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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 2 965-970
Copyright © 2004 by The Endocrine Society

Corticotropin-Releasing Hormone System in Human Adipose Tissue

Janette Seres, Stefan R. Bornstein, Peter Seres, Holger S. Willenberg, Klaus M. Schulte, Werner A. Scherbaum and Monika Ehrhart-Bornstein

German Diabetes Center (J.S., P.S., W.A.S., M.E.-B.), Department of Endocrinology, Medical Center (S.R.B., H.S.W.), and Department of Surgery (K.M.S.), Heinrich Heine University of Duesseldorf, Duesseldorf 65 40225, Germany

Address all correspondence and requests for reprints to: Monika Ehrhart-Bornstein, Ph.D., German Diabetes Center, Auf’m Hennekamp 65, 40225 Düsseldorf, Germany. E-mail: ehrhart-bornstein{at}ddfi uni-duesseldorf.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Mounting evidence exists for a role of the CRH system in energy balance, including a direct influence on human adipocytes, the regulation of adipose 11ß-hydroxysteroid dehydrogenase type 1 activity, and cortisol formation. We characterized the expression of CRH receptors 1 and 2 and CRH-like peptides stresscopin and urocortin in human adipose tissue in comparison with other peripheral tissues, adrenal, and heart. The effect of CRH on CRH receptor and CRH-like peptide expression was analyzed in isolated human adipocytes using quantitative TaqMan PCR. CRH receptors were detectable in fat tissue at mRNA and protein levels. CRH-R2 expression in fat was comparable with its expression in the heart, the organ with the highest CRH-R2 expression known. CRH-R1:CRH-R2 ratio varied according to fat-depot type; whereas CRH-R1 expression was higher in sc fat than in visceral fat, the opposite was true for CRH-R2. Adipose tissue also expressed urocortin and stresscopin, the predominant ligands of peripheral CRH-R2. CRH down-regulated CRH-R1 and CRH-R2 mRNA expression in isolated adipocytes. These data, together with the recently published observation that CRH regulates adipocyte metabolism by down-regulating 11ß-hydroxysteroid dehydrogenase, indicate that a CRH system exists within human adipose tissue. This system could be implicated in energy homeostasis and in mediating the anorexic effects of CRH at adipose level.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CORTICOTROPIN-RELEASING HORMONE is the principal hypothalamic factor in hypothalamic-pituitary adrenal axis regulation (1, 2). However, there is increasing evidence for an additional important role in energy balance regulation: CRH centrally inhibits appetite and activates thermogenesis via the catecholaminergic system (for review, see Ref.3). Peripherally, CRH inhibits gastric emptying and stimulates colonic motor function in various animal models (4, 5). CRH acts through two G-coupled receptors, CRH receptors (CRH-Rs) types 1 and 2, CRH-R1 and CRH-R2 (6). Although pituitary-adrenal axis activity via the release of ACTH is predominantly mediated by pituitary CRH-R1 (7), CRH-R2 is the major receptor in the peripheral organs of both rodents (6) and humans (8). Studies on CRH-R2-deficient mice (CRH-R2 -/-) have demonstrated that this receptor mediates responses involved in coping with stress such as feeding suppression, hypotension, and anxiolysis and is involved in energy balance and weight regulation (9, 10, 11). The major ligands for CRH-R2 are two CRH-related neuropeptides, urocortin II and urocortin III (stresscopin) (12, 13). Central (14) and ip (12) administration of either peptide induced significant anorexic effects in mice. In addition, there are peripheral CRH systems involved in autocrine/paracrine regulatory mechanisms, i.e. in the human adrenal (15, 16) and skin (17).

Hypothalamic-pituitary adrenal axis and consequently plasma glucocorticoid levels are closely linked to body adipose mass. Glucocorticoids regulate adipose tissue differentiation, function, and distribution; in excess, they promote visceral obesity; insulin resistance; central obesity; and ultimately insulin resistance, dyslipidemia, and hypertension (metabolic syndrome X) (18, 19). In patients with central obesity, increased intraadipose prereceptor glucocorticoid concentrations due to increased 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity seem to be responsible for the patients’ obesity (20). 11ß-HSD1 converts inactive cortisone to the active compound cortisol, and the classical clinical stigmata of metabolic syndrome X have been found in transgenic animals overexpressing 11ß-HSD1 in adipose tissue (21).

It has recently been demonstrated that 11ß-HSD1 activity is down-regulated by CRH in human sc adipocytes (22), suggesting a direct functional role of CRH in human adipose tissue metabolism and intracellular prereceptor cortisol concentration regulation. However, no data are available on the expression of CRH system components in adipose tissue.

We therefore analyzed the expression and localization of CRH-R1 and CRH-R2 as well as CRH-like peptides urocortin and stresscopin in adipose tissue from two different human fat depots (visceral and sc). In addition, the effect of CRH on CRH-R1 and CRH-R2 expression was characterized in human adipocytes in primary culture.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Human tissues

Visceral and sc specimens of white adipose tissue were obtained from normal-weight human subjects (body mass index < 27 kg/m2) undergoing abdominal surgery (n = 7) or surgical mammary reduction for cosmetic reasons (n = 4). For cell culture experiments, human adipose tissue was obtained from healthy women aged 25–30 yr undergoing surgical mammary reduction. All women were otherwise healthy and had no metabolic or endocrine diseases. The donors’ body mass index ranged between 21.4 and 29.2 kg/m2 (25.4 ± 2.8 kg/m2, mean ± SD).

Tissue samples were immediately transported to the laboratory in DMEM/nutrient mix F12 (Life Technologies, Karlsruhe, Germany) containing 2% BSA, 100 U/ml penicillin, and 100 µg/ml streptomycin at room temperature.

Informed consent was obtained from all donors before the surgical procedure. The study was approved by the Ethics Committee at the University of Düsseldorf.

Immunohistochemistry

Formalin-fixed normal white adipose tissue was sectioned and deparaffinized, and antigens were retrieved using Triton X-100 (1% in Tris-buffered saline, pH 7.6) before blocking endogenous peroxidase with 0.3% H2O2 for 15 min. Sections were preincubated with 2% normal swine serum and exposed to polyclonal goat antihuman CRH receptor antibody (dilution 1:50; CRF-RI; C-20, Santa Cruz Biotechnology, Santa Cruz, CA) for 30 min. Human CRF-RI antibody was diluted and eventually replaced by goat IgG (Dianova-Immunotech, Hamburg, Germany) to provide a negative control. No nonspecific staining was observed. After incubation with a biotinylated link antibody (15 min) and horseradish peroxidase-labeled streptavidin (15 min), visualization was achieved using 3-amino-9-ethyl-carbazole (Dianova-Immunotech) for 10 min. Slides were counterstained with hematoxylin for 10 sec, rinsed in water for 10 min, and mounted with glycerin gelatin. Pituitary tissue was used as a positive control.

Cell culture

Isolation and primary culture of fully differentiated, unilocular adipocytes was adapted from Fried and Moustaid-Moussa (23).This method proved to yield in the isolation of functionally active adipocytes, which released adipokinins such as leptin, adiponectin, IL-6, triglycerides, and free fatty acids (24).

After surgical removal, adipose tissue samples with a wet weight of 20–60 g were dissected free from fibrous material and visible blood vessels, minced to small pieces, and digested in Krebs-Ringer bicarbonate buffer containing 2% BSA and 120 U/ml collagenase type I from clostridium histolyticum (Sigma, Munich, Germany) in a shaking water bath for 45–60 min at 37 C. Digested tissue was filtered twice through nylon gauze (250 µm) and washed in Krebs-Ringer bicarbonate buffer containing 0.1% BSA. Differentiated adipocytes are well defined by their lipid content and due to the fact that they float they are easily separated from other cells. Two milliliters of isolated floating unilocular adipocytes were cultured in culture flasks (Becton Dickinson, Heidelberg, Germany) containing 5 ml of cell culture medium (DMEM/F12 containing 15 mmol/liter HEPES and 2.5 mmol/liter L-glutamine, supplemented with 1.125 g/liter NaHCO3, 10% fetal calf serum, 100 U/ml penicillin, and 100 µg/ml streptomycin). The medium was changed every 24 h. Cells were cultured for 48 h at 37 C in a humidified atmosphere of 5% CO2 before the experiment.

Incubation with CRH

Adipocytes were transferred into 24-well plates (Becton Dickinson) and incubated in cell culture medium for 24 h (0.4 ml adipocytes/0.5 ml medium) in the presence or absence of CRH (Ferring, Kiel, Germany) at concentrations of 10-10 M, 10-9 M, and 10-8 M. Four different fat cell preparations were used with four wells in each group.

RNA isolation and RT-PCR

Total RNA was isolated from human white adipose tissue and cultured adipocytes using a silica gel-based membrane method (RNeasy kit, Qiagen, Hilden, Germany) according to the manufacturer’s protocol. We performed an additional DNase digestion step with RNase free DNase (Qiagen). Total RNA from cultured adipocytes was directly reverse transcribed to cDNA. Total RNA from tissue samples was used for preparing mRNA using the Oligotex mRNA mini kit (Qiagen) according to the manufacturer’s protocol. mRNA samples from human adrenal, heart, and pituitary gland were purchased from Clontech (Palo Alto, CA).

One microgram of total RNA or 500 ng of mRNA were reversed transcribed to single-stranded cDNA to a final volume of 20 µl using a Thermoscript RT-PCR system kit (Invitrogen, Karlsruhe, Germany) as indicated by the manufacturer’s instructions. Two microliters of cDNA were used for the PCR. PCR was carried out in 25 µl (Roche, Mannheim, Germany) at the following conditions: 40 thermal step cycles of denaturation at 94 C (1 min), annealing at 60 C (1 min), and elongation at 72 C (2 min) in a thermocycler (model 9700, Perkin-Elmer, Foster City, CA). The annealing temperature was 64 C for urocortin. Primer pairs for CRH-R1, CRH-R2, urocortin, and stresscopin are listed in Table 1Go. As a positive control, we used mRNA from the pituitary gland (Clontech), and non-reverse-transcribed RNA preparations were amplified to provide a negative control.


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  		TABLE 1. RT-PCR primers and PCR conditions

 
Quantitative TaqMan PCR

To quantify expression of human CRH-R1, CRH-R2, urocortin, and stresscopin, we applied TaqMan PCR using the 7700 sequence detector (Perkin-Elmer Applied Biosystems). The reaction contained 1 x TaqMan universal PCR master mix, 900 nM of forward and reverse primers, and 200 nM of the TaqMan probes. Primers and probes for human CRH-R1, CRH-R2, urocortin, and stresscopin were designed as listed in Table 2Go using PRIMER EXPRESS (Perkin Elmer Applied Biosystems) primer design software. TaqMan probes were labeled with fluorescent reporter dye, FAM (6-carboxyfluorescein), at the 5' end and a fluorescent dye quencher, TAMRA (6-carboxy-tetramethyl-rhodamine), at the 3' end. The specificity of PCR primers was tested under normal PCR conditions in a thermocycler.


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  		TABLE 2. Primer and probe sequences for quantitative TaqMan PCR

 
As an internal control, we used commercial 18S rRNA primers and probe (TaqMan ribosomal control reagents, Perkin-Elmer Applied Biosystems). Internal control primers and probe were added at 50 nM concentration. Thermal cycling proceeded with 50 cycles at 95 C for 15 sec and 60 C for 1 min. Data were analyzed using Sequence Detector 1.7 software (Perkin-Elmer). Input RNA amounts were calculated using a multiple comparative method for the mRNAs of interest and 18S rRNA. Experiments were performed in triplicate for each data item.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Human adipose tissue express CRH-R and CRH-like peptides

The expression of CRH system component expression in human adipose tissue was examined at the mRNA level by RT-PCR and real-time quantitative TaqMan PCR and then compared with adrenal and heart. The cellular distribution of CRH-R protein was revealed by immunohistochemical labeling with specific antibodies.

Specific RT-PCR signals at the expected length were detected for CRH-R1, CRH-R2, and CRH-like peptides stresscopin and urocortin in human adipose tissue from visceral and sc fat and in the adrenal and heart (Fig. 1Go).



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  		FIG. 1. RT-PCR analysis of human messenger RNA from human visceral adipose tissue, sc adipose tissue, adrenal gland, and heart. mRNA was reverse transcribed, and the resulting cDNA was used as a template for PCR amplification. The 592, 615, 292, and 310-bp RT-PCR amplified products correspond to the predicted amplification products for CRH-R1, CRH-R2, UCN (urocortin), and SC (stresscopin), respectively.

 
Immunohistochemical staining for CRH-Rs was localized to the adipocytes in mammary and periadrenal adipose tissue. Immunostaining was confined to the cytoplasmic rim of the adipocytes (Fig. 2Go). Human pituitary gland was used as a positive control.



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  		FIG. 2. Immunohistochemical staining for CRH-Rs. A, Adipose tissue from mammary reduction. B, Periadrenal adipose tissue. C, Negative control. D, Pituitary gland as a positive control.

 
Quantitative expression of CRH system components in adipose tissue, compared with heart and adrenal

The expression of mRNA encoding the CRH system components in adipose tissue from different fat depots, adrenal, and heart was quantitatively compared using TaqMan PCR. In accordance with the RT-PCR data, adipose tissue expressed strong signals for CRH-R1 and CRH-R2 as well as CRH-like peptides urocortin and stresscopin (Fig. 3Go). CRH-R1 mRNA expression was considerably higher in fat tissue, compared with the peripheral organs, adrenal gland, and heart. CRH-R2 mRNA expression levels in fat tissue were comparable with the levels in heart but higher than in adrenal tissue. Urocortin mRNA expression was similar in adrenal and fat tissue but higher than in the heart; mRNA expression for stresscopin was higher in fat tissue, compared with either of the peripheral organs investigated.



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  		FIG. 3. Quantitative TaqMan PCR of CRH-R1, CRH-R2, urocortin (UCN), and stresscopin (SC) mRNA in human adipose tissue (n = 7), compared with human adrenal gland (n = 2) and heart (n = 2). Data represent the mean ± SEM.

 
We quantitatively compared CRH-R1, CRH-R2, urocortin, and stresscopin mRNA expression in two different fat depots, sc and visceral. Human sc adipose tissue showed higher CRH-R1, urocortin, and stresscopin mRNA expression but lower CRH-R2 mRNA expression, compared with visceral fat tissue (Fig. 4AGo).



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  		FIG. 4. A, Comparison of mRNA expression levels of CRH-R1, CRH-R2, UCN (urocortin), and SC (stresscopin) in human visceral (visc., n = 3) and sc (subc., n = 4) adipose tissue. CRH-R1 mRNA expression was significantly higher in sc adipose tissue (*, P < 0.05, visceral vs. sc adipose tissue), whereas CRH-R2 was the predominant receptor in visceral adipose tissue (*, P < 0.05, visceral vs. sc adipose tissue). Subcutaneous adipose tissue expressed higher mRNA levels for CRH-like peptides stresscopin and urocortin (*, P < 0.05, visceral vs. sc adipose tissue). Quantitative TaqMan PCR data represent the mean ± SEM. B, Effect of CRH on CRH-R1 and CRH-R2 mRNA expression in human adipocytes in primary culture. CRH dose-dependently down-regulated the mRNA levels of both receptors CRH-R1 and CRH-R2 as detected by quantitative TaqMan PCR. Data represent the mean ± SEM (***, P < 0.001, vs. control).

 
The pituitary RNA used as a positive control showed a very strong signal for CRH-R1 and -R2 mRNA as well as for stresscopin. The expression of urocortin in pituitary was comparable with fat tissue and adrenal (data not shown).

CRH down-regulates CRH-R expression in cultured adipocytes

We investigated the effect of CRH on CRH-R expression in mature human adipocytes in primary culture. Twenty-four hour incubation with CRH dose-dependently down-regulated CRH-R1 and -2 at transcriptional level. Maximal effects were reached at a CRH concentration of 10-8 M (Fig. 4BGo).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The central nervous system, especially the hypothalamus, is a target for adipostatic peptides produced by fat tissue, such as leptin. In the present study, we could demonstrate that CRH-Rs are expressed in human adipose tissue, which is therefore a direct target for hypothalamic CRH as well as CRH-related peptides such as urocortin and stresscopin with well-known metabolic and anorexic effects. This suggests a bidirectional communication between the hypothalamus and adipose tissue in humans. CRH-R2 is the predominant CRH-R in peripheral tissues; its highest demonstrated expression is in the heart in both rats (25) and humans (8). In the heart, CRH-R2 is critically involved in regulating cardiovascular stress responses (9). We have used quantitative PCR for our data, which has demonstrated that CRH-R2 expression in human fat tissue is comparable with its expression in the heart. In addition, CRH significantly down-regulated its own receptors in human fat cells. Therefore, adipose tissue seems to be another target for CRH and CRH-like peptides such as stresscopin and urocortin.

The expression of CRH-Rs in adipose tissue and adipocytes in primary culture agrees with the recent observation that CRH down-regulated adipose 11ß HSD-1 activity and the availability of cortisol for intracrine effect in mature human sc adipocytes in vitro. In addition, it caused a reduction in lipolysis in differentiated human adipocytes (22). Together, these data imply a functional role for CRH and CRH-like peptides in human fat.

CRH-R1 antagonist antalarmin did not block the effect of CHR on 11ßHSD in human adipocytes (22), suggesting a predominant action through CRH-R2 in human fat. This is in accordance with our finding of strong CRH-R2 expression in human fat cells.

In addition, adipose tissue expressed the main ligands for CRH-R2, urocortin and stresscopin. Both urocortin and the recently discovered stresscopin peptide (urocortin III) are anorexic peptides. Intracerebroventricular injections of urocortin reduce appetite and body weight (26). Additionally, stresscopin has been shown to be a potent food intake inhibitor (12). The local production of these peptides within the adipose tissue indicates a direct effect on fat cell function in addition to the central effects on weight regulation.

In summary, we have demonstrated the expression and localization of CRH-Rs in human fat tissue, with the most abundant receptor being CRH-R2. Urocortin and stresscopin were expressed concomitantly. CRH down-regulated its own receptors. These data together with the observation recently published that describes a regulatory influence of CRH on adipocyte cortisol production (22) suggest systemic and autocrine/paracrine effects of the CRH/CRH-R system in adipose tissue homeostasis.


   Acknowledgments
 
We thank Angela Schraven for her skillful technical assistance and Professor Dr. R. R. Olbrisch and his team (Department of Plastic Surgery, Florence-Nightingale Hospital Düsseldorf) for support in obtaining adipose tissue samples from mammary reductions.


   Footnotes
 
This work was supported by the Deutsche Forschungsgemeinschaft (Grant Eh 161/2-4) (to M.E.-B.).

Abbreviations: CRH-R, CRH receptor; 11ß-HSD1, 11ß-hydroxysteroid dehydrogenase type 1.

Received July 25, 2003.

Accepted October 29, 2003.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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