Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 1273e1280

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Diabetes & Metabolic Syndrome: Clinical Research & Reviews

journal homepage: www.elsevier.com/locate/dsx

Stress, glucocorticoid signaling pathway, and metabolic disorders

Roldan M. de Guia a, b, c, *
a
Joint Division Molecular Metabolic Control, DKFZ-ZMBH Alliance and Network Aging Research, German Cancer Research Center (DKFZ), Heidelberg,
Germany
b
Keio Global Research Institute (KGRI) and Department of Pharmacology, Keio University School of Medicine, Tokyo, Japan
c
Czech Centre for Phenogenomics (CCP), Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic

a r t i c l e i n f o a b s t r a c t

Article history: Background and aims: Glucocorticoids and the GR serve as an essential molecular mediator of stress and
Received 2 January 2020 different physiologic processes. This review summarizes main findings from studies on the role of the
Received in revised form GC/GR signaling in the modulation of genes for nutrient processing by the different organs involved in
15 June 2020
metabolic diseases.
Accepted 16 June 2020
Methods: Descriptive review of relevant papers known to the author was conducted.
Results: Several high-throughput screenings in the past 15 years have identified potential GR DNA-
Keywords:
binding regions in different cell types with genes that are annotated to be important for the control of
Glucocorticoids
Glucocorticoid receptor
metabolism. Transcriptional regulation of these GC-responsive genes provides links between the
Metabolism hypothalamic-pituitary-adrenal axis (HPA) and systemic energy homeostasis in both physiological and
Metabolic disorders pathophysiological states. Future studies must reconsider the use of agonist, the utilization of animal
models of stress and metabolic disorders, and validation in humans.
Conclusion: This review recapitulates the significant role of the GC/GR signaling in molecular metabolic
control and metabolic disorders. Potential future research focus and optimizations have also been
identified.
© 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.

1. Introduction
Stress refers to any processes that put a strain to all levels of
biological complexity. From population and groups down to the
individual, organ-tissue, cellular, and genetic levels, stress has
become a connotation of the definition of life encompassing
adaptation of the organism and capacity for metabolism. Stress
together with the mammalian HPA axis have been thoroughly and
widely studied for decades. Similar is true for the molecular basis of
stress response via the GC signaling pathway. The involvement of
GC signaling in the control of nutrient and energy metabolism
started from earlier studies on genes involved in gluconeogenesis.
With the current global epidemic of diabetes and obesity, the
contribution of the GC signaling to the pathophysiology of these
metabolic diseases has become a focal point of research as lipid
overload and defective carbohydrate metabolism may alter the
body’s stress response. It can be hypothesized for the purpose of
* Corresponding author. Czech Centre for Phenogenomics (CCP), Institute of
Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic.
E-mail address: roldan.deguia@img.cas.cz.
this review that despite the pleiotropic effects of GCs in the body,
inter-organ differences and similarities may exist in the gamut of
GC-responsive genes and that some of these genes might be
involved in metabolic diseases. Furthermore, important gaps in the
current knowledge of stress signaling in metabolism may be
identified.
2. The hypothalamic-pituitary-adrenal axis
GCs, as counter-regulatory hormone to insulin, serve a vital role
in metabolism and inflammatory response. The concentration of
GCs in the body is correlated to the activity of the HPA axis [1].
Fasting, starvation, and diabetes are perceived as stress by the
neuroendocrine system in response to changes in the levels of
glucose, fatty acids, and hormones [2e4]. The stress signal causes
the hypothalamus to secrete corticotrophin releasing factor (CRF)
which stimulates the anterior pituitary gland to produce
adrenocorticotrophin-releasing hormone (ACTH) (Fig. 1A) [5].
ACTH in the bloodstream then activates the adrenal glands to
produce hormones. The adrenal medulla secretes catecholamines
(norepinephrine and epinephrine) and the adrenal cortex produces

https://doi.org/10.1016/j.dsx.2020.06.038
1871-4021/© 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1274 R.M. de Guia / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 1273e1280

Fig. 1. Mechanism of glucocorticoid and receptor action. (A) The hypothalamic-pituitary-adrenal axis showing release of CRF from the hypothalamus and ACTH from the pituitary
gland. ACTH promotes synthesis of cortisol by the adrenal gland; (B) The pre-receptor function of hydroxysteroid dehydrogenase which interconverts cortisol and cortisone; (C) The
glucocorticoid receptor is rendered free from the complex allowing GC binding. The GC/GR complex moves into the nucleus to bind its target; (D) Types of glucocorticoid receptor-
DNA interaction with the target can be direct and composite allowing the use of glucocorticoid response elements in the DNA. GC/GR can likewise bind to other DNA-binding
proteins in tethering manner.

mineralocorticoids (from zona glomerulosa), androgens, and the
GCs (zona fasciculata & zona reticularis) [5]. ACTH stimulates fas-
ciculata and reticularis cells to synthesize cortisol from cholesterol.
Cortisol is the major stress hormones that acts on every cell of the
body including the brain where it negatively feedbacks on CRF and
ACTH secretion making the HPA a close neuroendocrine feedback
loop [6]. Once secreted in the circulation, majority of cortisol (75%)
bind to transcortin and corticosteroid-binding globulin (CBG) [7].
Levels of these GC-binding proteins are stress-regulated [8]. Free
cortisol concentration is being regulated by the HPA axis since it is
the unbound cortisol which is responsible for the biological func-
tion of GCs [9,10].
3. Mechanism of glucocorticoid and receptor action
The molecular mechanism of GCs can be divided into pre-
receptor and receptor-mediated actions. The pre-receptor ligand
control regulates the intracellular concentration of the active GC,
cortisol. It depends on the activity of the enzyme 11b-hydroxyste-
roid dehydrogenase (HSD) in the endoplasmic reticulum. The two
isozymes HSD1 and HSD2 are responsible for reductive (cortisone
/ cortisol) and oxidative (cortisol / cortisone) reactions,
respectively, that alter the concentration of the bio-active cortisol
in the cell [11] (Fig. 1B). Furthermore, the relative expression of
these two isozymes in different organs of the body contribute to the
tissue-specific effect of GCs [12]. HSD1 is expressed predominantly
in the liver, lungs, gonads, brain, and adipose tissues. HSD2, on the
other hand, is expressed in the kidneys, colon, and salivary glands
[13,14].
The GR mediates the function of the cortisol (corticosterone in
mice). It is ubiquitously expressed numbering from 2000e30,000
molecules/cell with mRNA levels particularly high in the lungs,
spleen, brain, and liver. It is a member of the nuclear receptor family
characterized by the presence of a highly conserved, centrally
located zinc-finger DNA-binding domain, a less conserved C-ter-
minal ligand-binding domain which contains the GC-binding re-
gion, and amino acid residues for dimerization and transactivation
functions [15,16]. The inactive GR in the cytoplasm is phosphory-
lated and forms a complex with other proteins which include
HSP90, HSP70, p59 immunophilin, FKBP52, and p23 phosphopro-
tein (Fig. 1C). GR is activated after it binds GC, hyper-
phosphorylated, and is freed from the inhibitory complex [17].
The GC/GR complex then translocates into the nucleus where it can
bind to the promoter regions of genes which harbors (1) GC
response elements (GRE) where the GR binds as a dimer to the
pentadecameric palindrome GGTACAnnnTGTTCT, (2) half-GRE
 R.M. de Guia / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 1273e1280
sites, or (3) negative GC response elements [17]. These GREs can
also function in composite manner together with other transcrip-
tion factors and co-regulators. Tissue specificity of GC action also
depends on the presence of these proteins which are produced in
accordance to the requirements by the tissue [18]. The GR action
can also be a secondary response where there is no direct GR-DNA
interaction but protein-protein interaction of the GR with other
proteins [19] (Fig. 1D). An example of this is the trans-repression by
the GR in inflammatory response together with NF-kB and AP1 [20].
Apart from the physiologic stresses that activate the HPA which
ultimately lead into cortisol production and GR binding, several
factors have been identified affecting GC/GR signaling. Cortisol
production follows a circadian rhythm where it is highest during
activity period (day for diurnal species, night for nocturnals)
peaking at ~6e8 am in humans and lowest 3e5 h after onset of
sleep [21]. Although the general pattern is circadian, endogenous
cortisol level follows an ultradian pattern where GCs are being
released every hour [22]. This pattern affects GR activity where
pulses in the levels drive transient activation of GR-dependent
genes [23]. The subsequent nuclear import of the active GR dur-
ing each pulse also affects GC response. Although still unclear, it
was reported that GR nucleocytoplasmic shuttling might be regu-
lated by the p38 mitogen-activated protein kinase (MAPK) pathway
[24]. Another factor that affects GR activity is chromatin accessi-
bility. Regulatory regions of GR-responsive genes have been shown
to have accessible DNA and acetylated histones where the GR can
interact with the chromatin remodeling complex made up of
coactivators CREB-binding protein (CBP), p300, activator of thyroid
hormone and retinoid receptors (ACTR), SRC1, p300/CBP-associated
factor (PCAF), and SWI/SNF complex [15,17]. PCAF has histone
acetyltransferase (HAT) activity while the latter complex possesses
the chromatin remodeling activity. Both of which are important for
further binding of other proteins and the components of the tran-
scriptional machinery [25,26].
4. Regulation of metabolism by glucocorticoids
GCs are involved in the regulation of carbohydrate, fat, and
protein metabolism in both the fed and fasted state (Fig. 2). GCs
work with glucagon, growth hormone, and thyroid hormone in
bringing about counter-regulatory effects of insulin in the cell
[27e29]. However, under normal physiologic fed state following
starvation, GCs work with insulin in a synergistic manner [13,17].
GCs and insulin potentiate lipogenesis and glycogenesis in the liver
and promotes differentiation, lipogenesis and increased activity of
LPL and GPDH in adipose tissues [30]. GCs also stimulate glycolysis
by activation of GCK, PFK, and PK [1].
Fasting and starvation activate enzymes important for lipolysis,
b-oxidation, protein degradation, glycogenolysis, and gluconeo-
genesis [1]. Most of the key enzymes involved in these processes
are also regulated by glucagon like PEPCK & G6Pase in gluconeo-
genesis, HSL in lipolysis, among others [31,32]. In peripheral
glucose uptake, GCs induce expression but inhibit the translocation
to the membrane of the GLUT4 transporter in both muscles and
adipose tissues [33,34]. GCs have also been shown to affect glucose-
stimulated insulin release in b-cells of the pancreas [35,36]. In both
rats and humans, GCs are reported to stimulate mitochondrial
NADPH production, Ca2þ and PLC/InsP3/PKC pathways which are
implicated in the release of insulin from b-cells [37].
In lipid metabolism under energy-deprived state, GCs activate
transcription of genes in lipolysis like ATGL, HSL, and MGL via in-
duction of FoxO transcription [30,38]. GCs also promote secretion of
ANGPTL4 from the liver and white adipose tissues [39]. ANGPTL4
has been demonstrated to be involved in dexamethasone-
dependent, hepatic ceramide production and dyslipidemia [40].
1275
In adipose tissue, ANGPTL4 activates lipolysis and inhibits LPL ac-
tivity resulting into elevation of free fatty acids in the circulation
[41]. This process is likewise implicated in fatty acid redistribution
from adipose tissue to the liver which in turn increases triglyceride
synthesis of hepatocytes [42,43]. GCs are known to affect lipopro-
tein metabolism. Studies done on primary hepatocytes and
dexamethasone-treated mice showed increased VLDL triglycerides
and plasma concentration of HDL particles [44e46]. Promotion of
VLDL secretion by GCs is possibly due to increased production and
stabilization of Apolipoprotein B (ApoB) together with increased
triglyceride synthesis [47]. ApoB is the major protein component of
VLDL and LDL. At least 50% of cholesterol needed by the adrenal
gland to produce GCs are shown to be provided by lipoproteins [48]
with adrenocortical LDLR playing an important role [49]. Elevated
plasma HDL, on the other hand, can be attributed to the inhibition
of hepatic lipase and activation of LCAT activity by GCs [50]. GCs
have also been shown to promote triglyceride synthesis and stea-
tosis in the liver by inhibition of the hairy and enhancer of split 1
(HES1) repressor [51]. The GR also controls induction of the Naþ-
taurocholate cotransporter (NTCP or SLC10A1) important for
transporting bile acids from the blood back to the liver [52].
Over the years, high-throughput chromatin immunoprecipita-
tion (ChIP) sequencing has been applied to identify genes that are
potentially being directly targeted by a transcription factor. GR ChIP
scanning studies revealed enrichment of GC-binding regions (GBR)
in the promoter of genes that function in transcription, cellular
transport, biomolecular synthesis, cell surface receptor linked cell
signaling, cell proliferation, metabolism, and inflammation, among
others [58,59]. Although common targets can be pinpointed, it can
be generalized that GCs regulate different genes in different cell
types due to the tissue-specific action of the GR (Table 1). In the
liver, adipose tissues, and muscles, most of the identified GC-
regulated genes in metabolism correlate with the results of
in vivo and in vitro functional studies utilizing GR agonist (dexa-
methasone, prednisone, etc.) treatment [55,57,61]. Furthermore,
enrichment analysis for transcription factors and cofactors in GBRs
revealed proteins that are possibly involved in composite or teth-
ering regulation by the GR. Some of these transcription factors
include AP1, C/EBP, FoxA, FOXP3, PXR, LXR, Med1, HNF3a, HNF6,
PPARa, PPARg, T3R, GABPA, ZFP281, PRRX2, GATA1, RelA, Jun, NF-
kB, and STAT5. Just like the gene targets, tissue-specificity is
observed in the set of transcription factors that are co-enriched
within GBRs [62].
Apart from enzymes and transcription factors that are being
controlled by the GR directly or indirectly, non-coding RNAs,
particularly microRNAs (miRNAs), has been reported also to be
involved in GC/GR signaling. The growth arrest-specific 5 (Gas5)
non-coding RNA has been reported to act as a decoy GRE in the cells
deprived of nutrients or growth factors [63] while in models of
acute lymphoblastic leukemia, GCs have been shown to regulate
miR-223 and the miR-15/16 cluster [64]. Reciprocally, the GC
biosynthetic pathway has been reported to be regulated by miRNAs
[65]. In the liver, we previously reported miRNAs of the miR-379-
410 cluster that are upregulated in diabetic-obese db/db mice
suffering from chronically elevated corticosterone [66]. We were
able to identify and validate GC-binding region in the putative
promoter region of the miRNA gene locus [66]. It is in these disease
state of GC excess (or insufficiency) where the importance of GC
and GR signaling in metabolism can further be justified.
5. Glucocorticoids and metabolic disorders
GC and GR signaling dysfunctions affect carbohydrate, lipid, and
protein metabolism making the GC/GR pathway an attractive target
for the management of metabolic diseases [67]. Disturbances in the
1276 R.M. de Guia / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 1273e1280

Fig. 2. Enzymes and cellular processes regulated by the glucocorticoid signaling during fasting and feeding. During the fasted state, glucocorticoids act together with other hor-
mones in favor of lipolysis, beta-oxidation, proteolysis, glycogenolysis and gluconeogenesis. In the fed state, glucocorticoids can act synergistically with insulin. Glucocorticoids can
also affect glycogenesis and lipoprotein production & processing by the liver.
NOTE: Up-regulated by GC/GR; Down-regulated; Atgl (adipocyte triglyceride lipase; also known as desnutrin or patatin-like phospholipase domain containing 2
(PNPLA2)); Hsl (hormone-sensitive lipase; also known as LIPE); Mgl (monoacylglyceride lipase); Angptl4 (angiopoietin-like 4); Lpl (lipoprotein lipase); Gpdh (Glycerol-3-
phosphate dehydrogenase); Ampk (AMP-associated protein kinase); Pdk4 (pyruvate dehydrogenase lipoamide kinase 4); Redd1 (regulated in development and DNA damage
response 1); Klf15 (Krüppel-like factor 15); Gys (glycogen synthase); Acc (acetyl-CoA carboxylase); Fasn (fatty acid synthase); Scd (stearoyl-CoA desaturase); Gpat (glycerol
phosphate acyltransferase); Agpat (1-acylglycerol-3-phosphate acyltransferase; also MOGAT, monoacylglycerol acyltransferase); Lpin (lipin or phosphatidate phosphatase); Dgat
(diacylglycerol acyltransferase); TAG hydrolase (triacylglyceride hydrolase); Ldlr (LDL receptor); LSR (lipolysis-stimulated lipoprotein receptor); Gck (glucokinase); Pfk (phos-
pofructokinase); Pk (pyruvate kinase); Pepck (phosphoenolpyruvate carboxykinase); G6Pase (glucose-6-phosphatase).

HPA axis, the pre-receptor function, and the GC/GR signaling have
been reported in almost all the components of the metabolic syn-
drome (MetSyn) e insulin resistance, hyperglycemia, dyslipidemia,
and hypertension [68e71]. The abnormal phenotypes of the Met-
Syn have been observed to occur with hyperactive HPA axis and
elevated cortisol levels in humans, a state called “functional
hypercortisolism” [67,72,73]. Chronic stress and low birth weight
have been reported to be associated with increased HPA activity
and circulating cortisol [72] and affects levels of GR and MR re-
ceptors in the brain [74]. Cortisol levels are also described to be
abnormal in people with central obesity where there is an
increased rate of secretion by the adrenal glands and clearance by
the kidneys [75]. It was shown that plasma cortisol increases with
age in obese individuals [76]. BMI is likewise positively correlated
with chronically elevated cortisol levels in shift workers [77]. Rats
treated with dexamethasone for 4 weeks displayed significantly
higher triglycerides, hematocrit, and insulin compared to controls
injected with the vehicle [78]. These findings further support the
involvement of the GC/GR signaling in insulin secretion, lipid
metabolism, and insulin resistance. GC-induced insulin resistance
was also observed in human skeletal muscles, omental fat, but not
in subcutaneous adipose tissues [79,80]. This suggest tissue-
specificity of the GC response in the context of insulin resistance.
The bone g-carboxyglutamate protein (BGALP) or osteocalcin,
which is important in bone turnover, has been reported to partic-
ipate in the regulation of insulin sensitivity [81]. Osteocalcin’s
ability to inhibit adiposity and hepatic steatosis has been shown to
be blunted by GCs [82]. A recent study in humans indicated that
GC-induced insulin resistance in both basal and post-exercise
conditions is correlated with reduced serum undercarboxylated
osteocalcin levels [83]. In the muscles and liver, GCs can induce
insulin resistance by inhibiting the transcription or phosphoryla-
tion of IRS-1 and increasing levels of tyrosine phosphatase (PTP1B)
and p38MAPK. The opposite scenario has been reported for the
latter in 3T3-L1 adipocytes [84].
GC-induced, selective insulin resistance is likewise implicated to
the pre-receptor function of the HSD. Animal models over-
expressing 11b-HSD1 in adipocytes resulted in obesity and insulin
resistance while gene knockout models showed the opposite
[85,86]. Humans suffering from morbid obesity have been reported
to have high levels of 11b-HSD1 in the liver and visceral adipose
tissues [87]. In this study, the liver had 20 times more of the
enzyme than the visceral fats although the hepatic levels were
negatively correlated with BMI suggesting possible secondary
 R.M. de Guia / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 1273e1280 1277

Table 1
Genes, cellular processes, and pathways enriched in glucocorticoid receptor ChIP-Seq.

Tissue/Cell Line Selected Genes or Enriched Cell Processes/Pathways in GR ChIP-Seq References

Rat Neonatal Positive regulation of transcription; Positive regulation of cell death; Response to lipopolysaccharide; Regulation of gene Severinova et al.,
Cardiomyocytes expression; Cellular response to molecular stimulus; Apoptotic processes; Liver regeneration, Cellular response to insulin 2019 [53]
stimulus; Axon guidance; Focal adhesion; ECM-receptor interaction; PI3K-Akt signaling; Protein digestion and absorption;
Dilated and hypertrophic cardiomyopathy; Adrenergic signaling; Rap1 signaling; Pathways in cancer; Insulin signaling
Human Primary Molecular mechanisms of cancer; Role of macrophages, fibroblasts, and endothelial cells in rheumatoid arthritis; Hepatic Singh et al., 2015
Subcutaneous Fat fibrosis/hepatic stellate cell activation; IL-8 signaling; HGF signaling; B cell receptor signaling; GC receptor signaling [54]
AHSP, BIVM-ERCC5, C16orf3, CCKBR, CNKSR2, DDX11L5, DEPTOR, DSTYK, EDC3, EEF1A1, GH1, HBB, HIST1 (H2BC, H4B, H4C,
H4H,H4I, H4L), HIST4H4, ING3, KIF9-AS1, LRRCC1, MIR4271, MOV10, NAF1, NR2F1-AS1, NR3C1, NR3C2, PABPC1, PAIP2,
SGK1, SLC18B1, USP14, VPS26A, ZNF219, ZNF385B
C2C12 Myotubes Insulin signaling: Grb10, Sorbs1, Cblb, Pid1, p85a, Redd1, Sesn1, Depdc6 Kuo et al., 2012
[55]
PC12 Neurons Neuronal development, cytoplasmic vesicle, neuron projection, metal ion binding, angiogenesis, synapse, protein tyrosine Polman et al., 2012
kinase activity [56]
3T3-L1 Adipocytes Insulin action (Insig2, Lcn2, Pi3kr1 or p85a, Ptgds), adipocyte differentiation (Tsc22d3, Ctsl, Sgk1), triglyceride synthesis (Scd, Yu et al., 2010 [57]
Gpat, Agpat, Lpin1), lipolysis (Hsl, Mgll), lipid transport (Cd36, Lrp1, Vldlr, Slc27a2or Fatp2), lipid storage (S3-12)
A549 Lung Epithelial Inflammation (CCL20, COX-2, IL11), growth and apoptosis (GADD45B, FGFBP1), metabolism (ANGPTL4, B3GNT5, EKI2, MGAM), Wang et al., 2004
Carcinoma transport (MT1L, SLC19A2, SLC26A2) | anatomical structure development, stress response, regulation of gene expression, [58]
apoptosis, transcription factor activity, signal transduction Reddy et al., 2009
[59]
Rat Hypothalamus Gadd45g, Sgk, Pdk4, Nfkbia, Plekhf1, Redd1, Gpd1, Mt1a, Hes5 Sato et al., 2008
[60]
Mouse Liver Adfp, Adh1, Aldh3a2, ApoA2, ApoC1, Abca1, Arg1, Creb1, Ch25h, Clock, Cs, Cyp11a1, Dld, Facl2, Gys1, Gys3, Hmgcs2, Hsd17b12, Phuc Le et al., 2005
Hsd3b4, Igfbp1, Idh1, Isl2, Il11ra2, Klf15, Lztr1, Lipc, Lipe, Lipc, Oat, Pck1, Pygl, Lrp4, Mgll, Nqo2, Ndufa7, Odc, Pgd, Pik3cg, Pdsm, [61]
Prkag3, Ppm1g, Ppp2r3a, Ptp4a2, Pdk2, Retnla, Sepp1, Serpin, Slc1a4, Sra1, Tgfb2, Tnf

NOTE: Complete list of genes, cell processes, and pathways at specific and different time of agonist incubations can be found in each respective source.
Abca (ATP binding cassette subfamily A), Adfp (perilipin 2), Adh1 (alcohol dehydrogenase 1), Agpat (1-Acylglycerol-3-Phosphate O-Acyltransferase), AHSP (alpha hemoglobin
stabilizing protein), Aldh (aldehyde dehydrogenase), ANGPTL4 (angiopoietin like 4), Apo (apolipoprotein), Arg1 (arginase 1), B3GNT (UDP-GlcNAc:BetaGal Beta-1,3-N-
Acetylglucosaminyltransferase), BIVM-ERCC5 (BIVM-ERCC5 readthrough), Cblb (Cbl proto-oncogene B), CCKBR (cholecystokinin B receptor), CCL (CeC motif chemokine
ligand), Clock (clock circadian regulator), Ch25h (cholesterol 25-hydroxylase), CNKSR2 (connector enhancer of kinase suppressor of Ras 2), COX (cyclooxygenase), Creb (cAMP
responsive element binding protein), Cs (citrate synthase), Ctsl (cathepsin L), Cyp (cytochrome P450), DDX11L (DEAD/H-Box Helicase 11 Like), Depdc6 (DEPTOR), DEPTOR
(DEP domain containing MTOR-interacting protein), Dld (dihydrolipoamide dehydrogenase), DSTYK (dual serine/threonine and tyrosine protein kinase), ECM (extracellular
matrix), EDC3 (enhancer of mRNA decapping 3), EEF (eukaryotic translation elongation factor), EKI (ethanolamine kinase), Facl (fatty-acid-coenzyme A ligase long chain),
FGFBP (fibroblast growth factor binding protein), GADD45 (growth arrest and DNA damage inducible beta), GH (growth hormone), Gpat (glycerol-3-phosphate acyl-
transferase), Gpd (glycerol-3-phosphate dehydrogenase), Grb (growth factor receptor bound protein), Gys (glycogen synthase), HBB (hemoglobin subunit beta), Hes (hes
family bHLH transcription factor), HGF (hepatocyte growth factor), HIST (histone cluster), Hmgcs (3-hydroxy-3-methylglutaryl-CoA synthase), Hsd17b12 (hydroxysteroid 17-
beta dehydrogenase 12), Hsd3b (hydroxy-delta-5-steroid dehydrogenase), Hsl (hormone-sensitive lipase), Idh1 (isocitrate dehydrogenase (NADP(þ)) 1, cytosolic), Igfbp1
(insulin like growth factor binding protein), IL (interleukin), ING (inhibitor of growth), Insig (insulin induced gene), Isl2 (ISL LIM homeobox 2), KIF9-AS (KIF9 antisense RNA),
Klf (kruppel like factor), Lcn (lipocalin), Lipc/e (lipase c or e), Lpin1 (lipin 1), Lrp (LDL receptor related protein), LRRCC (leucine rich repeat and coiled-coil centrosomal
protein), Lztr (leucine zipper like transcription regulator), MGAM (maltase-glucoamylase), Mgll (monoglyceride lipase), MIR (microRNA), MOV10 (Mov10 RISC complex RNA
helicase), MT (metallothionein), NAF1 (nuclear assembly factor 1 ribonucleoprotein), Ndufa7 (NADH:ubiquinone oxidoreductase subunit A7), Nfkbia (NFKB inhibitor alpha),
Nqo (NAD(P)H quinone dehydrogenase), NR2F1-AS (NR2F1 antisense RNA), NR3C (nuclear receptor subfamily 3 group C), Oat (ornithine aminotransferase), Odc (ornithine
decarboxylase), PABPC (poly(A) binding protein cytoplasmic), PAIP (poly(A) binding protein interacting protein), Pck (phosphoenolpyruvate carboxykinase), Pdk (pyruvate
dehydrogenase kinase), Pdsm (phosphorylation-dependent sumoylation motif), Pgd (phosphogluconate dehydrogenase), PI3K-Akt (phosphatidylinositol 3-kinase - protein
kinase B), Pi3kr1 or p85a (phosphoinositide-3-kinase regulatory subunit 1), Pid (phosphotyrosine interaction domain containing), Pik3 (phosphatidylinositol-4,5-
bisphosphate 3-kinase), Plekhf (pleckstrin homology and FYVE domain containing), Ppm (protein phosphatase, Mg2þ/Mn2þ dependent), Ppp2r (protein phosphatase 2
regulatory subunit), Prkag (protein kinase AMP-activated non-catalytic subunit gamma), Ptgds (prostaglandin D2 synthase), Ptp4a (protein tyrosine phosphatase type IVA),
Pygl (phosphorylase, glycogen, liver), Rap (Ras-related protein), Redd1/Ddit4 (DNA Damage Inducible Transcript 4), Retnla (resistin-like alpha), S3-12/PLIN4 (perilipin 4), Scd
(stearoyl-CoA desaturase), Sepp1 (selenoprotein P), Serpin (serine protease inhibitor), Sesn1 (Sestrin 1), SGK1 (serum/glucocorticoid regulated kinase 1), SLC (solute carrier),
Sorbs (sorbin and SH3 domain containing), Sra (steroid receptor RNA activator), Tgf (transforming growth factor), Tnf (tumor necrosis factor), Tsc22d3 (TSC22 domain family
member 3), USP (ubiquitin specific peptidase), Vldlr (very-low density lipoprotein receptor), VPS26A (retromer complex component A), ZNF (zinc finger protein).

effects of visceral adiposity and portal hypercortisolemia. Indeed,
mice overexpressing 11b-HSD1 in adipocyte had increased active
corticosterone secretion from visceral fats which in turn lead into
increased GC input into the liver without changing plasma levels
[85]. Hepatocyte-specific, 11b-HSD1 over-expression, on the other
hand, did not lead into obesity but displayed phenotypes of
metabolic syndrome like insulin resistance, fatty liver, dyslipide-
mia, and impaired hepatic lipid clearance [85]. All these reports
made 11b-HSD1 a potential target in mitigating phenotypes of the
MetSyn [88]. Besides the 11b-HSD1 activity, MetSyn phenotypes
have been implicated to the expression of the GR itself. High levels
of both hepatic 11b-HSD1 & GR expression have been reported to
correlate with hyperglucocorticoidemia, hyperinsulinemia, and
hyperglycemia in diabetic-obese db/db mice [89].
The vital role of the GC/GR axis in MetSyn syndrome is further
exemplified in conditions of GC excess and deficiency. Hyper-
cortisolemia is observed on individuals suffering from endogenous
and exogenous Cushing syndrome (CS) and people receiving GC
therapy [90,91]. While GC deficiency is a characteristic of primary
(Addison’s disease, AD) or secondary adrenal insufficiency. The
abnormally high levels of GCs in individuals suffering from
endogenous CS can be attributed to the presence of ACTH-secreting
pituitary adenomas (75e80% of cases) or ectopic corticotropin
syndrome [92]. Iatrogenic or exogenous CS, on the other hand, is
due to excessive use of topical or inhaled corticosteroids as part of
one’s medications [93]. Hypercortisolemia in patients with CS is
responsible for the development of insulin resistance, diabetes,
dyslipidemia, cardiovascular diseases, and osteoporosis [94].
Obesity is common to 95% of CS cases which further contributes to
the risk of cardiovascular morbidity [95]. Furthermore, proximal
muscle weakness, fatigue, menstrual irregularity, and neuropsy-
chological disturbances are also observed in individuals suffering
from CS [92]. Adult AD, on the other hand, is clinically characterized
by low blood pressure, hyperpigmentation of the skin, weight loss,
joint & muscle pains & weakness, fatigue, or in severe cases, pro-
gression into the so called ‘Addisonian or adrenal crisis’ [96]. The
1278 R.M. de Guia / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 1273e1280
latter manifests as mixed symptoms which may include severe
vomiting & diarrhea, syncope (loss of consciousness & inability to
stand), hypoglycemia, lethargy, hyponatremia, hyperkalemia, hy-
percalcemia, and fever [97]. AD is caused by adrenal cortex auto-
immunity (80% of cases), tuberculosis (10e15%), among others [96].
Secondary adrenal deficiency can develop when the causes of the
problem arose from outside the adrenal gland like in faulty pitui-
tary ACTH production.
6. Relevance of the review and future perspective
Whether the problem is congenital, induced by xenobiotics, or
from a secondary source, chronic disturbances in the HPA axis
affect normal function of the neuroendocrine system in handling
stress. The resulting damage is usually mediated by GCs, mineral-
ocorticoids, and androgens and their respective receptors which
impacts the immune system and metabolism. Treatment regimens
for stress and GC-related pathologies include drug therapy, surgery,
or even replacement therapy depending on the associated patho-
physiologic phenotypes [98]. Diabetes & dyslipidemia arising from
CS are treated in the same way as in the MetSyn [99]. Despite ev-
idences supporting the importance of GCs in nutrient and energy
metabolism and the connection between hyperactive GC/GR
signaling and metabolic dysfunction, knowledge is still limiting as
to how GR-dependent metabolic processes are being regulated or if
GCs regulate expression of transcriptional or translational regula-
tors. The census of high-throughput, ChIP-seq studies provided in
this review, which tabulates putative GR targets, clearly shows or-
gan specificity. Comparing one cell type to another in different GR
ChIP-seq studies is over simplistic. The list of genes and pathways
compiled in Table 1 might demonstrate specificity but it is still a
major question whether this is truly GR-mediated or due to study
design differences. Treatments of the cell lines or animals with the
agonist dexamethasone vary widely from one study to the next in
terms of concentration and duration of treatments. Addressing the
acute and chronic implications of the agonist treatment must be
done in future studies. Another important issue to consider is the
use of the agonist itself in the experiments. Dexamethasone is a
very potent agonist of the GR and therefore might mask some of the
true effects of GR activation if dosage and duration of treatments
are not optimized.
In the context of energy metabolism, although many studies
have been done transcriptomics of GR activation, few studies have
validated the results in GR ChIP experiments to show the type of GR
action on the target. This review included GR Chip-seq studies from
tissues like the lungs and the heart which might be of interest for
future metabolic studies on the GC signaling. Majority of the studies
presented on Table 1 were done in vitro. It will be more physio-
logically relevant if future studies are to be performed in animal
models of stress and metabolic disorders. Validation of the animal
studies in human intervention, cross-sectional, or prospective
studies will be valuable for translational relevance to human cases
of metabolic and adrenal disorders. Our recent findings on GC-
induced miRNAs of the miR-379-410 cluster might provide a
model for future studies to seek for the link between GC/GR
signaling and the dysfunctional phenotypes of the MetSyn in both
mice and humans [66]. Additional functional and pharmacological
studies are necessary to provide more light on this hypothesis.
Furthermore, efforts and resources must continue to be focused on
the growing interests on the potential pivotal contribution of epi-
genetics, sexual dimorphism, age at exposure to stressors, and the
microbiome to the impact of GCs on metabolic, cardiovascular,
immune, and neurological health [100e103].
Declaration of competing interest
The author declares that there are no conflicts of interest.
Acknowledgments
Support for this study was provided by the Helmholtz Interna-
tional Graduate School for Cancer Research, Heidelberg, Germany;
Keio Global Research Institute (KGRI), Tokyo, Japan; and the Czech
Centre for Phenogenomics (CCP), Institute of Molecular Genetics of
the Czech Academy of Sciences (LM2015040). Furthermore, the
author would like to thank Prof. Dr. Stephan Herzig of the Institute
for Diabetes and Cancer, Helmholtz Zentrum München and Prof.
Masato Yasui of the School of Medicine and Keio Global Research
Institute, Keio University.
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