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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2327
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 4 1508-1512
Copyright © 2006 by The Endocrine Society

Increased Activation of Nuclear Factor {kappa}B Triggers Inflammation and Insulin Resistance in Polycystic Ovary Syndrome

Frank González, Neal S. Rote, Judi Minium and John P. Kirwan

Department of Reproductive Biology (F.G., N.S.R., J.M.), Department of Medicine and Schwartz Center for Metabolism and Nutrition (J.P.K.), Case Western Reserve University School of Medicine, Cleveland, Ohio 44109

Address all correspondence and requests for reprints to: Frank González, MetroHealth Medical Center, Department of Obstetrics and Gynecology, Hamann S4-44, 2500 MetroHealth Drive, Cleveland, Ohio 44109. E-mail: fgonzalez{at}metrohealth.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Insulin resistance and chronic low level inflammation are often present in women with polycystic ovary syndrome (PCOS).

Objective: The purpose of this study was to determine the effects of hyperglycemia on nuclear factor {kappa}B (NF{kappa}B) activation and inhibitory {kappa}B (I{kappa}B) from mononuclear cells (MNC) in PCOS.

Design and Setting: This was a prospective controlled study conducted at an academic medical center.

Patients: The study population consisted of 16 reproductive-age women with PCOS (eight lean, eight obese) and 16 age- and body composition-matched controls (eight lean, eight obese).

Main Outcome Measures: Insulin sensitivity (IS) was derived from a 2-h 75-g oral glucose tolerance test (ISOGTT). Intranuclear NF{kappa}B and I{kappa}B protein expression were quantitated from MNC obtained from blood drawn fasting and 2 h after glucose ingestion.

Results: ISOGTT was lower in PCOS compared with controls (3.3 ± 0.3 vs. 6.4 ± 0.9, P < 0.004). The percent change in intranuclear NF{kappa}B was higher in lean and obese PCOS compared with lean controls (42.5 ± 19.1 and 54.5 ± 12.5 vs. –14.1 ± 10.9, P < 0.006). The percent change in intranuclear NF{kappa}B correlated positively with 2-h post-glucose ingestion levels (r = 0.37; P < 0.04) and plasma testosterone (r = 0.49; P < 0.006) and correlated negatively with ISOGTT (r = 0.39; P < 0.04). The percent change in I{kappa}B was lower in lean and obese PCOS compared with lean controls (–22.3 ± 3.2 and –17.0 ± 5.0 vs. 8.4 ± 11.8, P < 0.02).

Conclusion: In response to hyperglycemia, intranuclear NF{kappa}B increases and I{kappa}B decreases in MNC of women with PCOS independent of obesity. This may represent a cardinal inflammatory signal that contributes to the induction of insulin resistance and hyperandrogenism in PCOS.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN POLYCYSTIC OVARY syndrome (PCOS), activation of the proinflammatory transcription factor nuclear factor {kappa}B (NF{kappa}B) by hyperglycemia may play a role in altered release of TNF{alpha} from circulating mononuclear cells (MNC). We have recently shown that hyperglycemia causes an increase in reactive oxygen species (ROS) generation from MNC of women with PCOS (1). ROS-induced oxidative stress is a known activator of NF{kappa}B, a heterodimer consisting of two DNA-binding subunits known as p50 and p65 (2, 3). In resting MNC, NF{kappa}B is present in the cytoplasm complexed to its inhibitory protein known as inhibitory {kappa}B (I{kappa}B). After activation, I{kappa}B dissociates from NF{kappa}B and undergoes ubiquitination and degradation. NF{kappa}B is freed to undergo nuclear translocation and subsequent DNA binding that promotes the transcription of TNF{alpha}, a known mediator of insulin resistance (4, 5, 6, 7). We have previously reported that in PCOS, circulating TNF{alpha} levels are elevated independent of obesity and that MNC-derived TNF{alpha} release is altered in response to hyperglycemia (8, 9). Thus, nuclear translocation of activated NF{kappa}B within MNC in response to hyperglycemia may serve as a cardinal inflammatory signal in the induction of insulin resistance in PCOS.

We embarked on a study to determine the status of intranuclear NF{kappa}B in response to hyperglycemia in MNC of women with PCOS. We also examined the protein expression of the NF{kappa}B p65 subunit and I{kappa}B. We hypothesized that activated intranuclear NF{kappa}B and p65 protein expression are increased and I{kappa}B protein expression is decreased in MNC of women with PCOS in response to an oral glucose challenge compared with age- and body composition-matched controls.


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

Sixteen women with PCOS (eight lean and eight obese) between 19 and 33 yr of age and 16 weight-matched control subjects (eight lean and eight obese) between 20 and 40 yr of age volunteered to participate in the study. Subjects in the present report represent part of a larger cohort that are involved in our studies on PCOS and insulin resistance, and data from some of these subjects have been presented in previous publications (1, 9). The women with PCOS and control subjects were selected as previously described using the Rotterdam criteria to diagnose PCOS (1, 9, 10). All subjects provided written informed consent in accordance with the Case Western Reserve University and MetroHealth Medical Center guidelines for the protection of human subjects.

All subjects ingested a 75-g glucose beverage. Blood samples were drawn at 0 (fasting), 30, 60, 90, and 120 min for glucose and insulin determination. Insulin sensitivity (IS) was derived by an oral glucose tolerance test (ISOGTT) (11). Dual-energy absorptiometry was used to determine percent total body fat and percent truncal fat (Hologic Inc., Waltham, MA) as previously described (12).

MNC were isolated and nuclear-bound NF{kappa}B was quantitated by electrophoretic mobility shift assay (13). The protein expression of p65, I{kappa}B, and actin was quantitated by Western blotting using a 1:1000 dilution of a monoclonal antibody against p65 (Transduction Laboratories Inc., San Diego, CA), I{kappa}B (Transduction Laboratories), or actin (Santa Cruz Biotechnology, Santa Cruz, CA) (14). Densitometry was performed using Kodak 1D Image Analysis software version 3.6 (Kodak, Rochester, NY), and all values for p65 and I{kappa}B were corrected for loading using those obtained for actin.

Plasma glucose, insulin, testosterone, androstenedione, dehydroepiandrosterone sulfate, and C-reactive protein (CRP) were measured as previously described (1, 9). All samples were measured in duplicate in the same assay.

Statistics

Data were analyzed using StatView (SAS Institute, Cary, NC). Because of interindividual variability in densitometry values, alterations in nuclear-bound NF{kappa}B and the protein expressions of p65 and I{kappa}B were expressed as the percent change between the pre- and 2-h post-glucose challenge results. Descriptive and percent change data were compared using an unpaired Student’s t test or ANOVA for multiple group comparisons. Detection of significance by ANOVA was followed by a post hoc analysis. Differences between pre- and post-glucose challenge variables within groups were analyzed using the paired Student t test. Correlation analyses were performed by linear regression. All values are expressed as means ± SE. An {alpha}-level of 0.05 was used to determine statistical significance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Body mass index (BMI), percent total body fat, percent truncal fat, and waist circumference were greater (P < 0.03) in obese subjects compared with those who were lean whether or not they had PCOS (Table 1Go). Compared with control subjects, women with PCOS exhibited higher (P < 0.0001) circulating levels of testosterone (81.4 ± 7.7 vs. 38.8 ± 3.5 ng/dl), androstenedione (3.4 ± 0.2 vs. 1.8 ± 0.1 ng/ml), and comparable dehydroepiandrosterone sulfate levels (270 ± 32 vs. 183 ± 21 µg/dl). Androgen results were similar when subjects were grouped by body mass (data not shown). Fasting plasma CRP was higher (P < 0.02) in the obese whether or not they had PCOS (Table 1Go). These findings are similar to those in our previous reports (1, 9).


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  		TABLE 1. Subject characteristics

 
ISOGTT was lower (P < 0.02) in the obese whether or not they had PCOS compared with lean controls (Table 1Go). Lean women with PCOS exhibited an ISOGTT that was lower (P < 0.0009) than that of lean controls. ISOGTT was negatively correlated with BMI (r = –0.43; P < 0.02), percent body fat (r = –0.37; P < 0.04), percent truncal fat (r = –0.47; P < 0.008), and waist circumference (r = –0.37; P < 0.05) for the combined groups (data not shown). We have previously reported similar results (1, 9).

The percent change in MNC-derived p65 protein expression and intranuclear NF{kappa}B were higher (P < 0.04) in lean and obese women with PCOS and in obese controls when compared with lean controls. In contrast, the percent change in I{kappa}B protein expression from MNC was significantly (P < 0.05) reduced in both groups of women with PCOS and in obese controls when compared with lean controls (Fig. 1Go, A–D).


Figure 1
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  		FIG. 1. A, Representative Western blots showing the change in quantity of p65 and actin and densitometric analysis of p65 protein content in MNC homogenates when fasting samples (pre) were compared with the samples collected 2 h after glucose ingestion (post). Compared with lean controls, the percent change in p65 was greater in obese controls (*, P < 0.04), in lean women with PCOS ({dagger}, P < 0.04), and in obese women with PCOS ({ddagger}, P < 0.007). B, EMSA showing NF{kappa}B in nuclear extracts from MNC. A supershift of the NF{kappa}B band occurred during incubation with specific antibodies against NF{kappa}B subunits but not during incubation with nonspecific (NS) IgG. Neutralization of the NF{kappa}B band occurred during incubation with a specific cold competitor (SPC) of the oligonucleotide consensus sequence but not during incubation with a nonspecific cold competitor (NSC). C, Representative EMSA bands showing the change in quantity of NF{kappa}B in nuclear extracts and densitometric analysis of intranuclear NF{kappa}B protein content from MNC pre- and post-glucose ingestion. Compared with lean controls, the percent change in intranuclear NF{kappa}B was greater in obese controls (*, P < 0.03), in lean women with PCOS ({dagger}, P < 0.006), and in obese women with PCOS ({ddagger}, P < 0.002). D, Representative Western blots showing the change in quantity of I{kappa}B and actin and densitometric analysis of I{kappa}B protein content in MNC homogenates pre- and post-glucose ingestion. Compared with lean controls, the percent change in I{kappa}B was reduced in obese controls (*, P < 0.05), in lean women with PCOS ({dagger}, P < 0.01), and in obese women with PCOS ({ddagger}, P < 0.02).

 
Glucose levels 2 h after glucose ingestion were positively correlated with the percent change in p65 protein expression (r = 0.61; P < 0.002) and the percent change in MNC-derived intranuclear NF{kappa}B (r = 0.37; P < 0.04) for the combined groups. The 2-h glucose levels were also negatively correlated with I{kappa}B protein expression (r = –0.52; P < 0.004) for the combined groups. The percent change in MNC-derived intranuclear NF{kappa}B was positively correlated with percent truncal fat (r = 0.40; P < 0.03) and negatively correlated with ISOGTT (r = 0.39; P < 0.04) for the combined groups (data not shown).

Plasma levels of testosterone and androstenedione were positively correlated with the percent change in MNC-derived intranuclear NF{kappa}B (r = 0.49, P < 0.006; r = 0.52, P < 0.002) for the combined groups (Fig. 2Go, A and B). These correlations were not significant for the individual groups but were similar in magnitude for the women with PCOS.


Figure 2
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  		FIG. 2. A, Correlation between plasma testosterone and the percent change in intranuclear NF{kappa}B from MNC; B, correlation between plasma androstenedione and the percent change in intranuclear NF{kappa}B from MNC. {circ}, Control subjects; •, women with PCOS. Intranuclear NF{kappa}B MNC was quantitated from MNC when fasting samples (pre) were compared with the samples collected 2 h after glucose ingestion (post).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our data demonstrate for the first time that hyperglycemia activates NF{kappa}B, the cardinal signal of inflammation, in MNC of women with PCOS independent of obesity. There is also decreased protein expression of I{kappa}B, the cytoplasmic inhibitor of NF{kappa}B, in women with PCOS, which is again independent of obesity. Lean women with PCOS show increased p65 protein expression and increased intranuclear NF{kappa}B along with decreased I{kappa}B protein expression compared with lean controls. These alterations are similar to obese subjects whether or not they have PCOS. The changes in p65 protein expression and intranuclear NF{kappa}B were inversely related to insulin sensitivity and directly related to androgen levels. These findings provide support for the concept that, in PCOS, insulin resistance and hyperandrogenism may be a result of inflammation triggered by hyperglycemia. Furthermore, the independent associations of p65 protein expression and intranuclear NF{kappa}B with percent truncal fat suggest that increased abdominal adiposity may be a key determinant of the hyperglycemia-induced inflammatory response observed in obese women with PCOS and a potential modulator of insulin action in these individuals.

Suppression of NF{kappa}B activation precluding nuclear translocation may be the normal in vivo response to physiological hyperglycemia in young healthy lean women. There was a decline in MNC-derived p65 protein expression and intranuclear NF{kappa}B along with an increase in I{kappa}B protein expression in lean controls in response to hyperglycemia. Our findings differ from those of a previous study of normal subjects that reported an increase in intranuclear NF{kappa}B after an oral glucose challenge (15). The majority of subjects in this study were men, which may account for the different results. Because insulin is an antiinflammatory hormone (16), the postprandial insulin release in the more insulin-sensitive lean controls may reverse the hyperglycemia-induced proinflammatory response. In this scenario, suppression of NF{kappa}B activation in the presence of hyperglycemia may limit MNC-derived release of TNF{alpha}, a known mediator of insulin resistance (6, 7). This is consistent with our previous reports that TNF{alpha} release from MNC is suppressed during hyperglycemia in young healthy lean men and women (17, 18). Thus, facilitation of glucose disposal in lean controls may be partially a result of control of NF{kappa}B activation by limiting the amount of total and intranuclear NF{kappa}B and increasing the amount of I{kappa}B to optimize insulin signaling in the postprandial state.

The MNC of women with PCOS are in a proinflammatory state as evidenced by the increased sensitivity to physiological hyperglycemia and elevated plasma CRP, the latter of which may be a function of obesity (19, 20). The protein expression of p65 and intranuclear NF{kappa}B increased in response to the oral glucose challenge in lean women with PCOS compared with lean controls. Obese women with PCOS also exhibited increases in these parameters compared with obese and lean controls. The resultant inflammatory signal may be responsible for our previous observation that hyperglycemia alters TNF{alpha} release in women with PCOS (9). The stimulatory impact of hyperglycemia on NF{kappa}B activation is suggested by the direct relationship of the plasma glucose levels measured 2 h after glucose ingestion with p65 protein expression and intranuclear NF{kappa}B along with the inverse relationship between the 2-h glucose levels and I{kappa}B protein expression. Similar proinflammatory responses are elicited by lipid and protein intake (21). Thus, an acute inflammatory response to feeding may promote the insulin resistance observed in women with PCOS. This concept is supported by the inverse relationship of p65 protein expression and intranuclear NF{kappa}B with ISOGTT. Previous reports of a reduction in oxidative stress and inflammatory mediators after caloric restriction in the obese and after a 2-d fast in normal subjects provide further corroboration (22, 23).

Our data suggest that in PCOS, there may be a link between abdominal adiposity and inflammation. Although not evident in the present study, our group and other investigators have previously shown that aside from obese women with PCOS, abdominal adiposity can be increased in lean women with the disorder (9, 24). The change in MNC-derived intranuclear NF{kappa}B in response to hyperglycemia was directly related to abdominal adiposity. Migration of MNC into adipose tissue activates adipocyte TNF{alpha} production (25). Most importantly, MNC-derived macrophages present in the stromal-vascular compartment are the prime source of TNF{alpha} in excess adipose tissue (25, 26). Hyperglycemia-induced NF{kappa}B activation may be perpetuated by inflamed adipose tissue, especially in the abdominal region, to promote increased TNF{alpha} release from MNC in obese women with PCOS. The inverse relationship between insulin sensitivity and abdominal adiposity is consistent with previous observations in young adults demonstrating that changes in insulin sensitivity are a function of abdominal adiposity (27). Thus, an increase in MNC-derived NF{kappa}B activation may promote the insulin resistance observed in obese women with PCOS.

In PCOS, inflammation triggered by hyperglycemia may be capable of directly stimulating hyperandrogenism. This is suggested by the direct correlation of the plasma levels of testosterone or androstenedione with p65 expression and intranuclear NF{kappa}B. Infiltration of the ovary by MNC-derived macrophages has been previously demonstrated (28). In vitro studies have shown that the ovarian steroidogenic enzymes responsible for androgen production are stimulated by oxidative stress and inhibited by antioxidants such as statins (29, 30). TNF{alpha} stimulates in vitro proliferation of androgen-producing theca cells (31). We have recently shown that in PCOS, hyperglycemia causes an increase in ROS generation from MNC and that there is a direct correlation of ROS generation with androgen levels (1). Thus, NF{kappa}B activation after ROS-induced oxidative stress from glucose-activated MNC recruited into the polycystic ovary may cause a local inflammatory response that stimulates ovarian androgen production in women with PCOS.

In conclusion, women with PCOS exhibit increases in p65 expression and intranuclear NF{kappa}B and decreases in I{kappa}B expression in response to physiological hyperglycemia that is independent of obesity. The findings are consistent with a proinflammatory state that may contribute to insulin resistance and hyperandrogenism in PCOS. The association between the change in intranuclear NF{kappa}B and abdominal fat suggests that increased adiposity is an additional perpetuator of insulin resistance in PCOS.


   Acknowledgments
 
We thank the nursing staff of the General Clinical Research Center for supporting the implementation of the study and assisting with data collection.


   Footnotes
 
This research was supported by National Institutes of Health Grants HD-01273 (Women’s Reproductive Health Research Program) to the Department of Obstetrics and Gynecology at MetroHealth Medical Center and MO1 RR-00080 to the General Clinical Research Center.

None of the authors have anything to disclose regarding potential conflicts of interest.

First Published Online February 7, 2006

Abbreviations: BMI, Body mass index; CRP, C-reactive protein; I{kappa}B, inhibitory {kappa}B; ISOGTT, insulin sensitivity derived from oral glucose tolerance test; MNC, mononuclear cells; NF{kappa}B, nuclear factor {kappa}B; PCOS, polycystic ovary syndrome; ROS, reactive oxygen species.

Received October 24, 2005.

Accepted January 26, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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