Expert Review of Endocrinology &

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Links between HPA axis and : clinical implications in paradigms of stress-related disorders

Panagiota Papargyri, Evangelia Zapanti, Nicolaos Salakos, Loukas Papargyris, Alexandra Bargiota & George MASTORAKOS

To cite this article: Panagiota Papargyri, Evangelia Zapanti, Nicolaos Salakos, Loukas Papargyris, Alexandra Bargiota & George MASTORAKOS (2018) Links between HPA axis and adipokines: clinical implications in paradigms of stress-related disorders, Expert Review of Endocrinology & Metabolism, 13:6, 317-332, DOI: 10.1080/17446651.2018.1543585 To link to this article: https://doi.org/10.1080/17446651.2018.1543585

Accepted author version posted online: 01 Nov 2018. Published online: 13 Nov 2018.

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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iere20 EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 2018, VOL. 13, NO. 6, 317–332 https://doi.org/10.1080/17446651.2018.1543585

REVIEW Links between HPA axis and adipokines: clinical implications in paradigms of stress-related disorders Panagiota Papargyria, Evangelia Zapantib, Nicolaos Salakosc, Loukas Papargyrisd,e, Alexandra Bargiotaf and George MASTORAKOSa aUnit of Endocrinology, Mellitus and Metabolism, Aretaieion Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; bDepartment of Endocrinology, Alexandra Hospital, Athens, Greece; cSecond Department of Obstetrics and Gynecology, Aretaieion Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; dCRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France; eLabEx IGO “Immunotherapy, Graft, Oncology,”, Angers, France; fDepartment of Endocrinology and Metabolic Diseases, Larissa University Hospital, School of Medicine, University of Thessaly, Larissa, Greece

ABSTRACT ARTICLE HISTORY Introduction: In the human organism, a constant interplay exists between the stress system [which includes Received 12 March 2018 the activity of the hypothalamic-pituitary-adrenal (HPA) axis] and the . This interplay is Accepted 30 October 2018 mediated by of the HPA axis such as corticotropin-releasing (CRH), adrenocorticotropic KEYWORDS hormone (ACTH) and glucocorticoids (GCs) and adipokines secreted by the adipose tissue. Adipokines; adiponectin; Areas covered: In this critical review, the bi-directional interactions between HPA axis and the most ; eating disorders; studied adipokines such as and adiponectin, as well as the pro-inflammatory adipocytokines HPA axis; hypothalamic (TNF) and interleukin (IL) 6 are presented. Furthermore, these interactions are amenorrhea; IL-6; leptin; described in normalcy as well as in specific clinical paradigms of stress-related disorders such as eating stress; TNF disorders, hypothalamic amenorrhea, and stress-related endogenous hypercortisolism states. Wherever new therapeutic strategies emerge, they are presented accordingly. Expert commentary: Additional research is needed to clarify the mechanisms involved in the interplay between the HPA axis and the adipose tissue. Research should be focused, in particular, on the development of new therapeutic means targeting dysfunctional adipose tissue in stress-related situations.

1. Introduction studied adipokines such as leptin, adiponectin and the pro- inflammatory adipocytokines tumor necrosis factor (TNF) and The survival of complex organisms depends on the mainte- interleukin (IL) 6 focusing on stress-related disorders. nance of “homeostasis,” a condition of dynamic equilibrium Subsequently, research studies regarding the complex inter- resulting from the adaptive responses of regulatory mechan- play between the HPA axis and these adipokines in normalcy isms to internal or external potentially threatening stimuli and in specific stress-related clinical disorders such as eating called “stressors.” These regulatory adaptive mechanisms disorders, hypothalamic amenorrhea, and stress-related endo- represent the “stress system” located both in the central ner- genous hypercortisolism states are investigated. In addition, vous system and in peripheral organs [1]. The stress system is research targets regarding possible new therapeutic composed by the hypothalamic-pituitary-adrenal (HPA) axis approaches in these stress-related clinical disorders are and the ceruleus (LC)/ (NE) system. The presented. structures of the HPA axis are located in the paraventricular nuclei (PVN) of the (parvo- and magno- cellular neurons), the anterior lobe of the pituitary gland (basophilic 1.1. The Hypothalamic- Pituitary- Adrenal Axis and the cells) and the adrenal cortex [2]. The structures of the LC/NE stress response system are located in the stem (LC), the sympathetic The stress-induced activation of the HPA axis is initiated with adrenomedullary cells and the sympathetic spinal ganglia and the synthesis and release of corticotropin-releasing hormone parasympathetic system. There is a constant interplay (CRH) from neurons in the medial parvocellular subdivision of between the HPA axis and the adipose tissue. The latter the PVN of the hypothalamus, into the hypophysial- portal secretes proteins called adipokines as well as pro- vascular system [4,5]. Other neurons in the same hypothalamic inflammatory adipocytokines that have autocrine, paracrine, areas secrete another stress hormone, [arginine and systemic (endocrine) action [3]. vasopressin (AVP) or antidiuretic hormone (ADH)], which acts The aim of this critical review is to evaluate the bi- synergistically with CRH to stimulate ACTH secretion [6]. The directional interactions between the HPA axis and the most PVN depends on inputs from other hypothalamic nuclei [such

CONTACT George MASTORAKOS [email protected] Unit of Endocrinology, Diabetes Mellitus and Metabolism, Aretaieion Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece © 2018 Informa UK Limited, trading as Taylor & Francis Group 318 P. PAPARGYRI ET AL. as the arcuate nucleus, the dorsomedial hypothalamic nucleus signaling cascades which provide non-genomic effects [8]. (DMH), and the preoptic area (POA)] and/or other brain nuclei Circulating GCs exert either positive (to the amygdala) or (such as the amygdala, the LC, etc.) which are integrated to negative (to hypothalamus, pituitary gland and higher struc- positive stimulation of CRH secretion. On the other hand, the tures such as hippocampus) feedback via GRs in these tissues hippocampus and the prefrontal cortex suppress PVN activity aiming at restoration of ‘“homeostasis”’ (often as a new state and subsequently the activity of the HPA axis [4]. of equilibrium so-called ‘“allostasis”’)[1,2,7,9,10](Figure 1). Consequently, CRH acts on the CRH-R1 receptors of the ante- concentrations of GCs demonstrate a patent circa- rior pituitary corticotroph cells, stimulating the synthesis of dian rhythm in humans, with its zenith in early morning (active (POMC), the precursor of adre- phase) and its nadir in late night (inactive phase). This rhythm nocorticotropic hormone (ACTH), as well as the release of is endogenously controlled by SCN via both HPA axis and stored ACTH [7]. The latter, when released into the systemic direct sympathetic innervation, and by local molecular clocks circulation, acts on the type 2 of the in the adrenal cortex [11]. Chronic emotional stress in humans adrenal cortex and enhances the synthesis and release of leads to blunted GC diurnal rhythm and elevated GC concen- glucocorticoids (GCs) from the zona fasciculata [7]. GCs are trations in the evening which in its turn leads to increased the peripheral effectors of the HPA axis and control the organ- central [11]. ism’s adaptive response to the stressful situation via either Interestingly, it has been recently demonstrated that there intracellular-nuclear receptors such as the corticosteroid is a circadian fluctuation in the sensitivity of the GR via its receptors type I or mineralocorticoid receptors (MRs), and acetylation, which attenuates its transcriptional activity [12]. corticosteroid receptors type II or glucocorticoid receptors GR acetylation, is increased in the morning and decreased in (GRs) or via membrane-associated receptors [8]. The nuclear the evening, adversely to the physiological cortisol circadian receptors initiate transcriptional activation or repression of rhythm fluctuation [12]. This phenomenon represents prop- different GC-regulated , while the membrane-bound ably a local counter-regulatory mechanism that functions receptors are coupled to downstream G protein-dependent negatively in case of chronically stressed (or under frequent

Figure 1. Immune/inflammatory and neuronal regulation of the HPA axis. The activation of the immune/inflammatory system leads to secretion of proinflammatory cytokines that activate the HPA axis at multiple levels. Various brain nuclei contribute to the activation of the HPA axis [amygdala, locus caeruleus/norepinephrine (LC/NE), dorsomedial hypothalamic nucleus (DMH), arcuate nucleus (AN), preoptic area (POA)] while others [hippocampus and prefrontal cortex (PC)] to its inhibition. In turn, GCs activate amygdala and inhibit LC/NE, AN, DMH, POA, hippocampus and PC. EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 319

circadian shift) individuals whose mild evening cortisol eleva- Table 1. Most studied adipokines, as included in the following reviews [24,25]. tions demonstrate enhanced activity on target tissues result- Leptin ing in an overall increased GC effect with subsequent Adiponectin metabolic implications [13]. On the other hand, a constant interaction exists between the HPA axis and the immune system. It involves pro- Interleukin-6 (IL-6) Interleukin-1β (IL-1β) inflammatory cytokines such as TNF, IL-1, IL-6, IL-8, IL-12 and Interleukin-10 (IL-10) interferons (INF) α and β. These are glycoproteins secreted Visfatin into the circulation by a variety of cells such as , Omentin Vaspin antigen-activated immune cells (T-cells, macrophages), neuron Plasminogen activator inhibitor 1 (PAI-1) cells, fibroblasts and endothelial cells. These pro-inflammatory Monocyte chemoattractant protein 1 (MCP1) cytokines activate the HPA axis at multiple levels mainly via Retinol binding protein 4 (RBP4) Tumor necrosis factor (TNF) CRH and GCs stimulation and secretion [14,15]. More specifi- Progranulin cally, IL-6 is expressed in the supraoptic and PVN neurons and Complement C1q tumor necrosis factor-related protein 4 (CTRP-4) β β regulates the activity of both CRH and AVP genes, increasing Transforming growth factor (TGF ) Secreted frizzled-related protein 5 (SFRP5) CRH and AVP secretion by the corresponding PVN neurons [6]. Fibroblast growth factor 21 (FGF 21) In turn, endogenous or exogenously administered synthetic Angiopoietin-like protein 2 GCs suppress the secretion of these pro-inflammatory cyto- Bone morphogenetic proteins (BMPs) Cathepsins kines leading to control of the inflammatory chain reaction Lipocalin [1,4,7,16](Figure 1). Nesfatin- 1

1.2. Adipose tissue and adipokines factors have local (autocrine/paracrine) but also systemic The adipose tissue forms a large organ widely dispersed in (endocrine) actions. They communicate with other tissues to various sites of the body. It is involved in a variety of exert directly and/or indirectly pleiotropic functions, such as physiological activities while it consists of several types of feeding behavior, and lipid metabolism, inflammation cells such as pre-adipocytes, adipocytes (the predominant and coagulation [3]. type of cells), macrophages, endothelial cells, fibroblasts and leucocytes. Except its major role which is energy storage, the 2. Adipose tissue, adipokines and the HPA axis adipose tissue functions also as an endocrine organ [3,17]. The population of macrophages in the adipose tissue aug- During the past three decades, a complex interplay has been ments significantly in parallel with its total mass, oscillating revealed between the adipose tissue and the HPA axis [20]. between 1% and 25% (in lean and obese subjects, respec- Pro-inflammatory adipocytokines and adipokines secreted by tively) [18]. It is distinguished histologically and functionally the adipose tissue act directly and/or indirectly at all three in white adipose tissue (WAT) which represents its major distinct levels of the HPA axis (hypothalamus, pituitary, adre- volume in the body, and (BAT). The nals) (Figure 1). Indeed pro-inflammatory adipocytokines former stores extra energy in form of , their secreted by adipocytes and macrophages of the adipose tissue accumulation leading to obesity. Anatomically, WAT can enhance HPA axis function acting directly and/or indirectly on further be distinguished into visceral (VAT) and subcuta- the hypothalamic PVN, the pituitary and the adrenal glands, neous (SAT) adipose tissue [19,20]. The former is located while GC inhibit their secretion (Figure 1)[14,15,26–31]. mainly around the internal organs of the abdominal cavity, Of note, adipose tissue expresses both 11β-hydroxysteroid and is associated with central obesity, resistance, dehydrogenase type 1 and type 2 (11βHSD1 and 11βHSD2, (T2DM), dyslipidemia, and respectively) enzymes. In humans, 11βHSD1 catalyzes the con- high mortality. Subcutaneous adipose tissue is rather accu- version of hormonally inactive to active cortisol, mulated in periphery and is associated with beneficial playing a crucial role in the GC metabolism, while 11βHSD2 effects regarding the aforementioned metabolic risk factors acts inversely [32]. Adipocytes demonstrate low 11βHSD2 and [21]. Brown adipose tissue is inversely correlated to body relatively high 11βHSD1 activity [20]. In in vivo and in vitro mass index (BMI) and while is abundant in the newborn, in studies in human obesity, 11βHSD1 activity has been found adults is decreased. It is located in the neck, the supraclavi- increased both in SAT and in VAT [33,34], leading, thus, to cular, paravertebral, mediastinal, para-aortic and suprarenal increased intra-adipose tissue cortisol with deleterious meta- regions [22,23]. Interestingly, a sub-category of WAT consists bolic consequences [35]. In mice, there are data supporting of cells called beige or brite (brown-like-in-white) adipose the existence of an autocrine protective mechanism which cells which can function as BAT. These cells share common down-regulates the adipose tissue 11βHSD1 in response to thermogenic characteristics with BAT and demonstrate an chronic high fat feeding. This mechanism disappears with anti-obesity effect via fat consumption [17]. worsening of obesity [33]. Pharmaceutical research is focused The endocrine functions of the adipose tissue are mediated on therapeutic selective inhibition of 11βHSD1 aiming at by adipose tissue-derived proteins called adipokines (Table 1) attenuating the obesity-associated deleterious metabolic con- which are products of either the cells or other type sequences, by reducing intra-adipose cortisol concentrations of cells harbored within the adipose tissue [3]. These bioactive without inducing systemic cortisol deficiency [33,36]. In 320 P. PAPARGYRI ET AL. human obesity, the majority of studies found circulating basal given that significant elements are missing in this field of GCs concentrations increased while others found them unaf- physiology. The initial observations came from the homozy- fected. This discrepancy may be partially explained by the gote (ob/ob) mutant Zucker rat which presents complete reduced plasma cortisol half-life in obesity due to increased leptin deficiency and expresses a phenotype of obesity, hyper- urinary cortisol excretion [36–38]. However, HPA axis in obese phagia, hyperglycemia and infertility. This rat presents with subjects demonstrates loss of diurnal variation, increased increased ACTH and corticosterone serum concentrations responses to pharmaceutical stimulation (increased cortisol which decrease to normalcy following chronic administration response to low ACTH test and to CRH-AVP test) as well as of biosynthetic human leptin (subcutaneous administration of resistance to low oral suppression test [38]. In 100–300 μgr per rat per day for 30 days) [48–50]. In another fact, the obesity phenotype with excessive VAT, may repre- animal model, the diabetic db/db mouse, which has mutated sent, among other etiologies, a maladaptive response to and dysfunctional lepRs and presents with an obese, diabetic chronic stress, with local and eventually systemic disregulation phenotype and high concentrations of corticosterone [51], of the GC metabolism and the HPA axis activity [39]. hypercorticosteronemia does not normalize after exogenous GCs acting via GRs (present in preponderance in VAT rather administration of leptin [50]. Thus, leptin should exert its direct than SAT) and MRs (located in adipocytes) exert a dual action and/or indirect effects on the HPA axis via functioning lepRs. on adipose tissue. In one hand, GCs impair proliferation and In male Wistar rats, a bolus of 2 μg recombinant leptin admi- promote differentiation of pre-adipocytes to mature adipo- nistered intracerebroventricularly (icv.) induced CRH secretion cytes, while, on the other hand, they stimulate lipolysis in in a dose-dependent fashion while 2 injections icv. of 3.5 μgr mature adipocytes, regulating thus, body expansion and dis- of recombinant human leptin to Long-Evans rats during a 40 h tribution of the adipose tissue [39]. fast increased CRH in PVN by 38% [52,53]. The doses of 2 and 3.5 μg leptin are within the range of 10−9 M which is consid- ered within the physiological range for circulating proteins. It 2.1. Leptin and the HPA Axis has been suggested that this action participates in the central From the wide variety of adipokines, the most studied one in inhibition of food intake given that CRH is a potent anorexi- relation to the HPA axis is leptin. It is a 16kDa protein, product genic hormone. In addition, leptin acting in the arcuate of the ob located on 6 and 7 in mice and nucleus inhibits the expression of orexigenic [neuro- humans, respectively, discovered in 1994. Its name derives peptide Y (NPY) and agouti-related peptide (AgRP)] while it from the greek adjective ‘“leptos, λεπτός”’ meaning ‘“thin”’, enhances the expression of anorexigenic peptides [(POMC) because of its anorexigenic, and therefore weight-reducing and cocaine and amphetamine related transcript (CART)] lead- effects [9,40–42]. It is secreted mainly from the adipose tissue ing to decreased food intake [54]. In humans with congenital (but also in minimal quantities from mammary gland, sto- leptin deficiency, on the other hand, 24-h urine cortisol con- mach, , , pituitary gland and other centrations are found within normalcy while cortisol is sup- brain structures [43]) in a pulsatile, circadian fashion, peaking pressed by 1 mg dexamethasone to less than 5 μg/dL [54–58]. in late evening in humans [11]. It is produced mainly in Leptin replacement in those patients increases mean 24-h proportion to the amount of WAT (especially SAT) and in serum cortisol concentrations, altering the circadian rhythms conditions of food excess. The circadian oscillations in leptin of cortisol (decreased number but increased amplitude of concentrations in human plasma and in cerebrospinal fluid are pulses, increased morning peak) [58,59]. In humans with essential for its function and may play a critical role in meta- mutated lepR gene certain studies have found normal adrenal bolic regulations [11]. Leptin acts via (lepR) function [60]. Interestingly, in a class of patients with acquired which is represented by at least 6 isoforms in many peripheral hypoleptinemia, such as girls with hypothalamic amenorrhea organs such as , , lung, , testes, endocrine (including ), long-term (36 weeks) recombi- , skeletal muscles, bones, hemopoietic organs and nant human leptin (r-metHuLeptin; ) administra- adipose tissue (local paracrine action), central nervous system tion, led to significantly reduced serum cortisol (in choroid plexus, ventral tegmental area, ARC, PVN and concentrations. Nevertheless, 24-h urine collection for free DMH) pituitary and adrenal glands [9,44]. Leptin, acting in cortisol was not assessed in this study [61]. Further studies the hypothalamus, induces satiety and increases thermogen- are needed to elucidate the role of leptin on human HPA axis esis as well, contributing thus, to the maintenance of when it is administrated to correct either its congenital defi- a negative energy balance [45,46]. When found at low con- ciency (it regards morbidly obese patients) or its relative centrations in fasting state or during weight loss, appetite acquired deficiency (it regards abnormally low-weight increases and energy loss is limited [45,46]. Interestingly, in patients). obesity increased concentrations of leptin suggest a state of Alternatively, in humans, corticosteroids enhance leptin pro- leptin resistance resulting, eventually, from functional or duction and release by adipocytes in vitro [62–64] and in vivo, (more rarely) genetically impaired receptor sensitivity [47]. in normal-weight [65] and in obese subjects [66]. Specifically, Leptin, either secreted by the adipose tissue or locally administration of 2 mg dexamethasone twice daily resulted in secreted in the brain [43,46] interacts with the HPA axis. It elevated leptin concentrations at 08.00 am after 24 h of treat- seems that this interaction depends upon the level of HPA axis ment in healthy young men (mean age 24.9 years, mean BMI activation and circulating leptin concentrations. The informa- 24.4) [65]. In obese women (BMI 36.4 ± 0.82 kg/m2)butnotin tion gathered as yet, for the various aspects of physiology obese men (BMI 39.4 ± 1.55kg/m2) nor in normal weight sub- regarding this interaction should be interpreted with caution jects (BMI 22.1 ± 0.41 kg/m2), overnight administration of 1 mg EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 321

dexamethasone induced plasma leptin elevation, indicating subcutaneous infusion of 6 μg/kg/day metreleptin in female a probable greater sensitivity of female adipose tissue to GCs rhesus monkeys, had no effect on basal cortisol secretion but regarding leptin production [66]. attenuated cortisol and ACTH response to an acute HPA acti- Under acute stress (defined as the situation in which stress vation (injection of dexamethasone followed 18 h later by an stimuli exert their noxious effect over a short period of time) injection of CRH). Of note, the administrated dose is lower conditions, endogenous leptin concentrations increase due to than that observed in obese women and it reflects a state of stress-induced hypercortisolemia (Figure 2(a)). In animal mod- positive energy balance [72]. It has been suggested that els, acute exposure to noise (1–3 h), restraint, inmobilization increased leptin concentrations enhance the negative feed- (1–2 h) or 10 min forced swimming, resulted to an increase of back of GCs upon HPA axis via upregulation of the GR expres- both corticosterone and leptin [67,68]. Interestingly, when sion in the PVN and the hippocampus [73]. Indeed, a direct leptin is administrated acutely in pharmacological doses, the effect of leptin on the corticotrophs has been questioned and HPA axis response to stressors is attenuated via leptin- there is no ACTH response to leptin in cultures of rat pituitary associated inhibition of CRH release [67,69–72](Figure 2(a)). cells in vitro [69]. Nevertheless, other evidence suggests that When male mice were injected intraperitoneally (ip) with the intra-pituitary leptin production by other types of endo- 2–4 μg/g body weight (BW) mouse leptin, ACTH and corticos- crine cells, such as somatotrophs and gonadotrophs, may act terone plasma concentrations did not respond to restraint on corticotrophs in a paracrine fashion, serving in the integra- stress following treatment with the highest dose of mouse tion of main physiological functions of the organism such as leptin (4 μg/g BW) indicating an inhibitory, direct and/or growth, reproduction and feeding [9,74]. Of note, lepRs are indirect, effect of leptin upon HPA axis activation. Moreover, present in the anterior lobe of the pituitary on corticotroph CRH release in hemi-hypothalamic sections was found cells [75] and in the adrenal cortex. decreased in an injected-leptin dose-dependent manner, fol- In a human model of acute stress (acute perception of lowing euthanization of mice [69]. In another study, immobi- academic examination stress) employed in a recent study lization-induced increases of plasma corticosterone in Wistar with the help of a questionnaire derived from Hamilton rats, were reversed by 0.1 and 0.5 mg/kg recombinant rat Anxiety Scale in 85 healthy female students (aged 19–21 years; leptin-injected ip [70]. Moreover, chronic (28 days) BMI 21.9 ± 1.6), serum cortisol and leptin concentrations were

Figure 2. (a) The HPA axis-leptin interplay in acute stress: Acute stress leads to stimulation of leptin secretion via increased secretion of cortisol. Leptin, in turn, attenuates HPA axis response to stress. This, added to the inhibitory feedback of GCs over the HPA axis, points at the return of GC secretion to a basal state. The solid lines indicate stimulatory action; the dotted lines indicate inhibitory action. ACTH: adrenocorticotropin hormone; CRH: corticotrophin-releasing hormone; LepR: leptin receptors. (b) The HPA axis-leptin interplay in chronic stress: Chronic stress leads to non-stimulation of leptin secretion via induced intolerance to chronic cortisol secretion while hypothalamic LepR mRNA expression decreases. Thus, a non-inhibition of the HPA axis activity results. The solid lines indicate stimulatory action; the dotted lines indicate inhibitory action. The different line widths indicate differences in secretory quantities. ACTH: adrenocorticotropin hormone; CRH: corticotropin-releasing hormone; LepR: leptin receptors. 322 P. PAPARGYRI ET AL. monitored at baseline (beginning of academic session) and on effect on leptin concentrations in animal studies [83]. The the day of the academic examination. Their concentrations anorexigenic effect of the relatively low leptin concentrations increased between baseline and the examination day while is diminished in chronic stress while at the same time other those of cortisol correlated positively with the subjective per- animal studies have shown upregulation of the orexigenic NPY ception of academic examination stress [76]. This leptin eleva- system in relation to GCs excess, suggesting an explanation for tion could be attributed to stress-induced cortisol increase stress-induced food intake and visceral obesity [84,85]. (Figure 2(a)). On the other hand, the direct inhibitory action Of note, patients with Cushing syndrome present with of increased leptin concentrations on adrenal production of elevated leptin concentrations in comparison with BMI- GCs has long been documented (Figure 2(a)). When primary matched controls [86], suggesting that this effect is indepen- cultures of bovine adrenocortical cells were incubated with dent of the total body fat mass [87]. However, the hyperlepti- increasing concentrations (10–1000 ng/ml) of recombinant nemia in Cushing syndrome maintains its diurnal rhythm and mouse leptin for 24 h, ACTH-stimulated cortisol release was persists after surgical treatment, indicating that the prolonged inhibited in a concentration-dependent manner [77]. In hypercortisolism doesn’t affect leptin concentrations directly. another in vitro study, isolated primary cells of human adrenal Other factors such as body fat distribution and chronic hyper- glands from transplant donors were pre-incubated insulinemia may play more important roles in leptin secretion with metreleptin (10−10–10−7 M) for 6 or 24 h and basal or in Cushing syndrome [88]. However, it is noteworthy that in ACTH-stimulated cortisol secretion was subsequently mea- food-dependent Cushing syndrome there is a paradoxical sured. Basal cortisol secretion was unaffected by leptin, but response of the adrenals to leptin resulting to cortisol secre- a significant and dose-dependent inhibition of ACTH- tion. This phenomenon could be explained by the presence of stimulated cortisol secretion was observed [71]. either aberrant, maybe mutated, LepRs or mutations involved In one study, the authors investigated the relationship in the secondary messenger cascade [89]. between plasma leptin concentrations, hypothalamic opioid New therapeutic approaches have already emerged from tone, and plasma ACTH secretory dynamics. Plasma leptin this area of physiology. Research is focused on the use of concentrations did not change after naloxone administration. leptin as an anti-stress, anti-anxiety, anti-depressive factor However, there was a positive correlation between fasting, apart from the obvious interest in its anorexigenic potency. integrated plasma leptin concentrations, and plasma ACTH The only currently available pharmaceutical form of leptin is responses to naloxone. The correlation was stronger when metreleptin. Metreleptin is approved by the FDA for the treat- leptin was normalized to BMI [78]. On the other hand, in ment of congenital or acquired generalized lipodystrophy a placebo-controlled study where centrally acting stimuli (non-HIV related). For the rest of possible therapeutic indica- (naloxone, vasopressin, insulin-hypoglycemia test) of the HPA tions, it is not yet approved because of lack of evidence of axis were administrated to eight healthy male volunteers efficacy and/or safety. In obesity, metreleptin is only effective (aged 27–51, BMI 23.3–30.1) and led to acute hypercortisolism, in the rare cases of congenital leptin deficiency. In common leptin concentrations did not increase following any of these obesity, metreleptin is counter-indicated and ineffective as stimuli [79]. These studies suggest that central activation of these patients demonstrate both hyperleptinemia and central the HPA axis, does not seem to directly or acutely affect leptin resistance. To overcome central leptin resistance, plasma leptin concentrations. However, plasma leptin concen- research is focused on lepR sensitization methods [co- trations may influence hypothalamic opioidergic tone and administration of leptin with anti-inflammatory or other thus, modulate the magnitude of CRH release. weight-reducing drugs such as (an analo- Under chronic stress (defined as the situation of continuous gue)] [90]. or repeated over time exposure to stressors) studied in animal models of chronic mild stress (depression-like behavior), rats 2.2. Adiponectin and the HPA Axis exposed to various stressors over 3 weeks presented with hyperactivity of HPA axis, low leptin concentrations and low Adiponectin, firstly described in 1995, is a 30-kDa protein, hypothalamic LepR mRNA expression [80]. Although leptin product of the apM1 gene, mainly synthesized and secreted concentrations were greater in obese chronically stressed by adipocytes [91]. Apart from adipose tissue, adiponectin is male rats than in normal-weight non-stressed and in normal- found in tissues such as skeletal muscle, heart (cardiomyo- weight-stressed rats, they were lower than in obese non- cytes), bone (osteoblasts), placenta, testis, , liver, adrenal chronically stressed rats. In addition, an important down- and pituitary glands [92]. Adiponectin is expressed mostly in regulation of LepRs was observed in the hippocampus and SAT and is inversely correlated to the amount of visceral the hypothalamus of the obese chronically stressed rats result- adiposity [93,94]. Its concentrations are reduced in obesity ing to depressive and anxiety-like behavior as well as cognitive and lipodystrophy [95–97]. Peripheral administration of adipo- impairment [81]. In this case, the reduced leptin activity led to nectin decreases body weight and reduces visceral adiposity HPA axis hyperactivity [80,81](Figure 2(c)). Furthermore, in [98]. Three adiponectin receptors have been identified: the healthy young men and women (mean age = 22.4years; transmembrane adiponectin receptors (AdipoR) 1 and BMI = 23.19 kg/m2) treated with hydrocortisone the enhancing AdipoR2, which share a 66% in their amino acid effect of GCs on leptin secretion was dose-dependent for the sequence, and T-cadherin (CDH13). All three mediate its multi- first 3–4 treatment days [82] while chronic administration of ple metabolic actions in the tissues where they have been hydrocortisone (for 3 weeks) induced intolerance and had no detected (liver, muscle, vascular wall, pancreas, , EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 323 endometrium, testis, ovary, placenta, hypothalamus, pituitary, in these studies could be attributed, among others, to the cortical and subcortical neurons of the brain, adipose tissue, complex regulation of adiponectin by a large variety of dis- macrophages and osteoblasts) [92,99,100]. Its main metabolic tinct factors (transcription factors, signaling cascades and hor- actions include insulin sensitizing, anti-inflammatory and anti- mones) as well as the different response of the distinct types atherogenic actions. They are mediated by signaling pathways of adipose tissue (WAT, BAT, VAT, SAT) to these factors [134]. that include the adenosine monophosphate-activated kinase Adiponectin has been proposed as treatment for obesity (AMPK), the mitogen-activated protein kinase/extracellular sig- and its complications due to its multiple beneficial metabolic nal-regulated kinase (MAPK/ERK) and the peroxisome prolif- functions (insulin-sensitizing, anti-inflammatory, anti- erator-activated receptor alpha (PPARa) [101,102]. Low atherogenic). Oral administration of AdipoRon, an of adiponectin concentrations have been associated with clinical the 1 (AdipoR1), has shown promising components of the including negative results in improving diabetes in the obese rodent model db/ association with [103], T2DM [104–106], db and it is under investigation for administration to humans inflammation, lipid concentrations [107,108], obesity [93,95], [135]. However, unclear areas must be filled in till cardiovascular disease [109–111], gestational diabetes mellitus or antagonists can be proven beneficial for the treat- [112] and hypertension [94]. ment of metabolic problems and dysfunctions of HPA axis It seems that adiponectin is reciprocally associated to the and/or adipose tissue. HPA axis. In non-obese healthy men, the ultradian and circa- dian rhythm of adiponectin and cortisol share the same pat- 2.3. The pro-inflammatory adipocytokines TNF and IL-6 tern, with a significant decline of both hormones at night, and the HPA Axis evoking a potential relationship between the two hormones [113]. Indeed, in human WAT, mRNA levels of adiponectin TNF is a potent pro-inflammatory cytokine of 157 aminoacids, peak in the late morning [11]. Adiponectin mRNA expression produced mainly by activated monocytes and macrophages in was detected in rat adrenals where it enhances adrenocortical tissues rich in these cells such as the adipose tissue, the cell proliferation and stimulates corticosterone secretion in hypothalamus, the pituitary gland, the ovary, the testis and a dose-dependent manner [114]. Adiponectin can alter the the adrenal gland. TNF concentrations are increased in obesity expression of key genes involved in steroid synthesis. It affects while they increase in response to stimuli such as tissue injury, directly steroid secretion in the adrenocortical cell line Y-1 infection and aseptic or septic inflammation. Its secretion while in human adrenocortical cells, it stimulates the produc- depends also on local circadian clocks in immune cells, tion of cortisol via stimulation of the expression of steroido- although a concrete circadian pattern is not proven in humans genic acute regulatory (StAR) protein via the ERK1/2- and [11]. It is a main mediator of the immune response and AMPK- dependent pathways [115]. Interestingly, short-term inflammation while it plays an important role in the regulation treatment with adiponectin seems to inhibit basal and ACTH- of cell proliferation, differentiation, and apoptosis. It acts via induced steroid secretion in mice [116]. Regarding the effects two receptors (TNF-R1 and TNF-R2), widely expressed in the of HPA axis on adiponectin expression, data from various body, including hypothalamus and gland. studies are conflicting [117]. Some in vitro studies showed Thus, TNF is involved in the cytokine-mediated communica- inhibition of adiponectin expression by GC administration tion between immune system, adipose tissue and HPA axis [118–120], ACTH or stress-induced adrenal stimulation [136,137]. TNF, IL-1β and IL-6, stimulate the HPA axis acting in [114,121], while others did not show any GC-induced change the brain directly (by binding to cytokine receptors in the in adiponectin concentrations [122,123]. Animal studies have blood–brain barrier cerebral or by brain penetra- shown also conflicting results. Intraperitoneal injections of tion via capillaries or by acting on CRH- and AVP- secreting hydrocortisone in both obese and non-obese rats lead to neuron terminals at the median eminence through the fene- decreased adiponectin plasma concentrations [124] while strated endothelia of the circumventricular organ) or indir- decreased local intracellular GC action in adipocytes (pro- ectly, via action on peripheral ascending catecholaminergic duced by 11bHSD1 knockout or 11bHSD2 overexpression in neurons of the area postrema [14,15,26,27]. These cytokines transgenic mice) led to elevated adiponectin concentrations stimulate CRH and AVP secretion, leading to increased ACTH [125,126]. However, in other animal studies, a positive effect of production and finally, increased adrenal steroidogenesis administered GCs upon adiponectin concentrations was found [28,29]. In addition, TNF regulates directly steroidogenesis in [127,128]. In line with these results, adiponectin concentra- the adrenal, the ovary and the testis (by upregulation of tions increased in clinical studies following GC administration steroidogenic genes like StAR, 3β-HSD2, CYP17) [137] while it either to healthy, non-diabetic humans [129,130], or to alters GR function. Thus, it affects the feedback control of GCs patients with IgA nephropathy [131] or to patients with renal on the HPA axis [138]. By stimulating Iκb kinase, GCs lead to transplantation [132]. Interestingly, 4 mg dexamethasone inhibition of Nfκb, which in its turn inhibits TNF and the other administered to T2DM patients and to healthy controls, inhib- pro-inflammatory cytokines production [31]. Nevertheless, this ited AdipoR2 mRNA expression in nondiabetic subjects, while action was not demonstrated in patients with endogenous a small rise in plasma adiponectin concentrations was found hypercortisolism. In effect, in patients with Cushing syndrome, [129]. In contrast, other studies demonstrated a negative effect TNF concentrations were in the normal range or inappropri- of exogenous or endogenous GCs on the adiponectin concen- ately increased suggesting that in endogenous hypercortiso- trations of, respectively, healthy subjects or patients with lism, the inter-relationship between these two hormones finds Cushing syndrome [133]. The apparent discrepant conclusions a new level of homeostasis eventually through mechanisms 324 P. PAPARGYRI ET AL. such as down-regulation of receptors. This is due also to the IRS-1 and leading to insulin resistance [155–157]. At the same excessive production of TNF by the increased amount of time, the role of IL6 in the pathogenesis of insulin resistance visceral fat in this pathologic entity [39,139]. Furthermore, remains controversial, with studies supporting the hypothesis a modification of GR which occurs following chronic hypercor- that IL6 impairs insulin sensitivity [158,159] and others that IL6 tisolemia, leads to decreased ligand affinity and subsequently enhances both insulin function [160] and leptin action [161]. to decreased anti-inflammatory action of GCs [140,141]. Recent research indicates that IL6 and leptin share a common Interestingly, patients with long-term cured Cushing syn- intracellular signal transduction pathway downstream of their drome present with increased concentrations of TNF and respective receptor systems, glycoprotein 130 receptor β other inflammatory cytokines, maintaining a state of chronic (gp130Rβ) and LepRb. Interestingly, beyond leptin analogs, “low grade inflammation” [139]. gp130R agonists have been suggested as possible anti- IL-6 is another pleiotropic cytokine produced and secreted by obesity therapeutic options [162]. a variety of cells, including adipocytes, macrophages, fibroblasts Both of these pro-inflammatory cytokines demonstrate cru- and endothelial cells. It is also expressed in immune tissues, cial functional characteristics regarding both the stimulation of hypothalamus, anterior pituitary, and adrenal cortex [142]. IL-6, the HPA axis and the development of insulin resistance in like TNF, is expressed more in VAT than SAT [143] and demon- humans, which makes them interesting targets for pleiotropic strates local autocrine/paracrine action in the adipose tissue as pharmacologic interventions. well as systemic action, promoting coagulation and pro- inflammatory reaction. This cytokine is secreted in humans in a circadian rhythm, with a zenith in the early morning [144,145]. 3. Adipokines and the HPA Axis in stress-related Its secretion increases in case of disturbances of the homeostasis disorders such as tissue injury, septic (as in sepsis) or aseptic (as in rheu- 3.1. Food intake and eating disorders matoid arthritis) inflammation and in any type of physical or psychological stress such as exercise [5,31,142,146]. 3.1.1. Food intake and the HPA Axis Moreover, IL-6 plasma concentrations are significantly Feeding behavior is regulated by a complex interaction increased in obesity and decreased after weight loss [147]. It between neural and endocrine systems. The afferent periph- has been estimated that one third of total circulating concen- eral system, includes a variety of hormones such as insulin trations of IL-6 originate from the adipose tissue. Thus, obesity (secreted by the endocrine pancreas in response to a meal), represents a state of low-grade inflammation [148]. IL-6 stimu- leptin, (an orexigen produced by the gastrointestinal lates HPA axis via CRH and AVP neurons in the hypothalamus tract in absence of food intake) and gut hormones (they [146]. Indeed, in the past we have shown that administration of provide satiety signals) such as -like peptide 1 and recombinant IL-6 to humans led to substantial increase of the . These signals are interpreted by various brain AVP, ACTH, and GC peripheral concentrations [15,145,149,150]. centers such as the nucleus tractus solitarius (NTS) and the Furthermore, IL-6 may regulate steroidogenesis locally in the CNS food intake integrating unit, located in the ventromedial adrenals as it has been shown in vitro [5]. In turn, GCs inhibit IL- hypothalamus (VMH), the lateral hypothalamus (LHA) and 6 secreted by the cells of the immune system [30]. The tonic PVN. Then, efferent signals from these brain centers, in parti- negative feedback loop between endogenous cortisol and IL-6 cular , stimulate either the sympathetic nervous is shown in patients with Cushing syndrome who present with system to induce energy expenditure or the parasympathetic low concentrations of IL-6. In the immediate postoperative nervous system to increase insulin secretion which promotes period, when these patients become hypoadrenal, and energy storage. Energy expenditure is a significant increase of IL-6 is observed, while its concentra- mediated by the activation of β3 adrenergic receptors in tions decrease again after GC replacement therapy [151]. peripheral adipose tissue via induction of thermogenesis and With regard to insulin resistance, low-grade inflammation is lipolysis [45]. The neuropeptides implicated are either anorexi- associated with its pathogenesis particularly of that attributed genic (POMC, CART, and CRH) or orexigenic (NPY, AgRP, and to visceral obesity [152,153]. TNF is secreted by the increased MCH). CRH is a potent anorexigenic . Direct number of macrophages in the adipose tissue of obese sub- administration of CRH into PVN inhibits nighttime and fasting- jects and it contributes to insulin resistance while it decreases induced food intake. This hormone also induces energy following weight reduction [154]. Circulating TNF concentra- expenditure via stimulation of thermogenesis and lipoly- tions are higher in visceral obesity compared with peripheral sis [163]. obesity [153]. In the investigation of the underlying mechan- In addition, internal circadian function interferes with feed- isms, initial studies suggested an impairment of insulin recep- ing behavior. The former synchronizes constantly with exter- tor (IR) which exerts a tyrosine kinase activity [155,156]. nal environmental factors (i.e. light, food intake) to coordinate Accordingly, TNF administration in skeletal muscle in vitro diverse biological processes, such as sleep-wake rhythms, eat- impaired insulin stimulation of glucose uptake by the cells ing, energy metabolism and immune function [164]. Apart and GLUT4 translocation to plasma membrane [157]. The from the HPA axis, studies have recently shown that adipo- defect in insulin signaling was attributed to TNF-induced ser- kines (i.e. leptin, adiponectin) and pro-inflammatory cytokines ine phosphorylation of IR and IR substrate (IRS) 1, impairing (i.e. TNF, IL-6) demonstrate also circadian rhythms [164]. thus insulin-stimulated autophosphorylation of IR on multiple However, normal circadian physiology is threatened by exo- tyrosine residues and subsequent tyrosine phosphorylation of genous factors such as nocturnal light exposure, shift work, EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 325 and social jet lag (lack of sleep during workdays and excess of In FHA, the critical factor is energy deficit (independently of sleep during free days) [165]. The disruption of circadian phy- changes in body weight). Indeed, LH pulsatility is disrupted siology has been linked to serious health problems. Obesity (in even in women with normal body composition and regular particular VAT increase), cancer, cardiovascular disease, menstruation when energy availability is restricted below depression, autoimmune diseases, and insulin resistance- 30 kcal/kg of lean body mass (LBM) [178]. Energy deprivation associated situations (i.e. T2DM) are linked to the disruption states encountered in eating disorders, especially anorexia of the diurnal physiological rhythms of the HPA axis and the nervosa, chronic diseases and elite athletes, are characterized adipokines [164,166–168]. by undernutrition, low body fat mass, activated HPA axis (increased CRH, ACTH, and cortisol concentrations), increased 3.1.2. Eating disorders and the HPA Axis adiponectin and low leptin, IGF-1 and T3 concentrations Eating disorders are characterized by disturbances in feeding [177,179–181]. In FHA, leptin concentrations are significantly behavior and by pathological cognition of one’s body shape decreased reflecting the low body fat percentage or restrictive and weight. Accordingly, there are three main eating disor- eating behavior or a combination of both. Interestingly, ame- ders: anorexia nervosa (AN), bulimia nervosa (BN) and binge norrheic women present higher incidence of abnormal eating, eating disorder (BED). The latter is characterized by recurrent particularly bulimic type behavior, and present with lower uncontrolled binges with absence of purging or other com- leptin concentrations and higher cortisol concentrations, inde- pensatory behaviors [169]. HPA axis seems to be activated in pendently of body fat [179]. This fact underlies the importance AN and BN, as elevated cortisol is detected in both syndromes of restrictive eating behavior in the pathophysiology of FHA. [169,170] while cortisol suppression by exogenous GCs is There is also a loss of the circadian rhythm of leptin concen- impaired [171]. In BED, studies examining cortisol concentra- trations in FHA [180]. tions led to conflicting results. In obese subjects with BED, 24- Adiponectin, in contrast to leptin, is elevated in energy h urinary-free cortisol concentrations seem to be inversely deprivation states. In young women (18–35 years old; BMI correlated with the severity of the disease insinuating condi- 21.5 ± 0.4 kg/m2), adiponectin concentrations were signifi- tions typically linked to low HPA axis activity such as mood cantly elevated in those exercising and presenting with FHA and anxiety disorders [172,173]. In addition results of another compared to those exercising or being sedentary and present- study imply chronic down-regulation of the HPA axis in ing with ovulatory cycles [182]. A role for adiponectin in the patients with BED. Interestingly, acute activation of the axis reproductive function has been suggested including modula- is associated with feelings of stress and food craving in these tion of steroidogenesis within granulosa and thecal cells but subjects [174]. This can probably suggest poor response to pathophysiological mechanisms remain still unclear [183,184]. satiety signals while being under a stressful situation [175]. As There is a tight link between activation of HPA axis and it has been long observed in healthy individuals, in acute reduction in GnRH drive in women with FHA [177]. Indeed, stress, the activation of the HPA axis inhibits food consump- these women demonstrate higher concentrations of serum tion, probably due to the anorexigenic effect of CRH [45]. 24-h cortisol when compared to controls, similar to women Conversely, in case of chronic stress, the sustained activation with eating disorders. Interestingly, females with FHA demon- of the HPA axis leads to high circulating cortisol concentra- strate higher prevalence of disordered eating behavior such as tions and induces calorically dense food intake via diverse dieting, bulimia, and high food preoccupation [179]. Moreover, hormonal interferences including insulin, NPY, CRH, leptin in young athletes with amenorrhea, there are reported higher etc.). Indeed, high cortisol concentrations lead to insulin and nighttime cortisol concentrations than in eumenorrheic athletes leptin resistance while they stimulate NPY release via inhibi- and nonathletes [181]. HPA axis inhibits the hypothalamic- tion of CRH, all contributing to increased food intake (stress pituitary-ovarian (HPO) axis in multiple ways and levels [185]. eating) [176]. As for leptin concentrations, most studies have Leptin stimulates GnRH neurons indirectly as there are no detected low concentrations in AN and BN in basal and post- LepR in these cells. LepR expression is also limited in kisspep- prandial measurements. In BED leptin concentrations seem to tin neurons but is abundant in interneurons in the ventral be higher in obese subjects than in normal weight con- premamillary nucleus (PMv), in the median preoptic area trols [169]. (MPO) and in the ARH (NPY/AgRP and POMC/CART cells). These interneurons are necessary to transfer leptin signal to GnRH neurons. Leptin stimulates reproductive system through 3.2. Functional hypothalamic amenorrhea inhibition of the HPA axis, the POMC neuronal system and NPY Functional hypothalamic amenorrhea (FHA) is a condition of secretion (in women with negative energy balance) and via chronic anovulation with no apparent anatomic or organic activation of the LC/NE system [186]. Consequently, leptin cause. It is usually a reversible form of amenorrhea which is concentration can modulate the onset of puberty and repro- often associated with stressful situations, psychological dis- duction via indirect stimulation of GnRH neurons [187]. tress, excessive exercise, energy deficit (combined with weight There are a few studies that have evaluated the effect of loss or not) or chronic diseases. The diagnosis of FHA is leptin administration in FHA. In one prospective study, the a diagnosis of exclusion. The cause of anovulation is administration of metreleptin in women with FHA led to a functional reduction in GnRH drive, which manifests as increase of the ovulatory cycles and significantly increased reduced LH pulse frequency. Subsequently, LH and FSH con- concentration of LH, , IGF-1, hormone, and centrations are insufficient to maintain full folliculogenesis and bone-formation markers than in controls [188]. In another ovulatory ovarian function [177]. randomized, double-blinded, placebo-controlled trial, 326 P. PAPARGYRI ET AL. metreleptin administration for more than 36 weeks in women 4. Summary with FHA resulted in restoration of menses (>50% ovulatory) In summary, there is a constant bi-directional interplay and increased concentrations of estradiol, , IGF-1, between HPA axis and adipose tissue mediated in one hand fT3 and concentrations while cortisol concentra- by hormones, mainly CRH, ACTH and GCs and on the other tions decreased [61]. These data indicate an important role of hand by adipokines and pro-inflammatory adipocytokines. The hypoleptinemia in the pathophysiology of the reproductive, importance of this interplay is unraveled in diverse clinical neuroendocrine and bone abnormalities in FHA [61]. situations related to stress-related disorders such as eating disorders, hypothalamic amenorrhea, and stress-related endo- 3.3. Stress-related endogenous hypercortisolism states genous hypercortisolism. Regarding the investigation of this interplay, leptin comes A high proportion of patients who present overt visceral first among the most studied adipokines. Absolute leptin defi- obesity associated with insulin resistance and other signs of ciency (ob/ob Zucker rat, congenital leptin deficiency) leads to the metabolic syndrome, suffer a wide range of psychological enhanced HPA axis activity, a situation which in many cases is manifestations including melancholic depression and anxiety, reversed with leptin treatment [41,48–50,195]. In addition, in demonstrating frequently a perception of “uncontrollable” high pharmacological doses or under stressful situations, lep- stress [189]. These chronically stressed obese patients usually tin attenuates HPA axis in many different ways. First, by redu- present with mild endogenous hypercortisolism. These cing CRH release [67,69–72], second by upregulating GR patients present a blunted cortisol circadian rhythm (due to expression in the PVN (enhancement of the GCs negative evening nadir elevations and morning zenith decreases), along feedback on the HPA axis) [73] and third, by direct inhibitory with augmented cortisol elevation in response to lunch and action on adrenal glands [77]. In chronic stress, there is impaired cortisol suppression by low dose overnight dexa- a down-regulation of leptin/LepR signaling in hypothalamus methasone test [190]. This state of chronic stress- and obesity- which leads to enhancement of the HPA axis activity [80,81]. associated mild hypercortisolism leads to a “pseudo-Cushing” Of note, GCs (either endogenous or exogenous) enhance lep- state that has to be differentiated from frank Cushing syn- tin production from the adipose tissue [62–66], although resis- drome. It is long suspected that this stress- and obesity- tance in this action is developed after prolonged associated chronic adrenal stimulation might be associated hypercortisolism [83,88]. In states of leptin excess such as with the development of non- functioning adrenal incidenta- obesity or T2DM, a state of leptin tolerance is developed [47] lomas (NFAI) [191]. The latter, an “endocrine epidemia” of with subsequent loss of its anorexigenic action. During stress, nowadays, were considered in the past as hormonally inactive the activation of the HPA axis is involved in the feeding tumors of the adrenals. Nevertheless in many cases, subclinical response. While CRH is anorexigenic, GCs may be orexigenic hormonal activity of the cortex or medulla is justified. or anorexigenic depending on whether they activate receptors Subsequently, the initial hypothesis of stress- and obesity- in the hypothalamus (orexigenic action by increasing expres- associated functional hypercortisolemia in relation to the sion of NPY and decreasing expression of CRH) or in adipo- development of incidentalomas is transformed to a-hen-and- cytes (anorexigenic action by enhancing the release of egg enigma because the subclinical hormonal activity of inci- leptin) [67]. dentalomas (whenever manifesting) results in co-existence Adiponectin is another important adipokine because of its with metabolic diseases (subclinical or clinical Cushing syn- insulin sensitizing, anti-inflammatory and anti-atherogenic drome, pheocromocytoma, obesity, hypertension, DM type 2) actions [101,102]. Its concentrations are reduced in obesity [191,192]. Of note, a recent study aimed to reveal associations a situation linked to HPA axis dysregulation and many meta- between the hormonal activity of NFAI and possible overse- bolic abnormalities [95–97]. However, investigation on the cretion of adipokines and pro-inflammatory adipocytokines in reciprocal relationship of adiponectin and HPA axis has led relation to the pathophysiology of the associated metabolic to controversial results and the field remains open. syndrome [193]. In this study, 18 patients (aged 25–66 years, Another category of adipokines, the pro-inflammatory adi- mean: 54.11 ± 11.78; BMI 27.00 ± 4.24 kg/m2) with adrenal pocytokines (TNF, IL-1, and IL-6) have a well-studied stimula- incidentalomas without known hormonal activity were com- tory effect upon multiple levels of the HPA axis. Many stressors pared to 18 healthy volunteers. Patients with NFAI presented lead to increased concentrations of these pro-inflammatory with significantly higher concentrations of TNF and IL6 and adipocytokines. The latter are also elevated in obesity [147] significantly lower concentrations of adiponectin, which did while their production by immune cells is inhibited by GCs not correlate with excess cortisol or catecholamine secretion [14,15,26–31]. [193]. Six months after surgical removal of the incidentalomas In conclusion, a challenging field regarding the interplay in 5 patients, the concentrations of IL6 and leptin decreased between HPA axis activity (particularly during stress-related while adiponectin concentrations increased in all studied situations) and adipokines remains to be investigated in cases. The authors suggested that low adiponectin concentra- depth. The mechanisms of physiology involved should be tions may play a crucial role in the link between NFAI and uncovered and described in more detail. The development cardiovascular disease. In accordance to that, other studies of new therapeutic approaches might target a wide variety have demonstrated that even mild chronic subclinical hyper- of medical problems related to dysfunctional stress response cortisolemia of seemingly NFAI may lead to decreased adipo- in relation to food consumption, energy expenditure and nectin concentrations and predispose to metabolic finally the adipose tissue itself. diseases [194]. EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 327

5. Expert commentary Key issues The interaction between HPA axis and adipokines is an impor- ● There is a bi-directional interplay between stress response and tant part of a research field covering the relationship between adipose tissue. HPA axis interacts reciprocally with the adipose the stress response and the adipose tissue. The importance of tissue, via hormones such as CRH, ACTH, GCs, and adipokines this interaction has attracted attention in the last decades, due such as leptin, adiponectin and proinflammatory to the augmented concern regarding increasing health pro- adipocytokines. blems such as metabolic syndrome, obesity, eating disorders, ● Leptin interacts with the HPA axis in a complex way contribut- depression, mood and food disorders related to chronic stress ing to attenuation of the HPA axis activity in acute stress (either physical or emotional). In this context, adipokines seem situations. to play a crucial role. They are involved in the regulation not ● In chronic stress, there is a down-regulation of leptin/LepR only of the HPA axis but also of other endocrine axes. New signaling in hypothalamus which leads to enhancement of therapeutic approaches intent to take advantage of the ben- the HPA axis activity. eficial effects of the adipocytokines aiming to a better meta- ● In obesity, as well as in sustained HPA axis activation, bolic regulation. Metreleptin, the only currently available and a state of leptin resistance develops due to impaired leptin approved by the FDA, pharmaceutical form of leptin, is already receptor sensitivity (functional hypoleptinemia). used for the treatment of congenital or acquired generalized ● Adiponectin has reciprocal relationship with the HPA axis, alter- lipodystrophy (non-HIV related) and remains under investiga- ing the expression of key genes involved in steroid synthesis. tion with hopeful results for its use as an anti-stress, anti- ● Pro-inflammatory adipocytokines mediate the communica- anxiety, anti-depressive factor apart from the obvious interest tion between the immune system, the adipose tissue and in its anorexigenic potency. In addition, studies investigating the stress system, regulating the HPA axis centrally (in the the effect of metreleptin administration in women with FHA brain) but also peripherally (direct effect on steroidogenesis). have led to positive results with restoration of menses, ● Excessive, defective, or dysfunctional adipose tissue is increase of ovulatory cycles and improvement of the hormonal related to dysfunctional HPA axis and stress response. profile. Moreover, adiponectin has been proposed as treat- ment for obesity and its complications due to its multiple Funding beneficial metabolic functions (insulin-sensitizing, anti- inflammatory, anti-atherogenic). Oral administration of This paper was not funded. AdipoRon, an agonist of the (AdipoR1), is already under investigation for administration to humans after successful animal studies. However, unclear Declaration of interest areas must be investigated till adipokine agonists or antago- The authors have no relevant affiliations or financial involvement with any nists can be proven beneficial for the treatment of metabolic organization or entity with a financial interest in or financial conflict with the problems and dysfunctions of HPA axis and/or adipose tissue. subject matter or materials discussed in the manuscript. This includes employ- ment,consultancies,honoraria,stockownershiporoptions,experttestimony, In conclusion, there is a need for better understanding of the grants or patents received or pending, or royalties. physiology of adipokines to elucidate all their connections with the HPA and the other endocrine axes either in normal physio- logical states or in pathologic (eventually stress-related) states. Reviewer disclosures Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. 6. 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