatty acids, and their transport into peroxisomes [6]. PPARα deficiency results in hypoglycemia and
hypoketonemia, fatty liver, and elevated plasma fatty acids, revealing its
importance in the hypoglycemic response [7, 8]. When fed a high-fat diet, PPARα-null
mice are unable to catabolize fatty acids and develop severe
hypertriglyceridemias without aPPARent obesity [9]. It is therefore predicted that fibrates, which
selectively activate PPARα,
are effective in treating hyperlipidemias [10]. PPARβ/δ
is expressed ubiquitously and while biochemical and genetic evidence has linked
PPARβ/δ
to aspects of the metabolic syndrome [11–13], its emerging role in lipid metabolism remains to
be further ascertained. Although the benefit of targeting PPARα
and/or PPARβ/δ
in lipid disorders is not excluded, the current review specifically emphasizes
on PPARγ
and its metabolic control by growth hormone releasing peptides.


## 3. PPARγ, A Metabolic Regulator of Insulin Resistance

Insulin resistance is marked by hyperinsulinemia,
enhanced hepatic gluconeogenesis, and impaired insulin-stimulated glucose
uptake into skeletal muscle and fat. Elevated levels of circulating fatty
acids, associated with obesity and insulin resistance, increase fat
accumulation in insulin target tissues and contribute to defective insulin
action. In addition, obese adipose tissue-derived inflammation and altered secretion
of adipocyte proteins, also known as adipokines or adipocytokines, can also
impair insulin signals and affect systemic metabolism [14, 15]. The resulting hyperglycemia,
dyslipidemia, and hypertension of the metabolic syndrome cause endothelial
dysfunction and hasten vascular diseases.Over the
recent years, a number of adipokines, some of which being adipocyte-specific
while others are not, have been identified to be produced and secreted by
mature adipocytes. Adipokines, such as adiponectin and leptin which exhibit
insulin-sensitizing effects, or resistin, tumor necrosis factorα (TNFα), and interleukin-6
(IL-6) which act as insulin resistance factors, all share autocrine, paracrine, or endocrine activity that regulates insulin sensitivity, therefore,
establishing a role for the adipose tissue to function as an endocrine organ [14, 16, 17].Remarkably,
the thiazolidinediones (TZDs), which have been described as high-affinity
ligands for PPARγ [18, 19], can modulate in a beneficial manner the expression of many if not
all of these adipokines at the gene level, thereby correlating adipokine
production with PPARγ activation. Originally discovered because of their potent
insulin-sensitizing and glucose-lowering effects, TZDs are being used in
clinics to correct abnormalities of lipid and glucose homeostasis, such as in
type 2 diabetes, by reducing tissue insulin resistance [20]. For example, TZDs
enhance adiponectin gene expression and circulating protein levels [21, 22], and decrease resistin [23, 24], TNFα [25], and IL-6 [26]. This suggests that the effect by
which TZDs enhance insulin sensitivity likely resides in their ability to
promote a beneficial profile of hormones secreted by adipocytes, which can then
influence glucose disposal by the liver and muscle.However,
the mechanism by which TZD activation of adipocyte PPARγ leads to insulin
sensitivity is not completely understood. Adipocyte-derived leptin is a
circulating regulator of appetite and energy expenditure, whose increased
levels reduce food intake and minimize ectopic lipid deposition by promoting
fatty acid oxidation in peripheral tissues [27]. These effects contribute to the insulin-sensitizing properties of
leptin, but its expression was found downregulated by PPARγ ligands [28, 29]. TZDs were also found
to stimulate adipogenesis by upregulating many PPARγ target genes involved
in fatty acid metabolism and storage [30]. Studies in rodent models and in humans have shown that TZD
treatment causes weight gain [31, 32], an unwanted side effect that limits TZD efficacy on insulin
sensitivity by increasing adiposity. This paradox remains largely unexplained,
and among the likely hypotheses raised are a selective unequal accumulation of
subcutaneous fat compared to visceral depots, and a possible activation of
distinct yet overlapping adipogenic/antidiabetic gene programs in the adipocyte
induced by TZDs [20, 33].The use of genetic mouse
models including tissue-specific deletion of thePPARg gene has enabled
the identification of fat tissue as the primary target for TZDs but also
revealed that other insulin-sensitive organs, such as liver and muscle, albeit
expressing lower levels of PPARγ compared to fat,
were also responsive to some extent to TZDs. Mice lacking white adipose fat,
resulting in a phenotype similar to that
of humans with lipoatrophic diabetes, fatty liver, hyperglycemia, and insulin
resistance [31], or mice lacking adipose PPARγ, which
also exhibit an insulin resistance phenotype [34], were refractory to the antidiabetic, but not the hypolipidemic effect of
TZDs. In addition, these mice were highly predisposed to hepatic steatosis, an
effect mainly attributed to liver PPARγ [35, 36]. TZDs also retained their glucose-lowering effects
in liver- and muscle-specific PPARγ knockout mice [37, 38], arguying for a predominant role of adipose PPARγ in the
insulin-sensitizing effects of TZDs, although another study reported that
muscle PPARγ
contributes to some extent to insulin resistance which was not improved by TZDs
[39]. The kidney also appears as a target for TZDs in
which however, renal PPARγ activation lead to fluid retention by inducing the
Na+ transporter ENaC in the collecting duct [40, 41]. This adverse effect of TZDs is viewed as a
serious complication for patients with preexisting congestive heart failure [42]. In addition, the prototype TZD troglitazone was
withdrawn from clinics due to life-threatening hepatic toxicity, whereas the
other two TZDs, rosiglitazone and pioglitazone, are still being used in
large-scale clinical practice. Hence, the crucial benefit of TZDs to consistently lower fasting and postprandial glucose
concentrations as well as free fatty acid concentrations in clinical studies is
clearly established, but also tempered by other effects, mostly undesired, therefore adding
complexity in our understanding of the systemic response to PPARγ ligands [43]. It thus becomes essential
and of fundamental interest that other ways need to be identified in order to
avoid the adverse effects of TZDs while keeping the benefits of correcting whole body glucose
and fatty acid dysfunctions.


## 4. The GHRP-PPARγ Pathway in Macrophages

One
critical step initiating fatty streak formation in atherosclerosis consists in the accumulation of oxidized
lipoprotein particles, mainly oxLDL, into the intima and their subsequent
uptake by monocyte-derived macrophages, leading to the formation of
cholesterol-loaded foam cells. Many lines of evidence suggest that the endocytosis of
oxLDL by macrophages is mainly dependent upon their interaction with CD36, a
member of the class B scavenger receptor family [44–47]. Studies in macrophages have shown
that oxLDL uptake through CD36 provides a
source of oxidized fatty acids and oxysterols that activate,
respectively, PPAR and LXR (liver X
receptor; NR1H3), thereby inducing a metabolic cascade
resulting in enhanced expression of downstream genes, such as apolipoprotein E
and ABC sterol transporters, and ultimately in cholesterol efflux to high
density lipoproteins (HDL) [48]. However, these
aPPARent beneficial effects are opposed by a positive feedback loop in which
PPARγ
activation by internalized fatty acids enhances the expression of CD36, a
process shown to mediate foam cell formation [49–53].CD36
is an 88 kDa glycoprotein originally identified as a platelet receptor and also
known as fatty acid translocase, which is expressed in numerous cell types
including monocytes/macrophages, platelets, endothelial cells, and adipocytes [53–55]. CD36 is a multiligand receptor that is recognized
by fatty acids, anionic phospholipids, thrombospondin, and oxidized
lipoproteins. It is this latter property of scavenging (e.g., clearing) oxLDL
which implicates CD36 in the initial steps of atherogenesis, as evidenced with studies in mice [53, 56] and humans [57].The
findings that growth hormone releasing peptides (GHRPs) serve as ligands for
CD36 [58, 59] led to the evaluation of their potential role in
regulating cholesterol metabolism in macrophages. The GHRPs belong to a class
of small synthetic peptides known to stimulate growth hormone release through
binding to the GH secretagogue-receptor 1a (GHS-R1a), a G-protein-coupled
receptor originally identified in hypothalamus and pituitary [60] and later recognized as the receptor for ghrelin [61]. The peripheral distribution of the ghrelin GHS-R1a
receptor in tissues, such as heart, adrenals, fat, prostate, and bone, has
supported physiological roles of ghrelin and GHRPs not exclusively linked to GH
release. For example, GH-independent effects on orexigenic properties, fat
metabolism, bone cell differentiation, and hemodynamic control have been
reported for ghrelin and GHRPs [62, 63]. Also, in conditions in which GH release was not
promoted or in GH-deficient animals, the GHRP hexarelin was shown to feature
cardioprotective effects by preventing ventricular dysfunction [64, 65], and by protecting the heart from damages induced
by postischemic reperfusion [66]. These studies suggest that part of the beneficial
effects of hexarelin may not involve GH release.To
evaluate the potential of hexarelin to regulate cholesterol metabolism in vivo,
apolipoprotein E (apoE)-null mice maintained on a long-term high-fat and high-cholesterol
diet, a condition known to promote atherosclerosis, showed a significant
regression in plaque formation when treated with hexarelin compared to
saline-treated controls [67]. These beneficial effects were observed in
conditions in which GH was not upregulated by hexarelin [67], and also using EP80317, an hexarelin derivative
with no GH release activity [68], supporting a GH-independent role for GHRPs.To
address the mechanism by which hexarelin exerts these beneficial effects,
treatment of differentiated THP-1 macrophages or mouse peritoneal macrophages
with hexarelin resulted in an increase in cholesterol efflux, which correlates
with an enhanced expression of LXRα, apoE, and sterol transporters ABCA1 and ABCG1, all
involved in promoting the high density lipoprotein (HDL) pathway (see Figure 1).
In addition, these effects were severely impaired in treated peritoneal
macrophages isolated from PPARγ
heterozygote mice, implying an essential role for PPARγ
in mediating the response to hexarelin [67]. We further showed using cell reporter assays that
the interaction of hexarelin with CD36 or with ghrelin receptor resulted in an
enhanced transcriptional activation of PPARγ, suggesting that both receptors signal to PPARγ
[67]. These studies have
helped to define that the beneficial effects of hexarelin involved the
activation of the PPARγ-LXRα-ABC
metabolic cascade, thereby causing macrophages to mobilize excess cholesterol
into the HDL cholesterol reverse pathway [67]. These findings therefore support a novel regulatory
pathway by which CD36 and possibly ghrelin receptor may impact PPARγ-regulated functions. Consequently,
a detailed knowledge of the concerted modulation of CD36 and ghrelin receptor
signaling pathways may help to provide additional strategies in pathologic
conditions such as atherosclerosis.Figure 1
A
GHRP-PPARγpathway in macrophages. Overview of the effects of hexarelin which by
interacting with scavenger receptor CD36 and GHS-R1a ghrelin receptor promotes
the transcriptional activation of PPARγ. LXRα which is a target of PPARγ is then
upregulated with the subsequent increase in apolipoprotein E (apoE) and sterol
transporters ABCA1 and ABCG1 expression. Activation of the PPARγ-LXRα-ABC metabolic
pathway in response to hexarelin favors cholesterol efflux by macrophages
through high density lipoproteins (HDLs). Adapted from [52].


## 5. A GHRP-PPARγ Pathway in Adipocytes

Based
on our observations that hexarelin promotes PPARγ activation through CD36 and ghrelin receptors in
macrophages [67], we wanted to address whether hexarelin could exert
activation of PPARγ
and subsequent downstream effects in adipocytes. PPARγ
is considered a master regulator of fatty acid metabolism in fat through its
direct role in regulating the expression of a broad range of genes involved in
fatty acid and glucose metabolism. Among the genes upregulated by PPARγ
are found genes related to fatty acid uptake (fatty acid transport protein
FATP, CD36), glucose uptake (GLUT4), β-oxidation (acyl-CoA dehydrogenase, carnitine
palmitoyltransferase CPT-1, acyl CoA oxidase), gluconeogenesis (phosphoenolpyruvate
carboxykinase PEPCK), and lipid storage (adipophilin) ([69, 70], and references therein). Increased expression of many of these genes might
result in a net influx and trapping of fatty acids into adipocytes, which is
considered a mechanism by which TZDs consistently reduce circulating free fatty
acids.Mature
adipocytes are known to express CD36 but
not the other hexarelin receptor GHS-R1a ([71, 72], and data not shown). Whereas the role
of CD36 in mediating oxLDL-derived cholesterol and fatty acid uptake by
macrophages is recognized, the mechanisms by which CD36 may impact the overall
metabolic activity of fat storage and mobilization by adipocytes is not
completely understood. With these
considerations and the central role of PPARγ in regulating many aspects of fatty acid
metabolism, it was expected that hexarelin may impact PPARγ-regulated events in adipocytes.As
such, we recently reported the ability of hexarelin to regulate PPARγ-dependent
downstream events in cultured adipocytes and in fat tissues from treated mice [73], thereby providing evidence that hexarelin may
target different PPARγ
expressing tissues. In these
studies, we observed that treatment of differentiated
3T3-L1 adipocytes with hexarelin resulted in a
depletion in triglyceride cellular content,
accompanied by profound changes in the
gene expression profile of key markers of fatty acid metabolism [73]. Interestingly, many of these genes were shared
with TZD troglitazone treatment, indicating that PPARγ
may be considered as a common regulator in both responses. Consistent with
this, among the genes upregulated by hexarelin, we found many established PPARγ
targets, such as nuclear receptor LXRα, FATP1 (fatty acid transport protein), and F1-ATP
synthase (see Figure 2). Other genes involved in various aspects of entry,
transport, synthesis, and mobilization of fatty acids, such as
hormone-sensitive lipase (HSL), fatty acid synthase (FAS), and acetyl-CoA
synthase (ACS) among others, were also upregulated, whereas
glycerol-3-phosphate acyltransferase (GPAT), which catalyzes the initial and
committing step in glycerolipid biosynthesis, was downregulated by hexarelin [73]. All together, this type of profile is strongly
suggestive of an increase in the cellular mobilization of free fatty acids in
response to hexarelin.Figure 2
Hexarelin promotes mitochondrial
activity in adipocytes. Scheme of gene expression analysis of fatty acid metabolic regulators in 3T3-L1 adipocytes. Shown are a subset
of genes identified as upregulated (red) or downregulated (green) by hexarelin
compared to untreated cells. These effects of hexarelin require CD36 which is
expressed in adipocytes as opposed to GHS-R1a receptor; FAO, fatty acid
oxidation; FABP, fatty acid binding protein; FAS, fatty acid synthase; HSL,
hormone-sensitive lipase; ACO, acyl CoA oxidase; ACS, and acyl CoA synthase.
Other abbreviations appear in text.However,
the response to hexarelin was not totally mimicked by troglitazone as other
described PPARγ targets, such as adipocyte fatty acid binding protein FABP4 (also
referred to as aP2) and lipid droplet-associated protein adipophilin remained
mostly unchanged upon treatment with hexarelin [73]. It is also important to note that gene expression and protein
levels of CD36, a well-known target of PPARγ [49, 50], were not changed by
hexarelin, as opposed to troglitazone which significantly induced both in
treated adipocytes. Similar results were also found in macrophages, indicating
that this regulation is not cell-specific [67], and may prevent any undesired increase in macrophage CD36, a
situation that correlates with proatherosclerotic events [55, 74]. Also, as
opposed to troglitazone which decreased PPARγ expression, hexarelin
contributed to maintain expression and steady-state levels of PPARγ in adipocytes and
macrophages [67, 73]. The exact mechanism(s) by which hexarelin exerts such
gene-specific regulation compared to TZDs are not clearly understood, but
differences in PPARγ occupancy of targeted promoters and/or posttranslational
modifications of PPARγ are certainly among the likely possibilities to consider in the
response of PPARγ to hexarelin ([67],
see below).


## 6. Hexarelin Promotes Mitochondrial Activity and Biogenesis

Uptake of fatty acids and glucose by muscle and fat
tissues is an important component regulating energy expenditure and defects in
CD36 have been associated with impaired fatty acid and glucose homeostasis in
humans [75, 76]. However, the role of CD36 in regulating energy metabolism in
adipocytes remains an unresolved issue.By transposing the ability of hexarelin to promote
PPARγ activation to adipocytes,
it was interesting to observe that many genes upregulated by
hexarelin were characteristic of an enhanced profile of fatty acid oxidation
and mitochondria morphology [73]. More specifically, among the genes
upregulated were found acetyl CoA acyl transferase, CPT-1, and several subunits
of the ATP synthase and of the cytochrome c oxidase complexes, all suggesting
an increased fatty acid mobilization towards the mitochondrial oxidative
phosphorylation pathway [73].Enhanced
mitochondrial oxidative potential is required
to supply adequate ATP production in high energy-demanding processes, such
as adaptation to cold in brown fat, heart and skeletal muscle contraction, and
liver gluconeogenesis in response to fasting. Such mitochondrial
energy-producing capacity correlates with activeβ-oxidation of fatty acids and increased
expression of PPARγ coactivator-1 (PGC-1) in these tissues [77–82]. PGC-1α is a coactivator of most nuclear receptors that was discovered as a molecular switch that
turns on several key components of the adaptive thermogenic program in brown
fat, including the stimulation of fuel intake, mitochondrial fatty-acid
oxidation, and heat production [83, 84]. These metabolic changes are supported by
the ability of PGC-1 to upregulate the expression of UCP-1, a biological uncoupler
of mitochondrial oxidative phosphorylation, and of genes of gluconeogenesis,
such as PEPCK and glucose-6-phosphatase (reviewed in [84, 85]). Thus, modulating the relative activity of PGC-1 within a
particular tissue may lead to a fine tuning of mitochondrial function in fatty
acid oxidation and energy balance. Interestingly,
hexarelin induced an
increase in PGC-1α and UCP-1 in 3T3-L1
adipocytes as well as in epididymal fat of treated mice, indicating a potential
fat burning phenotype taking place in white fat in response to hexarelin [73]. Consistent with these changes, electron
microscopy of hexarelin-treated 3T3-L1 adipocytes showed an intense and highly
organized cristae formation that spans the entire width of mitochondria
compared to untreated cells, accompanied with an increase in cytochrome c
oxidase activity, two features characteristic of highly oxidative tissues [73]. A similar mitochondrial phenotype and gene expression profile was
detected in epididymal white fat of mice treated with hexarelin, and shown to
be dependent on CD36, indicating that the ability of hexarelin to promote a fat
burning-like phenotype was maintained in vivo [73]. These studies therefore support a functional GHRP-PPARγ signaling cascade in
adipocytes, which provides a potential role for CD36 to impact the overall
metabolic activity of fatty acid usage and mitochondrial biogenesis in fat. These aspects are particularly relevant to the emerging
association of mitochondrial dysfunction with insulin resistance and type 2
diabetes [86].


## 7. Hexarelin Increases PPARγ Phosphorylation

The exact mechanism(s) by which PPARγ activity is modulated in response to
hexarelin remains to be clearly defined. In an attempt to partly characterize
such a response, we found that PPARγ was highly phosphorylated in macrophages
treated with hexarelin, therefore providing a basis on how PPARγ can
respond to hexarelin signaling [67]. Although
macrophages do express both receptors recognized by hexarelin, our observation
that GHS-R1a activation by hexarelin enhanced PPARγ activity
in transfected heterologous cells may therefore suggest that GHS-R1a signals to
activate PPARγ [67]. Consistent with this, the activation
of GHS-R1a receptor by hexarelin or its natural ligand ghrelin leads to the
phosphorylation of PPARγ in macrophages, while a GHRP
selective for CD36 did not ([67] and unpublished observations). These findings rather implicate
GHS-R1a signaling in the phosphorylation of PPARγ, at least in macrophages.The effects of phosphorylation
on PPARγ activity have been reported to vary, often in
opposite directions, depending on the cellular and promoter context [87]. In that respect, it
is interesting to note that while PPARγ ligands of the TZD family are recognized to
upregulate CD36 gene expression [49, 50], no significant changes in CD36 expression were measured in response to
GHRPs despite PPARγ activation [67, 68, 73]. In order
to further investigate the mechanism by which this unexpected regulation of
CD36 by hexarelin may result, chromatin immunoprecipitation assay has revealed
that the relative occupancy of the CD36 promoter region by PPARγ remained mostly unchanged, whereas that of nuclear receptor LXRα, also a known target of PPARγ [88], was occupied by PPARγ in a greater extent in macrophages treated with hexarelin, indicating
that LXRα upregulation by hexarelin may
result from a preferred recruitment of PPARγ to the LXRα promoter, as opposed to CD36 [67]. Whether PPARγ phosphorylation may discriminate for promoter usage is not yet known
but interestingly, it was reported that PPARγ phosphorylation could decrease CD36 transcription in macrophages [53]. Given the ability by which posttranslational
modifications such as phosphorylation could regulate PPARγ transcriptional activity and that ligand-independent recruitment of
transcriptional coregulators is favored by nuclear receptor phosphorylation [87, 89–91], it is predicted that such
mechanism may contribute in the cellular response to hexarelin by selectively
regulating PPARγ-targeted genes. These aspects need to be further investigated in order to
ascertain such selectivity.


## 8. Concluding Remarks

Although
the exact mechanisms by which GHRPs promote their metabolic response are not
fully understood, it becomes clear that interacting with CD36 and/or GHS-R1a
receptors induces profound changes in metabolic activities of target tissues,
especially regarding PPARγ-regulated events.
However, it is important to note that the sole activation of PPARγ may not be exclusive
in translating the signal by hexarelin or other GHRPs. Indeed, in view that
hexarelin can also promote PPARα and PPARβ/δ activation [67], and with the propensity of PGC-1α to coactivate other
nuclear receptors besides PPARγ, such as thyroid
hormone receptor TRα, retinoic acid receptor RARα, estrogen-related
receptor ERRs, and PPARα [83], it is expected that these pathways may also be affected by
hexarelin. So clearly, the mechanism(s) by which hexarelin exerts its metabolic
effects represents a promising avenue which deserves further investigation to face problems
related to multipathological states associated with metabolic syndrome.



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