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Abstract

Background

Obesity is a risk factor for migraine and headache chronification. Adipocytokines may be involved in this correlation.

Objective

To relate serum adipocytokine levels to clinical and biochemical parameters associated with migraine.

Methods

We measured levels of leptin, adiponectin and other inflammatory (interleukin 6, interleukin 10, tumor necrosis factor α, high sensitivity C-reactive protein) and endothelial (pentraxin 3, soluble TNF-like weak inducer of apoptosis) molecules potentially related to migraine pathophysiology in a group of migraine patients (IHS 2013) and healthy controls.

Results

One hundred and eleven patients (mean age 39.7 years, 93% female) and 24 healthy controls (mean age 35.9 years, 90% female) were included. Fifty-six patients were diagnosed with episodic migraine (mean age 35.1 years, 98.2% female) and 55 patients with chronic migraine (mean age 44.4 years, 89.5% female). Leptin serum levels (15.2 ng/mL, SD = 10.5 vs. 3.1 ng/mL, SD = 0.9; p < 0.001) and adiponectin serum levels (72.3 µg/mL, SD = 38.5 vs. 37.7 µg/mL, SD = 16.9; p < 0.001) were significantly increased in migraine patients. Leptin serum levels (15.5 ng/mL, SD = 9.7 vs. 10.8 ng/mL, SD = 6.0; p < 0.001) and adiponectin serum levels (65.8 µg/mL, SD = 42.9 vs. 33.2 µg/mL, SD = 31.0; p < 0.001) were significantly higher in chronic compared to episodic migraine patients. We found a positive correlation between leptin levels and inflammatory biomarkers: IL6 (r = 0.498; p < 0.001), TNF-α (r = 0.389; p < 0.001), and hs-CRP (r = 0.422; p < 0.001).

Conclusions

Leptin and adiponectin are increased in migraineurs. There is a correlation between adipocytokine levels and other inflammation-related molecules. This suggests a potential role of adipocytokines in migraine pathophysiology and chronification.

Keywords

Adiponectin pathophysiology chronic migraine inflammation leptin

Introduction

Many of the risk factors that lead to an increase in frequency and intensity of migraine attacks are still controversial. Previous research has shown a relation between inflammation and migraine predisposition and progression (1). Likewise, several studies have demonstrated that the prevalence of migraine, either episodic or chronic, is higher in individuals who are obese and increases with increasing body mass index (BMI) (2,3). Also, the risk of progression from episodic to daily headache is higher in obese (4) or overweight subjects (5,6), both conditions also being related to chronic inflammation. However, the currently extensive epidemiological literature on obesity and headache does not yet allow us to determine causality in this relation (7). Adipose tissue is a highly functioning neuroendocrine organ producing multiple molecules involved in energy homeostasis and inflammation (8). Many cytokines with an active role in migraine, such as IL-6 and TNF-α, are produced by adipocytes (9), which also release specific inflammatory substances known as adipocytokines: Leptin and adiponectin (10,11). Likewise, adipocytokine receptors are abundantly expressed in the cortex, brainstem, and endothelium of the cerebral microvasculature and hypothalamus (12), which is involved both in regulation of feeding and several headache disorders, including migraine (13,14). Several studies have focused on levels of adipocytokines in migraineurs, measuring them either during interictal periods or during acute pain. They have shown controversial results, with increased levels of ADP (15,16,17) in migraineurs, decreased levels of leptin in migraineurs in one study (18) and no significant differences in the remainder (19,20, 21,22).

The aim of this study is to compare leptin and adiponectin serum levels during an interictal period in migraine patients and control healthy subjects. Likewise, we assessed the correlation of these adipocytokines with clinical evolution (frequency and intensity of headache) and biomarkers of inflammation and endothelial dysfunction to determine their potential role in migraine pathophysiology and progression.

Patients and methods

We performed a cross-sectional study with 135 subjects. One hundred and eleven individuals diagnosed with episodic and chronic migraine, with and without aura according to International Classification of Headache Disorders 3^rd Edition criteria (23), were selected in our Headache Clinic. Twenty-four healthy subjects, free of any type of headache, were recruited among co-workers and patient relatives as a control group between April 2013 and June 2015.

Exclusion criteria were: a) High blood pressure (known HBP or ≥ two measurements over 140/90 mmHg); b) coronary disease (coronary lesions >50% determined by angiography, myocardial infarction, angina pectoris or coronary recanalization); c) diabetes mellitus (known DM or ≥ 2 fasting serum glucose determinations >126 mg/dL); d) hypercholesterolemia (pharmacologically treated, or fasting serum cholesterol >200 mg/dL); e) infectious diseases; f) chronic inflammatory conditions; g) severe systemic diseases; h) pregnancy or lactation; i) recent consumption of vasoactive drugs (<4 times the medium half-life of the active substance).

The Research Ethics Committee of Servizo Galego de Saúde approved the study. All patients and control subjects provided written informed consent.

All subjects had a complete medical record including personal and family history, a normal physical examination and neuroimaging, when appropriated. Demographic and clinical data were recorded, including age, gender, type of migraine (episodic or chronic, with or without aura), frequency of attacks, intensity of headaches (patients were asked to give an average of their headache intensity using a visual analogue scale [VAS]), duration of attacks (4–8 hours, 9–24 hours, 25–72 hours) and duration of the disease (years). Clinical parameters of migraine were considered as an average of the patient’s episodes. Anthropometric measurements (weight and height) were determined using a mechanical column scale with a stadiometer and body mass index (BMI) (kg/m²) was calculated.

After a screening visit, eligible subjects were invited to perform a blood sample extraction, which was performed in the non-dominant forearm after an eight hour fast. Patients were headache free from the previous 72 to the 24 hours after the visit to avoid an effect of acute pain in biomarker levels. If a migraine occurred within the first 24 hours, measurements were repeated in another headache-free period. Chronic migraine patients with daily headache were asked to be at a baseline level of pain, with no acute headache in the previous 72 hours. Subjects had not previously consumed anti-inflammatory or analgesic medication. Preventative treatments were allowed.

Venous blood samples were collected in chemistry test tubes, centrifuged at 3000 g for 15 minutes, and immediately frozen and stored at −80℃. Leptin serum levels were measured by ELISA (DRG Instruments GmbH, Marburg, Germany); minimum assay sensitivity was 1.0 ng/mL, with an inter-assay CV of 8.66% and intra-assay CV of 5.95%. Serum levels of IL-6, IL-10, TNF-α and hs-CRP were measured using an immunodiagnostic IMMULITE 1000 System (Siemens Healthcare Global, Los Angeles, CA, USA). Minimum assay sensitivity for IL-6 was 2 pg/mL, with an intra-assay CV of 4.5% and a inter-assay CV of 5.3%. Minimum assay sensitivity for IL-10 was 1 pg/mL, with an inter-assay CV of 4.7% and intra-assay CV of 3.1%. Minimum assay sensitivity for TNF-α was 1.7 pg/mL, with an inter-assay CV of 6.5% and intra-assay CV of 3.5%. Minimum assay sensitivity for hs-CRP was 0.4 mg/mL, with an intra-assay CV of 2.0% and inter-assay CV of 3.5%. Serum levels of PTX3 and sTWEAK (Assay Biotech, Sunnyvale, CA, USA) as well as adiponectin (Sigma-Aldrich Corp. St. Louis, MO, USA) were measured using commercial ELISA kits following manufacturer instructions. Minimum assay sensitivity for PTX3 was 219 pg/mL, with an inter-assay CV of 6.2% and intra-assay CV of 4.2%. Minimum assay sensitivity for sTWEAK was 16 pg/mL, with an inter-assay CV of 6.4% and intra-assay CV of 4.3%. Minimum assay sensitivity for adiponectin was 1.5 pg/mL, with an inter-assay CV of 7.7% and intra-assay of 4.2%. Determinations were performed in an independent laboratory blinded to clinical data.

Statistical analysis

Based on reproducibility data acquired in our laboratory before the study, a sample size of 111 patients with migraine and 24 healthy controls was calculated to achieve a significance level of 0.05 and a statistical power of 80%. Sample size was calculated using the statistical EPIDAT software (http://www.sergas.es/MostrarContidos_N3_T01.aspx?IdPaxina=62714).

Results were expressed as percentages for categorical variables and as mean (SD) or median and range (percentiles 25–75) for the continuous variables depending on whether their distribution was normal or not. The Kolmogorov-Smirnov test was used for testing the normality of the distribution. Proportions were compared using the chi-square or Fisher test, while the continuous variables between groups were compared with the Student’s t-test or the Mann-Whitney test depending on whether their distribution was normal or not, respectively. Bivariate correlations were performed using Pearson’s coefficient (normally distributed variables) or Spearman coefficient (variables without normal distribution). The association of leptin and adiponectin serum levels and migraine was assessed by logistic regression analysis. The association of leptin serum levels and migraine was assessed by logistic regression analysis. Each logistic regression analysis was adjusted by those variables with a proven biological relevance for migraine to avoid the possibility of finding some spurious associations (age, sex, and BMI). Results were expressed as adjusted odds ratios (ORs) with the corresponding 95% confidence intervals (95% CI). A value of two-tailed p < 0.05 was considered significant. The statistical analysis was conducted in SPSS 18.0 (SPSS, Chicago, IL, USA) for Mac.

Results

One hundred and eleven patients (age: 39.7 ± 14.4 years; sex: 93.7% females) and 24 control subjects (age: 35.9 ± 8.8 years; sex: 90.0% females) were included in the study. Fifty-six patients were diagnosed with episodic migraine (mean age 35.1 years, 98.2% female) and 55 patients with chronic migraine (mean age 44.4 years, 89.5% female). Table 1 shows the main clinical characteristics of the patients. Twenty-four healthy controls were included. Patients suffering chronic migraine showed longer disease time of evolution (20.3 years; SD = 12.9 vs. 12.2 years; SD = 11.3), more frequent and intense migraine attacks (9 points in VAS vs. 8 points in VAS) and higher prevalence of concomitant tension type headache (61.8% vs. 42.1%).

Table 1.

Clinical characteristics of migraine patients and controls.

	Controls n = 24	Patients n = 111	p
Age (years)	36.1 ± 7.9	39.8 ± 12.4	0.161
Gender (% female)	91.7	93.7	0.661
Height (cm)	168.8 ± 7.3	162.4 ± 7.1	<0.0001
Weight (kg)	68.4 ± 7.2	67.5 ± 13.9	0.644
BMI	24.2 ± 2.7	25.5 ± 4.7	0.177
Hypertension (%)	0	5.4	0.592
Diabetes mellitus (%)	0	0.9	0.816
Dyslipidemia (%)	0	14.4	0.043
Smoking habit (%)	0	12.6	0.049
Alcohol use (%)	0	0.9	0.816
Hormonal contraceptives use (%)	16.0	22.5	0.337
Type of migraine (%)
With aura		44.2
Without aura		48.6
With/without aura		7.2
Migraine characteristics
Time of evolution (months)		16.2 ± 12.7
Pain intensity (VAS)		8.4 ± 1.7
Frequency (attacks per month)		10.6 ± 8.2
Duration of pain (minutes)		30.6 ± 38.2

Leptin serum levels (15.2 ± 10.5 ng/mL vs. 3.1 ± 0.9 ng/mL; p < 0.001) and adiponectin serum levels (72.3 ± 38.5 µg/mL vs. 37.7 ± 16.9 µg/mL; p < 0.001) were significantly increased in migraine patients compared to healthy controls. Furthermore, leptin serum levels (15.5 ± 9.7 ng/mL vs. 10.8 ± 6.0 ng/mL; p < 0.001) and adiponectin serum levels (65.8 ± 42.9 µg/mL vs. 33.2 ± 31.0 µg/mL; p < 0.001) were also significantly higher in chronic migraine patients compared to episodic migraine patients. However, no differences were observed between patients suffering migraine with or without aura for both leptin serum levels (15.8 ± 11.8 ng/mL vs. 14.4 ± 9.5 ng/mL; p = 0.82) and adiponectin serum levels (67.2 ± 33.2 µg/mL vs. 76.3 ± 9.5 µg/mL; p = 0.49).

On the other hand, we found a positive correlation between serum levels of leptin and BMI (r = 0.445; p < 0.001), whereas the correlation between BMI and serum levels of adiponectin was negative (r = −0.281; p < 0.001) (Figure 1).

Figure 1.

Scatter graphs showing correlation between adipocytokines and BMI.

Regarding clinical characteristics of migraine, leptin serum levels showed positive associations with time of evolution of migraine (r = 0.218; p = 0.023), as well as with frequency of migraine attacks (r = 0.228; p = 0.017). By contrast, adiponectin serum levels did not show a significant correlation with time of evolution of migraine, intensity, frequency or duration of migraine attacks (Table 2).

Table 2.

Correlation between adipocytokines and clinical and molecular markers of migraine.

	Leptin		Adiponectin
	Pearson Co.	p	Pearson Co.	p
Clinical features
Time of evolution	0.218	0.023	0.103	0.288
Intensity of pain	0.185	0.054	0.086	0.377
Frequency of attacks	0.228	0.017	0.162	0.092
Duration of attacks	0.166	0.085	0.108	0.258
Molecular markers of inflammation
IL6	0.498	<0.0001	−0.139	0.510
TNFα	0.389	<0.0001	0.043	0.661
PCRus	0.422	<0.0001	−0.147	0.129
Molecular markers of endothelial dysfunction
PTX3	−0.008	0.931	−0.046	0.632
sTWEAK	−0.046	0.638	0.044	0.649

We also studied the correlation between serum levels of these adipocytokines with those of molecular markers of inflammation (IL-6, TNF-a, hs-CRP) and endothelial dysfunction (PTX3, sTWEAK) (Table 2). Our results show a positive correlation between serum levels of leptin with IL-6 (r = 0.498; p < 0.001), TNF-α (r = 0.389; p < 0.001), and hs-CRP (r = 0.422; p < 0.001) (Figure 2). No correlation was found between adiponectin levels and other molecular markers related to migraine pathophysiology.

Figure 2.

Scatter graphs showing correlation between leptin and molecular markers of inflammation (IL-6, hs-CRP and TNF-α).

Finally, in the logistic regression analysis, leptin levels were independently associated with a diagnosis of migraine after adjustment by several inflammatory markers: IL6 (OR 2.4; 1.2–4.8 95% CI; p = 0.010), TNF-α (OR 2.7; 1.4–4.5 95% CI; p = 0.003); and hs-PCR (OR 2.7; 1.4–5.3 95% CI; p = 0.002).

Discussion

In our sample, migraine patients show increased serum levels of leptin and adiponectin compared with healthy controls. Chronic migraineurs also show increased levels of leptin and adiponectin compared to episodic migraine patients. Leptin levels show a significant correlation with BMI and certain clinical aspects of migraine such as time of evolution and frequency of migraine attacks. Finally, leptin levels are also increased in correlation with biomarkers of inflammation such as IL-6, TNF-α, and hs-PCR. We did not find any correlation between adiponectin levels and other biomarkers.

These results contribute to the existing research around the relation between adipocytokines and migraine. This relation may be explained by inflammation-related mechanisms. Migraine pathophysiology involves several inflammatory molecules such as CGRP (24), substance P (25), VIP (26), cellular adhesion molecules (sICAM-1) (9) and several cytokines (9). Adipose tissue, where adypocitokines are produced, is known to play a role in immunity regulation and inflammatory processes; in fact, adipocytes also produce some of the cytokines involved in migraine pathophysiology and activation of trigeminal endings (9), such as IL-6 and TNF-alpha (8). Moreover, adipose tissue is infiltrated by macrophages, which are also a major source of locally-produced proinflammatory cytokines. Recent research has shown that adipocytokines, produced exclusively by adipocytes, enhance inflammation and vascular hyperactivity in obese patients (27).

However, the exact role played by adipocytokines in migraine pathophysiology remains unclear. Leptin has a role in energy homeostasis, glucose and lipid homeostasis and takes part in inflammation, enhancing both innate and adaptive immune system activity (28). It induces the production of several cytokines, including TNF-α and IL-6 (7), which are also related to migraine. Moreover, leptin acts over several structures involved in migraine pathophysiology: Its receptors are abundantly expressed in the cortex, the arcuate nucleus and dorsomedial hypothalamus (29), both systems involved in pain regulation, as well as in the endothelium of the cerebral microvasculature. Our results agree with previous data showing that migraine patients have higher levels of leptin in peripheral blood and that there is a significant correlation between leptin levels and IL-6, hs-CRP and TNF-α.

Adiponectin also has an important role in energy homeostasis, glucose and lipid homeostasis and inflammation. It exists in different multimers from low to high molecular weight (15). The effects of adiponectin are not so clear, as it exerts dual effects in inflammation and fat tissue regulation. It seems that different oligomers of adiponectin may explain this apparent paradox (16): at normal levels, it has an anti-inflammatory effect, inhibiting IL-6, IL-8 formation and inducing IL-10 and IL-1; at lower levels, adiponectin induces a proinflammatory state, activating the nuclear factor κβ (NFκβ) (30,31). The current hypothesis states that chronic inflammation associated with visceral obesity inhibits production of adiponectin, perpetuating inflammation. Adiponectin also has endocrine effects in vasculature and has recently been reported to be associated with platelet aggregation (17). In our study, we found higher levels of adiponectin in migraineurs, independently of BMI, as were previously found in chronic inflammatory/autoimmune diseases (31). We did not find a significant correlation with other molecules involved in inflammation or endothelial dysfunction, and therefore we cannot suggest an effect of adiponectin in any of these mechanisms.

To date, results regarding levels of adipocytokines in migraineurs have been controversial. A recent review found five manuscripts addressing interictal levels of leptin in migraineurs (15). One study found lower leptin levels in migraine patients during headache-free periods (20), although those differences were not significant after adjusting for body composition. Four studies found no relationship between leptin levels and migraine diagnosis (18,19,21,22); however, in two of them levels of leptin were significantly higher in migraine patients after adjusting for age and BMI (15). There is only one study addressing ictal levels of leptin (32), and it suggests that leptin levels might be inversely correlated with headache intensity. Berilgen et al. (33) found higher levels of leptin in migraine patients, although their study was designed to address leptin changes in relation to preventive medication, and the increase in leptin levels was accompanied by an increase in BMI. One study from Bernecker et al. (34) found increased leptin levels in non-obese female migraineurs and a relation with glucagon-like peptides and insulin. Our results agree with these two studies mentioned, and are backed by certain features: We adjusted leptin levels by BMI, we found a correlation with time of evolution and frequency of migraine attacks, and therefore, with chronic migraine, and we also found a correlation with some inflammatory molecules involved in migraine pathophysiology.

Regarding adiponectin, our results agree with previous research. Adiponectin levels were raised in migraine patients compared to controls in three previous case-control studies (16,17,22). The first of these studies, performed by Peterlin et al. in 2008 (16) compared levels of total adiponectin between chronic migraineurs, episodic migraineurs and headache-free controls. Their results agree with ours, but they also analysed different multimers of adiponectin and found that the increase in total levels was largely due to increases in high molecular weight multimers (HMW) and middle molecular weight multimers (MMW). The study by Duarte et al. (17) found higher levels of adiponectin in migraineurs, but no differences between patients with chronic and episodic migraine. The last study by Dearborn et al. (22) showed only differences for men after adjusting for BMI and plasma glucose levels. Two other groups found no differences in adiponectin levels (18, 19). A recent study (35) showed that these results might depend on the molecular weight of the adiponectin form measured (high molecular weight, middle molecular weight and low molecular weight) (35). In our sample, adiponectin serum levels are higher in migraine patients compared to control subjects and in chronic migraineurs compared to episodic migraineurs. This increase in adiponectin levels with disease severity is an important finding, different from previous studies, which may be due to our larger sample size and suggests a relation between adiponectin and disease progression. We did not find any correlation between adiponectin and other molecules involved in inflammation or endothelial dysfunction.

In conclusion, our study supports the hypothesis that leptin and adiponectin are involved in migraine pathophysiology and chronification, and suggest that their role may be related to enhanced systemic inflammation. However, larger studies are necessary to broaden our knowledge about the relation between fat tissue, adipocytokines and frequency and intensity of migraine attacks.

Our study has several limitations. We did not match patients and controls by age or sex, even though these factors can influence adipocytokine levels (36,37). Leptin levels tend to increase with age in men, and vary in women in relation with reproductive status. Adiponectin levels also differ in men and women and increase with age, specially in men. In our study, patients and controls had similar age and sex distribution, but the fact that we did not control these cofounders could have modified our findings. Similarly, we did not assess levels of oestrogens and did not register the moment at the menstrual cycle when the samples were collected, even though the influence of sexual hormones over leptin levels is well known (38), neither did we address insulin or glucose levels that have been taken in account in previous studies (39). We also did not register the distribution of body fat or the abdominal perimeter, although it has been reported that there is an important correlation between distribution of fat and levels of pro-inflammatory cytokines (40). Regarding adiponectin, we did not measure ADP oligomers (high molecular weight, middle molecular weight, and low molecular weight) even if potential different roles of these oligomers in inflammation and migraine pathophysiology have been described (16). Although preventative treatments were allowed during the study, we did not register them or adjust results, which could have given us more information about biomarker levels and response to treatment or could also influence BMI and biomarker levels, as was seen in previous studies (41,42). We did not control some comorbidities of migraine that may influence levels of adiponectin, such as anxiety or depression. Regarding healthy control recruitment, some of them were selected among patient family members, so they may have undiagnosed migraine or migraine features that could have possibly modified some of the current findings.

Clinical implications

Migraine patients show increased serum levels of leptin and adiponectin compared with healthy controls.

Leptin and adiponectin levels are higher in chronic migraineurs compared to episodic migraineurs.

Leptin levels show a significant correlation with BMI and clinical aspects of migraine such as time of evolution and frequency of migraine attacks.

Leptin levels are increased in correlation with biomarkers of inflammation such as IL-6, TNF-α, and hs-PCR.

Leptin and adiponectin are involved in migraine pathophysiology and chronification, and their role may be related to enhanced systemic inflammation.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project has been partially supported by grants from the Spanish Ministry of Economy and Competitiveness – Instituto de Salud Carlos III (PI13/00292; PI14/01879; PI15/01578 and the Spanish Research Network on Cerebrovascular Diseases RETICS-INVICTUS (RD12/0014)), Xunta de Galicia (Consellería Educación GRC2014/027) and the European Union program FEDER. Finally, F. Campos (CP14/00154) and T. Sobrino (CP12/03121) are recipients of a research contract from Miguel Servet Program of Instituto de Salud Carlos III, and A Vieites-Prado is the recipient of a Fellowship (FPI) from the Spanish Ministry of Economy and Competitiveness (BES-2012-056027). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Role of adipocytokines in the pathophysiology of migraine: A cross-sectional study

Abstract

Background

Objective

Methods

Results

Conclusions

Keywords

Introduction

Patients and methods

Statistical analysis

Results

Discussion

Clinical implications

Footnotes

Declaration of conflicting interests

Funding

References