EJE
Adrenal-adipose tissue crosstalk in health and disease
Mingyan Jiang,1 Ulrich Stifel,2 Matthias Blüher,3,4,5 Herve Lefebvre, 60D Stefan R. Bornstein,1 and Nicole Bechmann7* iD
1Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
2Department of Pediatrics and Adolescent Medicine, University Medical Center, 89081 Ulm, Germany
3German Center for Diabetes Research, 85764 Neuherberg, Germany
4Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich, University of Leipzig and University Hospital Leipzig, 04108 Leipzig, Germany
5Department of Endocrinology, Nephrology, Rheumatology, University Hospital Leipzig, 04103 Leipzig, Germany
6Department of Endocrinology, Diabetes and Metabolic Diseases, University Rouen Normandie, Inserm, NorDiC UMR 1239, CHU Rouen, 76000 Rouen, France
7Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
*Corresponding author: University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden 01307, Germany. Email: nicole.bechmann@uniklinikum-dresden.de
Abstract
Adipose tissue (AT) closely interacts with the adrenal glands to regulate metabolism, energy balance, and stress responses. While the adrenal cortex secretes glucocorticoids and mineralocorticoids that influence AT distribution, lipid storage, and browning, the adrenal medulla releases catecholamines that acutely activate thermogenesis in brown and beige adipocytes. Under physiological conditions, this bidirectional crosstalk maintains energy homeostasis and cardiovascular stability. However, in adrenal diseases such as Cushing syndrome, primary aldosteronism, adrenocortical carcinoma, or pheochromocytoma, excess hormone secretion disrupts this balance, leading to AT dysfunction, altered adipokine secretion, and adverse metabolic profiles, including insulin resistance, visceral adiposity, and hypertension. Emerging evidence suggests that peri-adrenal AT may modulate adrenal tumor biology through endocrine and paracrine signals, and immune cell infiltration, with potential effects on disease progression and clinical presentation. Uncovering cellular and molecular mechanisms underlying the crosstalk between adrenal gland and AT may reveal new therapeutic targets for the reduction of cardiometabolic complications in patients with adrenal disorders. Here, we discuss how 2 endocrine organs-adrenal gland and AT-interact with each other under physiological and pathophysiological conditions and examine whether these interactions influence the progression of adrenal tumors and how this affects systemic metabolic health.
Keywords: steroids, catecholamines, fat browning, Cushing syndrome, paraganglioma, primary aldosteronism, adipokines
Significance
The adrenal gland and adipose tissue interact in a bidirectional crosstalk that is essential for maintaining metabolic and car- diovascular homeostasis. Adrenal hormones play a role in the regulation of adipose tissue distribution, lipid storage, and adipocyte thermogenesis. Conversely, adipose-derived mediators can influence adrenal function and stress responses. Excess hormone secretion disrupts the balance in adrenal disorders such as Cushing syndrome, primary aldosteronism, adre- nocortical carcinoma, and pheochromocytoma, promoting adipose dysfunction, insulin resistance, visceral adiposity, and hypertension. Furthermore, emerging evidence suggests that peri-adrenal fat may influence adrenal tumor behavior. A better understanding of the cellular and molecular mechanisms controlling adrenal-adipose interaction could reveal new thera- peutic targets to mitigate cardiometabolic complications and improve outcomes in patients with adrenal diseases.
Adrenal medulla
Stress
Sympathetic nervous system
Hypothalamus
Brain
HEALTH
Norepinephrine (NE)
CRH
Anterior pituitary
Activation
HPA axis
.
ACTH
Browning/beiging
Feedback
F
Adrenal cortex
ỌH
O
HO
White adipose tissue (WAT)
I NAFROH
Brown/beige adipose tissue (BAT)
H
1
H
H
0
Aldosterone
DISEASE
Glucocorticoids (cortisol)
Hormone-producing adrenal tumors
Tumor-dependent adrenal hormone access
Metabolic consequences
Introduction
The adipose tissue (AT) has been recognized as an active endo- crine organ that plays a key role in maintaining homeostasis and is involved in the pathogenesis of different diseases.1-3 Extensive research has revealed that distinct adipose depots regulate not only energy storage and consumption, but also the secretion of adipokines and signaling molecules that affect local and distant organs. Patients with adrenal tumors show an increased prevalence of metabolic and cardiovascular compli- cations.4 The adrenal gland comprises the steroid-producing cortex and the catecholamine-producing medulla, both en- closed within a common capsule and surrounded by peri- adrenal AT (peri-AT; Figure 1A). However, potential crosstalk between these endocrine tissues remains poorly understood.
The adrenal gland maintains body homeostasis by producing neuronal, metabolic, and endocrine signals that regulate metabol- ism, stress response, electrolyte balance, and cardiovascular func- tion. The adrenal cortex comprises 3 zones: the zona glomerulosa (zG) produces mineralocorticoids controlling electrolyte balance and blood pressure, the zona fasciculata (zF) synthesizes glucocor- ticoids (GC) regulating metabolism and immunity, and the zona reticularis (zR) generates androgens, precursors of sex hormones. The cortex also mediates stress responses via the hypothalamic-pi- tuitary-adrenal (HPA) axis, where internal and external stimuli trigger corticotropin-releasing hormone (CRH) secretion from the hypothalamus. Corticotropin-releasing hormone stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland, resulting in the release of GC by the zF.5 Furthermore, during acute stress (fight-or-flight response),
chromaffin cells of the adrenal medulla secrete catecholamines (epinephrine and norepinephrine (NE)).6 Since cortex and me- dulla share a common capsule, changes in one compartment affect the other. Interactions between cortical and chromaffin cells are es- sential for maintaining adrenal function under physiological and pathophysiological conditions.7
Pathophysiological alterations of the adrenal are usually associated with an over- or underproduction of adrenal hormones, leading to local and systemic metabolic changes. Pheochromocytomas are catecholamine-producing tumors with heterogeneous presentations, ranging from dopamine- only to epinephrine- or NE-producing phenotypes or even non-functional tumors.8 Chronic catecholamine excess associ- ated with these tumors drives a pro-inflammatory and hyper- metabolic state, causing weight loss despite normal food intake.9-11 In contrast, adrenal Cushing syndrome (CS), caused by autonomic cortisol hypersecretion due to an adrenal tumor, results in profound metabolic changes, including insu- lin resistance, dyslipidemia, and increased visceral adiposity, which contributes to significant weight gain and redistribu- tion.12,13 The overproduction of aldosterone in patients with primary aldosteronism (PA) has also direct consequences on body fat distribution.14 For instance, patients with bilateral PA tend to be more obese and have larger visceral fat areas than patients with lateralized PA.14
Adrenal tumors frequently cause metabolic and cardiovas- cular comorbidities through hormone-induced disruption of systemic homeostasis, profoundly affecting AT. Here, we provide novel insights into the bidirectional crosstalk between adrenal, AT, and adrenal tumors, to reveal how these
interactions shape tumor biology, local remodeling, and dis- ease manifestations.
Fat depots and fat beigeing/browning
Visceral adipose tissue (VAT) is an independent risk marker for cardiovascular and metabolic morbidity and mortality,15,16 whereas accumulation of abdominal subcutaneous adipose tis- sue (SAT) is a much weaker indicator of cardiovascular risk.16 Emerging evidence also suggests that an accumulation of peri- organ AT is associated with an increased risk for cardiovascular and metabolic disease.17,18 Adipose tissue accumulation may directly induce organ dysfunction through local mechanisms. For example, peri-vascular AT is involved in the pathogenesis of hypertension.19 Epicardial AT is associated with atheroscler- osis and coronary heart disease,2º while peri-renal adipose tis- sue (PRAT) is involved in chronic kidney disease (CKD).21 This emphasizes the direct influence of AT on adjacent organs.
Previously considered primarily as fat storage depots, adipo- cytes are now recognized as metabolically active endocrine, autocrine, and paracrine cells that synthesize, store, and secrete hormones and proteins (adipokines). There are 3 major types of adipocytes, which differ in morphology, cellular origin, and physiological function (Figure 1B). White adipocytes are derived from myogenic factor 5 (myf5)-negative progenitors,22 store en- ergy in the form of triglycerides and secret adipokines.23 In con- trast, brown adipocytes in mice originate from myf5-positive precursor cells and feature multilocular lipid droplets, a round central nucleus and cristae-enriched mitochondria that express
uncoupling protein 1 (UCP1).23 Uncoupling protein 1 is the hall- mark of brown adipocytes and promotes energy expenditure. Brown adipocytes are regulated by the sympathetic nervous sys- tem and are able to maintain body temperature through thermo- genesis. Main depots of human brown adipose tissue (BAT) are located in the supraclavicular and cervical regions, with some additional mediastinal, peri-vertebral, peri-cardial, and peri- renal locations.24 Beige (or brite or browning of white or inducible) adipocytes resemble brown adipocytes in terms of thermogenic properties25,26 and are also UCP1-positive, but are unilocular and derived from myf5-negative precursors25 under specific environmental or hormonal stimuli (eg, cold exposure,27 3-adrenergic agonists,28 and irisin29). Brown adipose tissue is found in various depots in humans and can exhibit features of both brown and beige adipocytes. Peri-renal adipose tissue and peri-AT are BAT hot-spots with many brown adipocytes near the adrenals.30
Peri-renal adipose tissue is a metabolically active hybrid VAT, which is located in the retroperitoneal space surround- ing the kidneys and adrenal glands. Peri-renal adipose tissue exhibited age-dependent molecular and morphological progressive regression, continuously transforming BAT into predominantly white adipose tissue (WAT).31 In human adult PRAT, dormant unilocular UCP1-expressing adipocytes are widely distributed, whereas active multilocular UCP1- expressing adipocytes are predominantly located around the adrenal, in areas with high numbers of sympathetic nerve end- ings,30 which suggests that PRAT and peri-AT are both related and distinct from each other. Peri-renal adipose tissue is more
A
Adrenal
Capsule
Zona glomerulosa- Mineralocorticoids (aldosterone)
Zona fasciculata- Glucocorticoids (cortisol, corticosterone)
Cortex
Zona reticularis - Adrenal androgen (DHEA, DHEA-sulfate)
Peri-adrenal adipose tissue
Medulla
Catecholamines (epinephrine, norepinephrine, dopamine)
Kidney
| B | Function | Secreted factors | UCP1 | Mitochondria abundance | Location (human) | Origin |
|---|---|---|---|---|---|---|
| White adipocytes | Energy storage Lipolysis Glucose uptake Adipokine secretion | Leptin Adiponectin Resistin | Negative | Low | Subcutaneous, visceral | Myf5 mesenchymal stem cells |
| Beige adipocytes | Thermogenesis Catabolism | FGF21 IL-6 SLIT-2 | Some negative | High | Supraclavicular, but predominantly in subcutaneous WAT | Myf5 mesenchymal stem cells |
| Brown adipocytes | Thermogenesis Lipid clearance Catabolism Batokine secretion | FGF21 IL-6 (Batokines) | Positive | High | Anterior cervical, supraclavicular, axillary, paravertebral | Myf5+ mesenchymal stem cells |
Figure 1 Adrenal and adipocyte function and secretion. (A) Adrenal zonation and hormone production. (B) Function and characteristic features of white, beige and brown adipocytes. Created by BioRender.com.
active than other typical VATs in metabolizing, synthesizing, and secreting adipokines and inflammatory cytokines.32 A var- iety of adipokines and cytokines secreted by peri-AT regulate adrenal function and metabolism by local mechanisms. Conversely, adrenal hormones affect peri-AT through para- crine and endocrine pathways, which may contribute to tumor- related pathophysiology. 28,36-40
Adrenal hormones and activation/browning of AT
Brown adipose tissue activity is tightly regulated by adrenal hormones and the sympathetic nervous system (Figure 2). Stress activates the HPA axis, causing cortisol secretion, which suppresses BAT activation and promotes VAT accumula- tion,41 while NE released by sympathetic nerves and the ad- renal medulla stimulates BAT thermogenesis and white fat beiging via ß3-adrenergic receptor activation.42 Other factors such as cold exposure, ACTH, and fatty acids also enhance browning, whereas insulin inhibits this process. Given the key role of adrenal hormones in AT regulation, their dysregu- lation profoundly disrupts metabolism and has major clinical
consequences. Accordingly, adrenal tumors show hormone- dependent differences in BAT prevalence. While 62.5% of pa- tients with pheochromocytoma (PCC) have brown adipocytes in their retroperitoneal fat mass, this is only the case in ~33.3% of patients with cortisol-producing adenomas and 46.9% of patients with aldosterone-producing adenomas (APAs).43 The following sections discuss molecular and meta- bolic mechanisms behind these differences and effects of tumor-related adipose remodeling.
AT-adrenal cortex interactions
Glucocorticoids, mainly cortisol, regulate numerous biologic- al functions in adipocytes, including adipogenesis. GC stimu- lates differentiation of pre-adipocytes into mature white adipocytes, 44,45 but GC also inhibits development and activa- tion of peri-renal BAT in rodents. 46,47 In humans, GC acutely increases BAT activity but chronically suppresses it, suggest- ing a time-specific effect of GC on UCP1 and BAT activity.41,48 This effect is highly species-specific, as GC reduce BAT activity in mice. 48 Moreover, GC inhibit the response of cultured hu- man brown adipocytes to adrenergic stimulation.49 As an
Adrenal medulla
Stress
Sympathetic nervous system
Hypothalamus
Brain
Norepinephrine (NE)
Insulin
CRH
Activation
Anterior pituitary
HPA axis
Cold exposure Adenosine ATP Secretin
ACTH®
Feedback
Adrenal cortex
OH
Browning/beiging
0
HO
White adipose tissue (WAT)
1 MANKOH
Brown/beige adipose tissue (BAT)
H
I
H
H
0
Aldosterone
Glucocorticoids (cortisol)
Tissue specific secretion
Extracellular
NE
ADCY
Leptin Adiponectin Resistin
FGF21 IL-6
Intracellular
ß3AR
ATP
CAMP
Impact on adjacent organs including the adrenal
UCP1 DOWN
PKA
Fatty acids
>Heat
antagonist, ACTH, which is responsible for the release of cor- tisol in the adrenal, promotes browning of adipocytes.50,51
Intracellular GC activity and metabolism is regulated by 2 isoforms of 11ß-hydroxysteroid dehydrogenase (HSD). While type 1 (11ß-HSD1) is localized in several tissues, includ- ing AT, and converts inactive cortisone to cortisol that binds to the intracellular glucocorticoid receptor (GR), type 2 (11ß-HSD2) causes the reverse conversion of cortisol to cortisone, thereby preventing cortisol from occupying the mineralocorticoid receptor (MR) in aldosterone target tis- sues.52,53 Under physiological conditions, cortisol is 100-1000 times higher concentrated than aldosterone, and this effect is exacerbated in patients with hypercortiso- lism.54,55 Moreover, due to the saturation of 110-HSD2 en- zymatic activity under conditions of cortisol excess, cortisol is even able to bind to MR in aldosterone target tissues.56 Inflammatory signals, including tumor necrosis factor (TNF) and interleukin (IL)-16, modulate expression of HSD en- zymes, thereby altering cellular sensitivity to GC.57 The GR, encoded by NR3C1 (nuclear receptor subfamily 3, group C, member 1), has a much higher affinity for cortisol than aldos- terone and is most likely responsible for the inhibitory effects of GC on BAT development and activity.43,58 However, MR, encoded by NR3C2 (nuclear receptor subfamily 3, group C, member 2), has a similar affinity for aldosterone and cortisol, and coregulators recruited upon GR and MR binding largely overlap.59,60 Glucocorticoids play a crucial role in AT metab- olism and cause multiple transcriptomic changes and epigenet- ic modifications.61-63 Glucocorticoid receptor activation exerts highly tissue-specific effects on the epigenome, which can be controlled by a cell-type-specific binding of GR to tar- get genomic sites64,65 and can even persist after stimulus is re- moved. However, studies on the epigenetic regulation of GC or other adrenal hormones in AT are lacking.
Glucocorticoids induce an increased leptin secretion from adipocytes, suggesting a mechanism that may contribute to anorexia and weight loss during stress when these conditions are accompanied by a sustained increase in plasma leptin con- centrations.66 Furthermore, leptin inhibits GC secretion in hu- man adrenocortical cells by the suppression of steroidogenic enzymes,67 which demonstrates the complex regulation of this system, particularly under stress.
The renin-angiotensin-aldosterone system (RAAS) is a cen- tral regulator of blood pressure, fluid, and electrolyte balance, and also affects adipocyte function via MR signaling68 (Figure 3). Aldosterone prevents ACTH-induced expression of UCP1.47,51,69 Mineralocorticoid receptor is expressed in BAT cells and MR antagonists are able to induce browning of visceral and subcutaneous AT in mice.7º Mineralocorticoid receptor an- tagonists can improve BAT function in response to cooling in hu- mans.71 However, administration of classic steroidal MR antagonists to mice fed a moderately high-fat diet reduces the spread of WAT, induces the activation of interscapular BAT, and stimulates the browning of WAT.70 The activation of MR also causes adipocyte hypertrophy, which leads to oxidative stress, local hypoxia, and a pro-inflammatory state.72 In line, MR blockade reduces the expression of pro-inflammatory and prothrombotic factors and enhances adiponectin expression in AT of obese, diabetic mice, revealing a potential mechanism for the cardioprotective effects observed under MR blockade. 73 In vitro, aldosterone appears to be able to induce adipocyte dif- ferentiation and intracellular lipid accumulation, suggesting that both MR and GR are vital for adipocyte differentiation.
Renin
Ang I
Ang II
Blood pressure
Aldosterone
CYP11B12
Adrenal
Arterial stiffness Atherosclerosis Renal fibrosis Stroke Cardiovascular disease
Kidney
Leptin CTRP1 Adiponectin Fatty acids
…
UCP1
Adipose tissue expansion
Aldosterone
Inflammation
Mineralocorticoid receptor
ROS production
Moreover, adipocytes play a regulatory role in steroidogene- sis. Adipocyte-conditioned medium stimulates aldosterone pro- duction in adrenocortical cells (NCI-H295R).76,77 Adipokines, including C1q/TNF-related protein (CTRP1), adiponectin and leptin, can stimulate the production of aldosterone in the ad- renal, which links obesity directly with hypertension.78 Leptin directly regulates aldosterone synthase expression in the adrenal and thus aldosterone secretion, contributing to high aldosterone levels observed in obese mice.81
Visceral and subcutaneous AT can also produce angiotensi- nogen and possesses a local renin-angiotensin system.82 Activation of this local RAAS system in the peri-AT of patients with CS causes high blood pressure levels even 6 months after the remission of hypercortisolism.33 Adipocyte-derived aldos- terone regulates adipocyte differentiation and vascular func- tion providing a potential link between vascular dysfunction in diabetes mellitus-associated obesity.83
AT-adrenocortical tumor interactions
Adrenocortical tumors are neoplasms that arise from the ad- renal cortex and range from benign adrenal adenomas to high- ly aggressive adrenal carcinomas. They may be hormonally active and cause clinically significant endocrine syndromes (Table 1), or they may be non-functional and discovered inci- dentally during imaging examinations.
Cushing syndrome
Adrenal Cushing is caused by autonomous overproduction of cortisol in the adrenal due to benign or malignant adrenal tu- mors, or due to bilateral primary micro- and macronodular adrenal hyperplasia and accounts for ~20% of all CS cases.95 Patients with CS typically present with metabolic manifesta- tions such as hyperglycemia, hypertension, and excessive fat deposits in face, neck, and visceral organs.85,96 The severity
| Adrenal disorder | Hormone production | Metabolic changes associated with the disease | Main effects on peri-AT or peri-renal AT | Further key publications |
|---|---|---|---|---|
| Adrenal medulla Pheochromocytoma | Excess catecholamines (epinephrine, norepinephrine) | Hyperglycemia, insulin resistance, weight loss, increased lipolysis10 | Promotes brown adipose tissue activation and browning phenotype in peri-AT9,40 | Ref.9,40,84 |
| Adrenal cortex Cushing syndrome | Excess cortisol | Central obesity, insulin resistance, type 2 diabetes, dyslipidemia85 | Adipocyte hypertrophy, macrophage infiltration, inflammation86 | Ref.87,88 |
| Primary aldosteronism | Excess aldosterone | Subtype specific features14; hypertension, hypokalemia, insulin resistance, impaired glucose tolerance, increased cardiovascular risk 89 | Increased fibrosis, inflammation, altered adipokine secretion38,90 | Ref.38,91 |
| Adrenocortical carcinoma | Variable; often cortisol and/or androgen excess | Features of Cushing syndrome and/or virilization, metabolic syndrome features if hypercortisolism92 | Increased peri-adrenal adipose tissue mass, potential tumor-induced fibrosis and altered adipokine profiles in dependence of the hormone secreted | Ref.93,94 |
| Non-functional adenomas | None significant | Often incidental; might be associated with mild metabolic alterations if subclinical present | Minimal direct effects unless subclinical hypercortisolism induces changes | Ref.93 |
Abbreviations: AT, adipose tissue; peri-AT, peri-adrenal adipose tissue.
of hypercortisolism correlates with higher visceral adiposity.87 In patients with active CS, hypercortisolism induced PRAT adipocyte hypertrophy, which is associated with increased macrophage infiltration and elevated leptin levels, as well as reduced adiponectin levels.86 Another study identified higher leptin levels in peri-AT than in PRAT and subcutaneous AT in patients with CS.34
Primary bilateral macronodular adrenal hyperplasia (BMAD) is a rare cause of CS, often misdiagnosed as bilateral adrenal in- cidentalomas with subclinical cortisol production. Interestingly, BMAD frequently occur alongside myelolipoma, especially those associated with food-dependent (glucose-dependent insu- linotropic polypeptide-dependent) hypercortisolism, due to KDM1A mutations.97-99 However, the mechanisms by which these 2 lesions develop in parallel and influence each other re- main unknown. Paradoxically, leptin stimulates cortisol secre- tion in nutrition-dependent BMAD.100 Moreover, BMAD tissue expresses abnormal levels of ACTH.101 It is therefore con- ceivable that adrenal cortex cells influence intra-adrenal adipo- cytes via a paracrine mechanism involving locally produced ACTH.102,103Reciprocally, AT may activate cortisol production through leptin release.
It is well known that acute or prolonged glucocorticoid admin- istration decreases C-reactive protein (CRP), IL-6, and TNF-alpha (TNF-a). However, long-term hypercortisolism is characterized by chronic, low-grade inflammation. 88,104,105 Even after achieving a long-term cure, patients who have experi- enced CS exhibit a persistent accumulation of central fat, similar to that seen in active hypercortisolism, associated with an unfavorable adipokine profile and a state of low-grade inflamma- tion.88 Moreover, amelioration of visceral fat mass cannot be achieved in all patients, suggesting the presence of a potentially persistent epigenetic mechanism.88,106 Compared to body mass index (BMI)-matched controls, patients with CS ex- hibit an increased number of infiltrating macrophages in subcuta- neous AT and PRAT.86,107 Macrophages stimulate expression of pro-fibrotic factors and interfere with the differentiation of pre- adipocytes, thus promoting AT fibrosis. Excess exposure to GC also has a pro-fibrotic effect on AT, which requires the presence
of macrophages.108 Consistently, chronic exposure to endogen- ous GC results in increased oxidative stress, inflammation, and fibrosis in PRAT.12
The adipokine leptin may promote proliferation and inva- sion of cancer cells by the activation of pathways such as phos- phoinositide 3-kinases, mitogen-activated protein kinase (MAPK), and signal transducer and activator of transcription 3 (STAT3), while adiponectin may inhibit tumor growth and spread by inhibition of pathways such as nuclear factor kap- pa-light-chain-enhancer of activated B (NF-KB), STAT3, and mammalian target of rapamycin (mTOR).109,110 However, studies examining effects of adipokines on adrenal tumors are mostly lacking. Hypercortisolism lead to changes in the levels of circulating adipokines, with higher fatty acid-binding protein 4 (FABP4), retinol-binding protein 4 (RBP4), and resistin levels compared to healthy controls.111,112 Additionally, leptin expression was significantly higher in peri-AT than in PRAT or subcutaneous AT in patients with CS, while adiponectin expression was significantly lower.34 Plasma leptin levels are also elevated in patients with CS and decrease following tumor resection.113 Although fasting in- hibits leptin secretion in healthy subjects, inhibitory effects of short-term fasting are less pronounced in patients with CS.114 Leptin is known to decrease the corticotropin- stimulated release of steroids in vitro,115 potentially providing a hint for an important feedback loop and illustrating the dir- ect interaction between tumor, AT, and adrenal.
Primary aldosteronism
Primary aldosteronism is characterized by the autonomic secretion of aldosterone caused by unilateral or bilateral adrenal lesions, associated with fundamental metabolic consequen- ces.116,117 Compared to patients with essential hypertension, pa- tients with PA exhibit a higher prevalence of insulin resistance, impaired glucose tolerance, and type 2 diabetes.89 Excess aldos- terone promotes AT dysfunction, inflammation, and fibrosis. Furthermore, visceral obesity and altered adipokine secretion have been associated with increased cardiometabolic risk
observed in this population.119,120 For example, APAs are asso- ciated with obesity in males, but not in females,121 which may be related to the increased prevalence of KCNJ5 mutations in fe- males compared to males.122,123 Furthermore, patients with bi- lateral PA present with a higher BMI and greater visceral adiposity than patients with unilateral disease,14 reflecting the heterogeneity of metabolic characteristics across different PA subtypes, which are not yet fully understood. Treatment with MR agonists (eplerenone or spironolactone) lead to a significant reduction in VAT in these patients.124 Adipocytes adjacent to APAs exhibit a browning phenotype, as evidenced by smaller adi- pocyte size and higher UCP1 expression.91 The authors of this study proposed the following mechanism: APA cells release retin- oic acid, which promotes tissue browning and leads to the release of lactate by beige adipocytes, thereby increasing aldosterone production.91 As outlined before, treatment with MR antago- nists rather induce browning,47,69,70 suggesting that aldosterone might not be the principal mediator of fat browning in patients with APA. In vitro studies revealed that only pharmacological concentrations of aldosterone reduced glucose uptake in adipo- cytes, suggesting: (1) insulin resistance in patients with PA may occur in compartments other than AT, and/or (2) it may depend on secondary factors, such as retinoic acid.125 RNA sequencing revealed a downregulation of inflammation-associated pathways in SAT and peri-AT of patients with APA compared to patients with non-functional adrenal adenomas, while steroid-related pathways were upregulated, particularly in peri-AT of patients with KCNJ5-mutant APAs, which suggest a paracrine actions of aldosterone.9º Moreover, cortisol co-secretion has been re- ported in up to 30% of patients with PA, 126,127 which might fur- thermore affect the adipose tissue phenotype in these patients.
Leptin expression in the PRAT was significantly higher in pa- tients with APAs compared to patients with non-functional ad- enomas.34 Leptin receptor (LEP-R) levels in APA tissues correlate positively with plasma aldosterone concentrations in these patients.128,129 However, expression of the adiponectin receptor 1/2 (AdipoR1/2) and LEP-R is significantly lower in benign adrenal neoplasms compared to adrenocortical carcinomas (ACCs).130 Aldosterone excess in patients with PA is furthermore associated with elevated resistin levels and car- diac alterations, independently of the presence of metabolic syn- drome.119 Moreover, PRAT of patients with APA exhibites significantly higher levels of IL-6, TNF-a and of genes related to fibrosis compared to normotensive individuals and patients with essential hypertension.38 Whether these effects are related to increased macrophage infiltration, as in CS, is largely un- known.38 In rats, it has been shown that administration of al- dosterone plus salt mediates an inflammatory M1 macrophage phenotype and increased renal fibrosis via activation of min- eralocorticoid receptors.131 This suggests that APAs induce PRAT dysfunction associated with a pro-inflammatory and fibrotic state that can worsen cardiovascular impairment.
Adrenocortical carcinoma
Adrenocortical carcinomas often produce excess steroid hor- mones, most commonly cortisol and androgens, leading to clin- ically overt endocrine syndromes such as CS or virilization. The clinical presentation of patients with ACCs greatly depends on whether the tumor is hormonally active or “non-functional.”92 Metabolic effects and effects on peri-AT of the cortisol or aldos- terone (rare) excess in these patients have already been discussed above. Additionally, in rare cases, ACCs can release estrogen,
which can lead to feminization. Under physiological conditions, estrogen promotes lipolysis and inhibits adipogenesis.132 Thus, estrogen enhances insulin sensitivity.133 Androgens also play a critical role in AT homeostasis, by improving insulin sensitivity and glucose tolerance and by regulating the expression of vari- ous adipokines and regulating lipolysis.134 However, the impact of ACC-driven androgen or estrogen excess on adipocytes and metabolism remains unknown.
A correlation has been found between an increase in intra- abdominal fat tissue and a reduced survival rate in patients with ACC.135 Moreover, mixed cortisol/androgen-secreting ACCs are associated with worse overall survival compared to non-secreting ACCs, while cortisol or androgen secretion alone is not associated with worse overall survival.136 Patients with ACC have higher IL-6, TNF-a and monocyte chemoattractant protein 1 (MCP1) serum levels compared to healthy controls, indicating similar to patients with CS a pro-inflammatory state.93 However, little is known about the interaction of adipocytes and ACCs.
Monotherapy with mitotane is the first-line treatment for less aggressive ACCs after surgery, while patients with more aggres- sive forms of the disease are treated with mitotane plus chemo- therapy.137 However, due to its lipophilic nature, mitotane concentration is 200-fold higher in AT than in plasma.138 Therefore, high dosages of mitotane are required to reach the therapeutic plasma concentration, which result in several ad- verse effects.139 For example, mitotane has profound impact on lipid levels marked by increased total, low-density lipopro- tein and high-density lipoprotein (HDL) cholesterol levels in more than half of the patients. 140,141 To the best of our knowl- edge, no studies have investigated the influence of BMI or body fat distribution on how ACC patients respond to mitotane treatment, though including these factors could improve out- comes and reduce side effects. Overall, ACC-adipose crosstalk remains poorly understood. Transcriptomic profiling of peri-AT alongside tumor hormone status and clinical parame- ters, as well as analysis of adipokine changes during rapid ACC progression, could provide valuable insights.
AT-adrenal medulla interactions
Catecholamines are well known to stimulate lipolysis by bind- ing to ß-adrenergic receptors expressed on adipocytes, 42,142 which leads to increased activity of adenylyl cyclase, resulting in evaluated levels of cyclic adenosine monophosphate (cAMP)143 (Figure 2). Cyclic adenosine monophosphate further activates protein kinase A (PKA) that leads to phosphorylation of downstream targets including hormone-sensitive lipase. Hormone-sensitive lipase is capable of breaking down triacylgly- cerol to diacylglycerol, but to a lesser extent than the adipose tri- glyceride lipase (ATGL). Protein kinase A phosphorylates perilipin, which is associated with the lipid droplet in the basal state and impedes ATGL access and activity.144 Insulin and GC furthermore affect this pathway by altering cAMP levels. 143,145 The activation of PKA further lead to an activation of rapamycin- sensitive mTOR complex 1 (mTORC1)146 and p38 MAP kinase, resulting in the induction of target genes involved in fat browning (UCP1 and Pparg coactivator 1 alpha (PGC1a)).42 Furthermore, co-culture experiments revealed that catecholamines block vesicle transport and secretion of leptin and resistin via B-adrenergic receptors, whereas leptin and resistin promote ves- icle transport and secretion of catecholamines via PKA, protein kinase C (PKC), MAPK kinase, and Ca2+-dependent signaling
pathways.39Leptin is secreted mainly by white adipocytes and stimulates the synthesis of catecholamines, 147,148 while catechol- amines reduce leptin production.149-151 Additionally, B-adrenergic stimulation of AT, rather than macrophages, seems to be responsible for enhanced plasma IL-6 concentrations ob- served in obesity.152 Interleukin-6 is known to modulate adrenal steroid production indicating a crosstalk between AT and ad- renal cortex. 153,154
Approaches to promote energy consumption through the in- duction of thermogenesis are of high clinical relevance, especially given the widespread prevalence of obesity. ß3-Adrenergic recep- tor is highly expressed in human BAT and WAT, as well as in oth- er tissues such as the gallbladder, gastrointestinal tract, and prostate.155 Therefore, various ß3-agonists have been investi- gated for the treatment of obesity due to their potential appetite- suppressing and thermogenic effects.156 None of the investigated agonists, however, advanced beyond clinical phase II due to a lack of efficacy and cardiovascular side effects, mainly caused by insufficient selectivity of available agonists.157 While short- term exposure to high doses of ß3-adrenergic agonist mirabegron leads to activation of BAT, catecholamine-secreting tumors (pheochromocytomas), as well as long-term exposure to mirabe- gron even promote fat browning.156 To further evaluate the therapeutic potential for obesity and metabolic syndrome, more selective and potent ß3-adrenergic receptor agonists with fewer off-target effects are needed.
AT-PCC interactions
Excessive catecholamine production by adrenal medullary PCC triggers a B3-adrenergic response that activates BAT and peri-AT browning.28,36 This promotes a hypermetabolic state as- sociated with increased glycogenolysis, lipolysis, and the release of proinflammatory cytokines.10 Patients with functional PCCs exhibit higher prevalence of BAT activation9,158 and weight gain after PCC resection has been observed.11 The presence of ac- tive BAT is associated with higher plasma NE levels and de- creased overall survival in patients with PCC.159,160 Moreover, patients with BAT activation seem to be younger.158 However, there is no significant correlation between changes in plasma cat- echolamines or metanephrines and changes in fat mass. 161,162 A meta-analysis identified elevated catecholamine levels, particu- larly NE/normetanephrine, to be associated with the presence of activated BAT on imaging in patients with PCC.163
Brown adipose tissue activation in PCC exhibits regional dis- tribution differences, with stronger activation closer to the tumor (peri-AT) than further away from the tumor (subcutaneous).40 This may be due to a hormonal gradient or to differences in the response of AT at different sites to adrenal signaling. Surprisingly, no difference in 18F-fluorodeoxyglucose uptake by the peri-renal AT between the side of the PCC and contralat- eral side has been observed.9 Moreover, pheochromocytomas and paragangliomas (PPGLs) are genetically heterogeneous tu- mors with a strong genotype-phenotype correlation, but no dif- ference in the prevalence of BAT activation was observed between sporadic cases or patients with succinate dehydroxyge- nase (SDHx) or von Hippel-Lindau (VHL)-related PPGLs.9 Discrepancies between studies on the prevalence of activated BAT in patients with PPGLs and a possible correlation with excess catecholamine/NE9,11,158-160,162,163 could be related to differences in the timing and implementation of an adrenergic receptors blockade. Since intraoperative mobilization of the tu- mor often leads to a sudden rise in blood pressure in these patients
due to the release of catecholamines, guidelines recommend preoperative treatment of symptomatic patients with a-adrenoreceptor antagonists.164,165 Depending on when adren- ergic receptor blockade is initiated, this might affect the results.
Adrenergic stimulation triggers a series of molecular events through activation of ß-adrenergic receptor signaling in AT, including altered gene expression and splicing regulation, ul- timately leading to browning of AT, increased thermogenesis and enhanced metabolism.84 In AT of patients with PCC, ele- vated expression of genes associated with mitochondrial heat production (eg, UCP1 and CKMT1A/B) and lipid and carbo- hydrate catabolismis observed, while pro-inflammatory path- ways are decreased.84 Peri-renal brown adipocytes in patients with PCC recapitulate activated classical brown adipocytes with the reduced expression of markers selective for beige adi- pocytes (CD137 and TBX1).166 In retroperitoneal VAT of pa- tients with PPGL UCP1 expression correlate negatively with the BMI and positively with HDLc levels. 167
Fibroblast growth factor-21 (FGF21) plays a systemic role by promoting glucose uptake, insulin secretion, and brown adipogenesis.168,169 NE activates the transcription of the FGF21 through a cAMP-dependent PKA- and p38 MAPK-mediated mechanisms in BAT.170,171 FGF21 is released from BAT into circulation during thermogenic activation.170 Visceral adipose tissue of patients with PCC significantly ex- pressed FGF21 and UCP1 with a positive correlation, suggest- ing that FGF21 is involved in human BAT activation in these patients.169 Adrenomedullin (ADM), a peptide released, for ex- ample, by chromaffin cells of the adrenal medulla or PCCs, may also be involved in tumor-AT interactions since ADM causes browning of adipocytes in proximity to breast cancer cells.172 However, it is not known whether this effect plays a role in browning of peri-AT in patients with PCC, which even presents with elevated plasma ADM levels. 173
Adiponectin expression is significantly higher in BAT than in WAT around PCC, and urinary metanephrine levels correlate positively with UCP1 expression in BAT.174 AdipoR1 and AdipoR2 expression is significantly higher in PCC than in adre- nocortical tumors.130 Moreover, AdpR1 expression is higher in epinephrine-producing PCCs than in NE-producing PCCs.175 Leptin receptor is more frequently expressed in PCC than in ACCs,130 but leptin does not appear to be involved in the regu- lation of cell proliferation in adrenal tumors.176 Moreover, pa- tients with PCC have higher mitochondrial content in peri-AT and significantly higher peridroplet mitochondria content, as- sociated with increased energy expenditure.177 Peridroplet mitochondria is a functionally independent subpopulation of mitochondria in AT involved in browning and energy metabol- ism. Up to one-third of PCC patients develop diabetes due to im- paired glucose tolerance and insulin resistance.178,179 Compared to patients with non-functional adenomas, the peri-AT of patients with PCC exhibits reduced phosphorylated AMP-acti- vated protein kinase expression, increased expression of pyru- vate dehydrogenase kinase (PDK4), pIRS1, and oxidative stress markers.179 Due to PDK4’s involvement in glucose up- take, it may play a role in the catecholamine-induced insulin re- sistance in patients with PCC.
Conclusion and perspectives
Adrenal-AT interactions play a pivotal role in regulating sys- temic energy homeostasis, stress responses, and metabolic health. Adrenal tumors are associated with impaired adrenal
hormone secretion, which leads to dysfunction of AT, promot- ing visceral obesity, insulin resistance, and cardiovascular complications. Moreover, chronic stress also impairs this tightly regulated system, contributing to the widespread prevalence of obesity, insulin resistance, and cardiovascular disease in our society. Targeting this bidirectional system therapeutically may not only be a promising approach to im- prove care for patients with adrenal tumors, but it may also help to cure obesity and type 2 diabetes.
Emerging evidence indicates that peri-AT can influence adrenal tumor biology via endocrine, paracrine, and immune signaling, affecting tumor progression and therapy response. However, the precise mechanisms remain unclear. Multiomics studies of matched tumor and AT correlated with clinical parameters are needed to identify novel targets, miti- gate metabolic and cardiovascular risk, and enable personal- ized management. Whether modulating adipose inflammation or browning can improve adrenal disease outcomes remains unknown, highlighting the need for further translational re- search into this complex crosstalk.
Authors’ contributions
Mingyan Jiang (Conceptualization [lead], Writing-original draft [lead], Writing-review & editing [equal]), Ulrich Stifel (Conceptualization [equal], Writing-review & editing [equal]), Nicole Bechmann (Conceptualization [lead], Funding acquisition [lead], Project administration [lead], Supervision [lead], Visualization [lead], Writing-original draft [equal], Writing-review & editing [lead]), Stefan R. Bornstein (Funding acquisition [equal], Supervision [equal], Writing-review & editing [equal]), Hervé Lefebvre (Conceptualization [equal], Writing-review & editing [equal]), and Matthias Blüher (Conceptualization [equal], Writing-review & editing [equal])
Conflict of interest: M.B. received honoraria as a consultant and speaker from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Lilly, Novo Nordisk, Novartis, and Sanofi. All other authors declare no conflicts of interest.
Funding
This research was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) within the CRC/Transregio 205, Project No. 314061271-TRR205 “The Adrenal: Central Relay in Health and Disease.”
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