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Plasma Concentrations of Fibroblast Growth Factors 19 and 21 in Patients with Anorexia Nervosa

Ivana Dostálová, Petra Kaválková, Denisa Haluzíková, Zdena Lacinová, Milo Mráz, Hana Papeová and Martin Haluzík

Third Department of Medicine (I.D., P.K., D.H., Z.L., M.M., M.H.) and Departments of Sports Medicine (D.H.) and Psychiatry (H.P.), First Faculty of Medicine, Charles University and General University Hospital, 128 00 Prague 2, Czech Republic

Address all correspondence and requests for reprints to: Martin Haluzik, M.D., Ph.D., Third Department of Medicine, First Faculty of Medicine, U Nemocnice 1, 128 00 Prague 2, Czech Republic. E-mail: mhalu{at}lf1.cuni.cz.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Fibroblast growth factor 19 (FGF19) and FGF21 are novel metabolic regulators that improve insulin sensitivity and decrease adiposity in mice. However, little is known about the nutritional regulation of these factors in humans.

Objective: The objective of this study was to measure plasma FGF19 and FGF21 levels in patients with anorexia nervosa (AN) and to explore its relationship with anthropometric and endocrine parameters.

Design: This was a single-center cross-sectional study.

Setting: The study was performed in a university hospital.

Patients: Seventeen untreated women with a restrictive type of AN and 17 healthy women (control group) were included.

Main Outcome Measures: Fasting plasma FGF19 and FGF21, serum insulin, leptin, soluble leptin receptor, adiponectin, resistin, and C-reactive protein were the main outcome measures.

Results: Plasma FGF19 levels did not significantly differ between the groups studied, whereas plasma FGF21 levels were significantly reduced in AN relative to the control group. Plasma FGF21 positively correlated with body mass index and serum leptin and insulin and was inversely related to serum adiponectin in both groups. In contrast, plasma FGF19 was not related to any of parameters studied. Partial realimentation significantly reduced plasma FGF21 levels in AN.

Conclusion: Circulating levels of FGF21 but not FGF19 are strongly related to body weight and serum levels of leptin, adiponectin, and insulin in both anorectic and normal-weight women. We suggest that reduced plasma FGF21 levels could be involved in the pathophysiology of AN or in a complex adaptive response to this disease.

	Introduction

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Members of the fibroblast growth factor (FGF) family play numerous roles in cellular processes including growth, angiogenesis, and development (1, 2, 3). Recent findings indicate that FGF19 and FGF21 may regulate metabolic homeostasis in a paracrine and/or endocrine manner (4, 5, 6, 7).

FGF21 is expressed predominantly in the liver (8) and has emerged as a potent stimulator of glucose uptake and lipolysis in adipose tissue (6). The animal studies have shown antiinflammatory, antidiabetic, and hypolipidemic effects of FGF21 (6, 7, 9). In mice, the expression of FGF21 in the liver is tightly nutritionally regulated. It is increased by starvation and the ketogenic state (10, 11, 12) and decreased by feeding (11). Despite an important metabolic role of FGF21 in animals, little is still known about the nutritional regulation of FGF21 in human.

FGF19 is another recently characterized member of the FGF family (13, 14). Transgenic mice overexpressing human FGF19 exhibit increased metabolic rate and decreased adiposity (4, 5). Circulating FGF19 exhibits a diurnal rhythm controlled by the transintestinal bile acid flux. Such a diurnal rhythm of FGF19 is abolished by fasting (15). In humans, FGF19 originates from intestine and modulates hepatic bile acids synthesis (16).

The exact knowledge of FGF19 and FGF21 bioactivity and its mode of action in malnourished humans have been lacking to date. Here we explored whether circulating FGF19 and FGF21 levels are regulated by nutritional status in humans. We selected severely malnourished patients with a restrictive type of anorexia nervosa (AN) as a model of extreme state of chronic negative energy balance. The restrictive form of AN represents a bordering example of psychosomatic-based malnutrition induced by chronically decreased food intake caused by inappropriate fear of obesity and distorted body image (17). The factors that play the crucial role in severe metabolic alterations in patients with AN are still only partially understood.

To our best knowledge, neither FGF19 nor FGF21 have been studied in patients with AN. Here we tested the hypothesis that increased levels of FGF19 and FGF21 may contribute to the etiopathogenesis and/or some of the metabolic changes in patients with AN. To this end, we measured fasting plasma concentrations of FGF19 and FGF21 in patients with a restrictive type of AN and in healthy normal-weight women and studied the relationship of these factors to nutritional status and selected endocrine parameters. Furthermore, we studied the effect of partial realimentation of patients with AN on plasma levels of FGF19 and FGF21.

	Subjects and Methods

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Study subjects

Seventeen previously untreated female patients with restrictive subtype of AN [age, 25.0 ± 1.34 yr; body mass index (BMI), 15.9 ± 0.33 kg/m²] and 17 age- and sex-matched healthy controls (age, 24.7 ± 0.59 yr; BMI, 22.9 ± 0.41 kg/m²) were included in the study. The diagnosis of eating disorder was based on the Diagnostic Statistical Manual IV diagnostic system (17). A clinical evaluation of the patients was performed by an experienced psychiatrist. The Structured Clinical Interview MINI 5.0 was used for diagnostic assessment of patients. None of the studied subjects suffered from diabetes mellitus, thyroid disorder, and/or acute infectious disease. All subjects included in the study were nonsmokers, had no allergies, and had been free of medication for at least 3 months before the study. Healthy women had no history of obesity or malnutrition, hypertension, gastrointestinal disease, eating disorder, or other psychiatric disorder. Blood tests confirmed normal blood count and liver and renal functions. All patients with AN had amenorrhea, whereas all healthy women had regular menstrual cycles. Patients with any acute or chronic stress situations were excluded. All subjects were asked to fast and drink only water on the night before the study. Written informed consent was provided by all participants before being enrolled in the study. The study was approved by the Human Ethical Review Committee, First Faculty of Medicine and General University Hospital, Prague, Czech Republic, and was performed in accordance with the guidelines proposed in the Declaration of Helsinki.

Anthropometric examination and blood sampling

All patients were examined at a basal state before the beginning of any treatment. Ten of the patients were examined also after 2 months of partial realimentation. All subjects were measured and weighted. Blood samples for FGF21, FGF19, resistin, adiponectin, leptin, leptin receptor, insulin, and biochemical parameters measurements were withdrawn between 0700 and 0800 h after 12 h of overnight fasting. Plasma samples for FGF19 and FGF21 analysis were collected into chilled polypropylene tubes containing Na₂-EDTA and antilysin. Plasma was separated by centrifugation at 4 C and stored at –80 C until being assayed.

Hormonal and biochemical assays

Plasma FGF19 concentrations were measured by a commercial ELISA kit (BioVendor, Brno, Czech Republic). The samples were diluted with dilution buffer 1:1. The sensitivity was 4.8 pg/ml, and the intra- and interassay variability was 7.0 and 8.5%, respectively. Plasma FGF21 concentrations were measured by a commercial ELISA kit (BioVendor). The samples were diluted with dilution buffer 1:1 or 2:1, respectively. The sensitivity was 5.0 pg/ml, and the intra- and interassay variability was 5.0 and 9.0%, respectively. Serum insulin concentrations were measured by commercial RIA kit (Cis Bio International, Gif-sur-Yvette, France). Sensitivity was 2.0 µIU/ml, and the intra- and interassay variability was 4.2 and 8.8%, respectively. Serum leptin concentrations were measured by commercial ELISA kit (BioVendor). Sensitivity was 0.12 ng/ml, and the intra- and interassay variability was 1.7 and 8.0%, respectively. Serum soluble leptin receptor concentrations were measured by commercial ELISA kit (BioVendor). Sensitivity was 0.4 U/ml, and the intra- and interassay variability was 4.4 and 7.2%, respectively. Serum adiponectin concentrations were measured by commercial RIA kit (Linco Research, St. Charles, MO). Sensitivity was 1.0 ng/ml, and the intra- and interassay variability was 1.8 and 9.3%, respectively. Serum resistin concentrations were measured by commercial ELISA kit (BioVendor). Sensitivity was 0.2 ng/ml, and the intra- and interassay variability was 3.1 and 6.5%, respectively. Serum levels of IGF-I were measured by commercial immunoradiometric assay kit (Immunotech, Prague, Czech Republic). Sensitivity was 2 ng/ml, and the intra- and interassay variability was 6.3 and 6.8%, respectively. Serum total ketone bodies were measured by commercial cyclic enzymatic kit (Wako Chemicals, Neuss, Germany). Serum levels of free fatty acids (FFA) were measured by enzymatic colorimetric assay (Roche, Basel, Switzerland). Serum levels of thyroid hormones and biochemical parameters were measured by standard laboratory methods.

Statistical analysis

The statistical analysis was performed on SigmaStat software (Jandel Scientific, San Rafael, CA). Results are expressed as mean ± SEM. Unpaired t test or Mann-Whitney U test was used for groups comparison as appropriate. The levels of FGF19 and FGF21 in patients with AN before and after partial realimentation were compared using paired t test or Wilcoxon signed rank test as appropriate. Multiple regression analysis was used to show the independent relationship of FGF21 with other parameters. The correlations between the values were estimated by Spearman correlation test. A P value < 0.05 denoted statistical significance.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Anthropometric characteristics of study subjects

The study groups were age matched. Patients with a restrictive type of AN were extremely malnourished as evidenced by severely decreased BMI (Table 1).

Fasting serum glucose, insulin, glycated hemoglobin, total cholesterol and triglycerides did not significantly differ between the groups studied. Fasting serum leptin, IGF-I, FFA, free T₃ (fT₃), free T₄ (fT₄), total ketone bodies, and C-reactive protein levels were significantly reduced in the AN group, whereas fasting serum adiponectin and soluble leptin receptor levels were markedly increased in patients with AN relative to the control group. Fasting serum resistin did not significantly differ between the AN and control group (Table 1).

Plasma levels of FGF19 and FGF21: comparison of AN and normal-weight women

Fasting plasma FGF19 levels did not significantly differ between the groups studied, whereas fasting plasma FGF21 levels were significantly reduced in patients with AN relative to control group (Table 1).

Relationship of FGF19 and FGF21 with other studied parameters

The relationship of FGF19 and FGF21 with other studied parameters was calculated in the combined population of both groups (Table 2). Plasma FGF19 was not related to any of the other parameters studied. In contrast, plasma FGF21 significantly positively correlated with BMI, serum leptin, and serum insulin and was significantly inversely related to serum adiponectin levels. The above mentioned relationships were calculated also in each group separately (data not shown) and were found similar to those of the combined population. We failed to find significant relationships between FGF21 and serum ketone bodies, fT₃, fT₄, TSH, IGF-I, FFA, and homeostasis model assessment of insulin resistance (HOMA) in patients with AN (data not shown) and in a combined population of both groups (Table 2). However, FGF21 was significantly inversely related to fT₃ in the control group only (Fig. 1). Multiple regression analysis showed that leptin (P = 0.002) and adiponectin (P = 0.018) were independent predictors of FGF21 plasma levels.

View larger version (16K): [in this window] [in a new window]   FIG. 1. Relationship of FGF21 with fT3 in healthy control women (n = 17).

All studied patients with AN gained weight (pretreatment BMI, 15.6 ± 0.2 kg/m²; posttreatment BMI, 17.4 ± 0.3 kg/m²) and body fat (pretreatment percent body fat, 9.6 ± 1.7%; posttreatment percent body fat, 14.0 ± 1.6%) during realimentation. Plasma levels of FGF21 in patients with AN were significantly reduced after 2 months of realimentation (Fig. 2A). Plasma levels of FGF19 tended to decrease after realimentation, but the difference did not reach statistical significance (Fig. 2B). Pretreatment plasma FGF21 significantly positively correlated with change in BMI during treatment (Fig. 3).

View larger version (15K): [in this window] [in a new window]   FIG. 2. Plasma levels of FGF21 (A) and FGF19 (B) in patients with AN (n = 10) before starting of any treatment and after 2 months of refeeding.

View larger version (19K): [in this window] [in a new window]   FIG. 3. Relationship of pretreatment plasma levels of FGF21 with BMI after nutritional treatment in patients with AN (n = 10).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Only a few animal studies previously described the possible role of FGF21 in the metabolic response to starvation (10, 11, 12). In mice, the hepatic expression of FGF21 was up-regulated both by the starvation and by the ketogenic state induced by a high-fat/low-carbohydrate diet, and it decreased upon feeding (11). The fasting-induced FGF21 in turn contributed to initiation of the response to fasting in mouse liver and adipose tissue, including ketosis and lipolysis (10). Here we show, contradictory to acute fasting animal studies, that the chronic malnutrition in humans is associated with markedly reduced circulating levels of FGF21. A recent study by Arner’s group (18) demonstrated that FGF21 attenuated hormone-stimulated lipolysis in human adipocytes in vitro. Therefore, decreased FGF21 levels could contribute to the increased rate of lipolysis in adipose tissue of patients with AN (19). Collectively, both Arner’s and our data suggest that FGF21 in humans may exhibit different effects and/or bioactivity relative to rodents. Similarly, administration of FGF21 in rhesus monkeys led to significant weight loss, whereas no weight loss upon its administration was observed in mice (6, 9).

Our results showed that plasma FGF21 levels are tightly nutritionally regulated in patients with AN. Even more interestingly, the pretreatment plasma FGF21 levels predicted the weight gain during realimentation in AN. We therefore suggest that decreased FGF21 levels may represent an important part of the complex neuroendocrine response to chronic malnutrition in AN patients and possibly also a valuable predictor of the effectiveness of realimentation therapy.

The relationship of FGF21 with insulin and adiponectin further indicates the possible role of this factor in the regulation of glucose metabolism in human. The role of FGF21 as an antidiabetic molecule in animals (6, 7, 9) and its relation to metabolic syndrome (20) and diabetes (21) in humans has been recently described. In our study, we failed to find a direct relationship between HOMA index and plasma FGF21 levels, which may be explained by the fact that HOMA is only a rough measure of insulin sensitivity. In general, whether patients with AN are insulin resistant (22) or have normal (23) or increased insulin sensitivity (24, 25) is still questionable. Nevertheless, a positive correlation of baseline FGF21 levels with change of body weight in AN patients after partial realimentation raises the possibility that reduced FGF21 levels may help to maintain euglycemia and protect energy stores in chronically malnourished patients with AN.

Although several obvious changes occur in transgenic mice expressing FGF19, including increased metabolic rate, decreased adiposity, increased food intake, decreased lipids, and increased insulin sensitivity (4), our results do not confirm that circulating FGF19 is related either to nutritional status or to circulating insulin in humans. However, we cannot exclude the possible changes of local FGF19 concentrations in the liver, adipose tissue, and/or intestine that are not reflected in the circulation. We are aware that our results are based on a single measurement after overnight fasting and possible nutrition-related changes in the dynamic secretion pattern of FGF19 may not have been noticed here. Furthermore, it cannot be excluded from the present results that the longer realimentation in a larger patient group could significantly reduce circulating FGF19 levels.

In conclusion, we demonstrated that circulating levels of FGF21 are significantly reduced in patients with a restrictive type of AN relative to normal-weight women. FGF21 levels were closely related to BMI and leptin, adiponectin, and insulin in both AN and normal-weight women. Plasma FGF21 levels in patients with AN were tightly regulated by nutritional treatment. In contrast, we did not find any significant relationship of circulating FGF19 levels to either anthropometric or endocrine variables in our study. We suggest that reduced plasma FGF21 levels could be involved in the pathophysiology or adaptive metabolic response in patients with AN.

	Footnotes

 
Disclosure Statement: All authors have nothing to declare.

This work was supported by MZO FN2005.

First Published Online June 17, 2008

Abbreviations: AN, Anorexia nervosa; BMI, body mass index; FFA, free fatty acids; FGF, fibroblast growth factor; fT₃, free T₃.

Received April 4, 2008.

Accepted June 5, 2008.

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