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Abstract

Migraine is a common disorder, characterized by recurrent episodes of headache and associated symptoms. The full pathophysiology of migraine is incompletely delineated. Current theories suggest that it is a neurovascular disorder involving cortical depression, neurogenic inflammation and vasodilation. Various neuropeptides and cytokines have been implicated in the pathophysiology of migraine including calcitonin gene-related peptide, interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-α. There is evidence demonstrating an association between migraine and processes associated with inflammation, atherosclerosis, immunity and insulin sensitivity. Similarly, adiponectin, an adipocytokine secreted by adipose tissue, has protective roles against the development of insulin resistance, dyslipidaemia and atherosclerosis and exhibits anti-inflammatory properties. The anti-inflammatory activities of adiponectin include inhibition of IL-6 and TNF-induced IL-8 formation, as well as induction of the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. Adiponectin levels are also inversely correlated with C-reactive protein (CRP), TNF-α and IL-6 levels. Likewise, recent studies have shown a possible correlation between CRP, TNF-α and IL-6 and migraine attacks. In addition, insulin sensitivity is impaired in migraine and obesity is a risk factor for the transformation from episodic to chronic migraine. In this review we discuss the basic science of adiponectin and its potential connection to the pathophysiology of migraine. Future research may focus on how adiponectin levels are potentially altered during migraine attacks, and how that information can be potentially translated into migraine therapy.

Keywords

Adiponectin cytokines headache migraine

Introduction

Migraine is a common, chronic disorder, which presents with recurrent episodes of disabling headache, affecting approximately 12% of American adults (1). Although our understanding of migraine pathophysiology has dramatically improved over the past 15 years, the full picture has not been delineated (2). Current theories suggest that migraine is a neurovascular disorder.

Although it is not clear if the first neurological event giving rise to migraine is from brainstem activation or cortical spreading depression, the pain of migraine is a result of neurogenic inflammation and consequent meningeal vasodilation (3). Neurogenic inflammation may be a result of a release of inflammatory neuropeptides from nerve endings in the activated trigeminal system, ultimately resulting in vasodilation, plasma extravasation and mast cell degranulation (4, 5).

Various neuropeptides and cytokines have been implicated in the pathway resulting in neurogenic inflammation, including calcitonin gene-related peptide (CGRP), substance P, neurokinin A, interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-α (4). In addition, new and accumulating data demonstrate active participation of adipose tissue in physiological and pathological processes associated with immunity, inflammation and insulin sensitivity.

Adipose tissue produces chemokines and cytokines as well as adipocytokines such as leptin, resistin and adiponectin. Adiponectin is an adipocytokine that plays a role in energy homeostatsis, has protective roles against the development of insulin resistance and atherosclerosis and exhibits anti-inflammatory proporties (6–8). We speculate that a sustained elevated level of adiponectin is a potential protective component in the inflammatory cascade resulting in migraine or other types of headache. Since insulin sensitivity is impaired in migraine, since insulin resistance is linked to obesity and since obesity is a major risk factor for migraine transformation from episodic to chronic, adiponectin could manifest a preventive effect in migraine pathological progression. In this review, we will first briefly describe the basic science of adiponectin and its receptors. We will then discuss the potential influence of adiponectin on nociception and how adiponectin may be connected to the pathophysiology of migraine.

The basics of adiponectin

Adiponectin [also called adipocyte complement-related protein of 30 kDa (ACRP 30) and AdipoQ] is a recently discovered serum protein, composing approximately 0.01% of total plasma protein (8, 9). Of the known adipocytokines, adiponectin is that found in highest concentration in the circulation (6). Adiponectin structurally belongs to the complement 1q family and is also a structural homologue of the TNF-α family of cytokines (8, 10). It is primarily secreted by adipocytes (6).

Plasma adiponectin can exist as either full-length or a small fragment, globular adiponectin (gADP). However, almost all plasma adiponectin appears as a full-length form (8). In addition, several studies have shown that several characteristic units or multimers are present in both humans and mice, including trimers, hexamers and high-molecular-weight multimers of adiponectin. The trimer or low-molecular-weight adiponectin (LMW-ADP) is the basic unit of multimeric adiponectin. In addition, there is middle-molecular-weight (MMW)-ADP, which is a hexamer, composed of two trimers, and the hexamer, high-molecular-weight (HMW)-ADP, which is composed of MMW-ADP (11, 12) (see Fig. 1).

Figure 1

Structure of adiponectin. The basic unit is the trimer or low-molecular-weight (LMW) adiponectin. Trimers are connected by disulphide bonds at the amino terminus to form medium-molecular-weight (MMW) hexamers of adiponectin, which combine to form high-molecular-weight (HMW) multimers of adiponectin. Adapted with permission from reference 12.

The different units of adiponectin appear to activate different pathways and have distinct functions. Waki et al. have reported that HMW-ADP activates protein kinase in hepatocytes (12), However, in contrast, Tsao et al. have reported that only LMW-ADP activates the protein kinase pathways in muscle tissue and that only HMW- and MMW-ADP activate nuclear factor (NF)-κB pathways (13).

Functionally, only HMW-ADP suppresses endothelial cell apoptosis (14). It is also the most active form in causing depression of blood glucose levels in mice; it has also been proposed that it is the ratio of HMW-ADP to total adiponectin that determines insulin sensitivity in humans and rodents (15). In addition, Neumeier et al. have shown that while HMW-ADP induces the secretion of IL-6 in human monocytes, LMW-ADP reduces endotoxin-mediated IL-6 release in human monocytes and stimulates secretion of the anti-inflammatory cytokine, IL-10 (16).

Similarly to HMW-ADP, Tsatsanis et al. have shown that gADP can induce IL-6 secretion as well as TNF-α in human macrophages. However, they also showed that exposure to gADP induces self-tolerance to re-exposure to gADP, as well as tolerance to endotoxin. When the initial exposure was to low-dose gADP, followed by re-exposure to high doses of gADP, stimulation of TNF-α and IL-6 occurred. However, when the initial exposure was to high doses of gADP, followed by restimulation with high doses of gADP, self-tolerance was induced as well as inhibition of TNF and IL-6 production (17).

Adiponectin receptors

The different forms of adiponectin probably have different modes of action at different receptor subtypes (AdipoR1 and AdipoR2) Adiponectin receptors have been identified in skeletal muscle, the liver and recently in the brain endothelium of mice (8, 18, 19). AdipoR1 is abundantly expressed in skeletal muscle and is a high-affinity receptor for gACRP, while AdipoR2 is predominantly found in the liver and exhibits an intermediate-affinity receptor for both full-length ACRP and gACRP.

The levels of AdipoR1 and AdipoR2 expressed in the liver and skeletal muscle increased after fasting in mice rendered hypoinsulinaemic and were restored to those equal to the fed state after refeeding as well as after insulin treatment. Thus, insulin may negatively regulate AdipoR1/R2 levels. In addition, obesity decreases the expression of AdipoR1/R2 levels, causing adiponectin hyposensitivity and insulin resistance (8).

The pharmacological properties of adiponectin

Plasma adiponectin levels range from 3.0 to 30 µg/ml and there is an inverse relationship between the adiponectin levels and body mass index (BMI) (20,21). Arita et al. have shown that human plasma adiponectin levels in non-obese subjects range from 1.9 to 17 µg/ml, and while non-obese subjects have a mean adiponectin level of 8.9 µg/ml, obese subjects have a mean of 3.7 µg/ml (21).

Cerebrospinal fluid (CSF) concentrations of adiponectin have been reported to be 1–4% of that in the serum. Although it is not entirely clear if adiponectin can cross the blood–brain barrier, there is evidence suggesting mammalian adiponectin can. Qi et al. have shown that intravenous injections of mammalian adiponectin in mice are associated with a rise in CSF adiponectin, which is consistent with brain transport from the circulation (22). However, Spranger et al. and Pan et al. evaluated the ability of globular ADP to cross the blood–brain barrier and determined it could not (18, 23). The differences in these studies may be explained by the different forms of adiponectin which were used. While Qi et al. used mammalian adiponectin, Spranger and Pan used bacterially produced globular adiponectin. (Globular adiponectin is the head of full-length ADP.) It has also been reported that adiponectin produced in mammalian cells is much more potent than bacterially generated adiponectin in enhancing subphysiological concentrations of insulin (24). Thus, it is possible there are also other physiological differences between mammalian and bacterial produced adiponectin. In addition, it is not certain whether the HMW, MMW, LMW units may show evidence of brain transportation from the circulation.

The half-life (T½) of adiponectin has been studied by injecting human adiponectin into rabbits and the T½ of adiponectin appears to be about 14 h. HMW-ADP showed a T½ of 13 h while LMW-ADP had a T½ of 17.5 h (25).

Adiponectin and cytokines

It is still not known whether adiponectin is in fact an anti-inflammatory hormone or merely a modulator of innate immunity. However, it is known that adiponectin modulates several cytokines (26). Proinflammatory cytokines such as IL-1, IL-6, IL-8, and TNF are predominantly produced by activated immune cells and are involved in amplification of the inflammatory response. Anti-inflammatory cytokines such as IL-1 receptor antagonist (RA) and IL-10 are involved in reduction of the inflammatory response. In addition, IL-1β, IL-6 and TNF can indirectly induce hyperalgesia through release of prostaglandins and thromboxanes, modulation of sympathetic fibres or increasing nerve growth factor and bradykinin receptors (27).

The anti-inflammatory activities of adiponectin include inhibition of IL-6 and TNF-induced IL-8 formation, as well as induction of the anti-inflammatory cytokines, IL-10 and IL-1RA. Adiponectin also strongly inhibits the expression of vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1 and E-selectin, resulting in suppression of monocyte and platelet adherence to the endothelium and, ultimately, the inhibition of pro-atherogenic processes (6, 19, 20).

Adiponectin, TNF, IL-6 and headache

Adiponectin has been shown to reduce secretion of IL-6 from brain endothelial cells, as well as to down-regulate production and activity of TNF in mice (18, 28) (see Fig. 2). Both, IL-6 and TNF are proinflammatory cytokines, which have been implicated in the pathogenesis of insulin resistance, obesity, coronary artery disease (CAD) and possibly migraine (28–32).

Figure 2

Adiponectin's role in the inflammatory cascade. Adiponectin and tumour necrosis factor (TNF)-α mutually inhibit each other's production in adipose tissue. In addition, adiponectin inhibits TNF-α-induced monocyte attachment and endothelial adhesion, TNF-α expression in macrophages and smooth muscle cell (SMC) proliferation. Expression of adiponectin is suppressed by interleukin (IL)-6. C-reactive protein (CRP) is negatively regulated adiponectin. NF-κB, Nuclear factor kappa beta; VCAM-1, vascular cell adhesion molecule-1. Adapted with permission from reference 20.

Empl et al. analysed TNF-α, its antagonistic soluble receptor (sTNF-RI), as well as IL-6 and its soluble receptor (sIL-6R) in 27 migraine patients compared with eight controls. No differences in IL-6 or TNF-α concentrations were found. However, migraine patients tended to have less sTNF-RI than controls. The authors suggested that if TNF-α plays a role in migraine pathophysiology, migraine patients may lack sufficient antagonistic sTNF-RI to neutralize the hyperalgesia TNF-α could cause during a migraine attack (33).

Empl et al. have also noted that the failure to detect an elevation of TNF-α or IL-6 during migraine attacks in their study could be related to the short half-life of these cytokines. As the concentrations were measured from the antecubital vein, the serum samples may have reflected a dilution effect, not the local process of these short-lived cytokines. In fact, such a dilution effect has been seen with CGRP and could be shown only if samples were collected from the jugular vein (32–34).

More recently, Sarchielli et al. studied the levels of soluble adhesion molecules sL- and sE-selectins, soluble ICAM-1 and VCAM-1 along with TNF, IL-1 and IL-6 levels, in the internal jugular venous blood in seven migraine patients without aura during attacks. A transitory increase in the levels of TNF and IL-6 were observed in the migraine patients and both peaked at 1 h from catheter insertion and then progressively decreased towards baseline levels. IL-1 also showed a slight increase from 1 to 4 h, then decreased to levels similar to those measured at the time of catheter insertion. However, this just reached statistical significance. ICAM-1 levels showed a transient increase at 2 h after onset of migraine attack and then reduced progressively and were lower at termination than those levels measured at onset. No significant variations were observed in the levels of the selectins and VCAM-1. It is possible that baseline levels of adiponectin were low in these migraineurs and a proinflammatory stimulus resulted in a rise of adiponectin levels and the subsequent rise of TNF and IL-6 (32).

Adiponectin, headache and IL-8

Similar to IL-6 and TNF, adiponectin has been shown to inhibit IL-8 generation. It does so through inhibition of NF-κB (a proinflammatory transcription factor) and through activation of PI3K, a cell survival pathway (9). IL-8 possess proinflammatory as well as tumorigenic and proatherogenic properties (6). Circulating levels of IL-8 are increased in patients with acute myocardial infarction, promoting neutrophil infiltration and inflammation (6, 35). Similarly, patients with migraine have a higher cardiovascular risk profile and are at an increased risk for early-onset ischaemic stroke (36, 37). The mechanism for this higher cardiovascular risk profile and increased risk of stroke in migraineurs has not been fully elicited. It is possible that adiponectin may play a beneficial role in cereberovascular risk reduction as with CAD, through its inhibition of IL-8.

Adiponectin, headache and IL-1 and IL-10

Unlike IL-8, IL-10 and IL-1RA have anti-inflammatory properties. In addition, IL-10 enhances the production of IL-1RA and inhibits synthesis of IL-6. Wolf et al. have shown that adiponectin induces the expression of IL-10 and IL-1RA in human monocytes, monocyte-derived macrophages and dendritic cells. In addition, in endotoxin-stimulated cells, the production of IL-10 is further enhanced by adiponectin, whereas IL-1 is decreased (19, 38).

Munno et al. studied the levels of IL-4, IL-5 and IL-10 in 10 migraine patients before and after treatment with sumatriptan and found a decrease in IL-10 plasma levels after treatment. They suggested that perhaps IL-10 is increased during migraine attacks to counteract the effects of some cytokines, and that after treatment with sumatriptan it reverts to the cytokine profiles observed during the interictal period (38, 39). This suggestion would be consistent with adiponectin's role in inducing IL-10, if adiponectin has both a negative role in generating headache (such as from significant changes in the magnitude of adiponectin levels) and a protective role (such as from sustained elevated levels.) This hypothesis will be discussed further under adiponectin, sex hormones and headache.

Adiponectin, nitric oxide and headache

Not only cytokines are modulated by adiponectin—it also influences control over other molecules, such as nitric oxide (NO). Both full-length and gADP have been found to enhance NO production (40). NO has also been implicated in migraine genesis and acts by increasing guonosine monophosphate (GMP). Headache is a well recognized side-effect of medications which are NO donors such as nitrogylcerine (41); and NO synthase inhibitors effectively improve spontaneous migraine headaches (42). However, although migraine patients exposed to glyceryl trinitrate (GTN) immediately developed a mild to moderate headache, a 5–6-h delay occurs before a characteristic migraine attack develops. The long latency period between GTN and a fully developed migraine attack indicates that activation of NO or the steps in the NO–cGMP cascade initiate a slow or indirect process that results in a migraine attack (43). Nitroglycerin infusion in a rat meningeal inflammation model has been shown to cause expression of IL-1β and IL-6 with a delayed expression of inducible nitric oxide synthase (iNOS) (44). Furthermore, Sildenafil (a cGMP-hydrolysing phosphodiesterase 5 inhibitor), which acts further along the NO–cGMP cascade by increasing cGMP, has been show to induce migraine without detectable effects on the middle cerebral artery (45). This indicates that NO itself may not be necessary to induce migraine, but a cGMP-dependent mechanism may be implicated (43).

In addition, a recent study has suggested that NO can either increase or decrease the mechanical responsiveness of nociceptors and that the action of NO might depend on baseline neuronal excitablity (46). This suggests that both NO and adiponectin have the potential to be inhibitory or stimulatory with regard to headache generation. Although the role of NO in nociception is not straight forward, the association between NO with headache and the tie of NO to adiponectin suggests that NO and migraine could be linked through adiponectin or its modulation.

Adiponectin and headache: potentially shared genetic mechanisms

In addition to the above potential shared pathophysiological components, there are also potential genetic similarities between adiponectin and headache. The adiponectin gene has been shown to be located on chromosome 3q27 (47), while AdipoR1 is located at chromosome 1p36.13-q41 and 1E4 and AdipoR2 at chromosome 12p13.31 and 6F1 (48). Although familial hemiplegic migraine (FHM) has been most notably linked to chromosome 19p13, FHM-2, as with AdipoR1, has been mapped to chromosome 1. Specifically, in about 20% of FHM families FHM-2 has been mapped to chromo1q21-q23. In addition, 30% of FHM remains unlinked to either chromosome 1 or 19 (49). It is possible that if at least one chromosome is shared between FHM and an adiponectin receptor, others could be shared.

Another potential for a shared genetic basis between adiponectin and migraine is through the insulin receptor gene (INSR). McCarthy et al. analysed 16 families for cosegregation of migraine with aura and chromosome 19p13 markers. They found five single-nucleotide polymorphism alleles in the INSR associated with migraine (50). As diabetics have been shown to have a higher relative frequency of migraine than non-diabetics (51) and adiponectin has been shown to modulate insulin sensitivity, there is potential for an association between adiponectin and migraine through the INSR, in addition to the potential association with chromosome 1.

Adiponectin, headache and prolactin

Migraine and adiponectin have both been associated with changes in several hormones, including prolactin. Nilsson et al. have shown that adiponectin secretion in human adipose tissue is reduced by prolactin (PRL) (52). Although female migraineurs have normal PRL levels in all phases of the menstrual cycle, their response to exogenous thyrotropin-releasing hormone (TRH) is enhanced during a migraine attack (53, 54). Furthermore, women with menstrual migraine show an enhanced PRL release by dopamine antagonists (55, 56). As inhibition of PRL release by l-dopa is less marked in migraineurs, these responses cannot be accounted for by dopaminergic receptor supersensitivity. It is possible that these associations are due to the modulation of adiponectin (57, 58).

Adiponectin, headache and sex hormones

Both migraine and adiponectin are modulated by sex hormones and exhibit a sexual dimorphism. Prior to puberty migraine prevalence is slightly greater in boys than in girls. However, migraine prevalence then increases more rapidly in girls than in boys in adolescence and by adulthood is three times greater in women than in men, with the 1-year prevalence of migraine in women being 18% and 6.5% in men. After 40, migraine prevalence then declines (1, 59).

As with migraine, total adiponectin levels and HMW-ADP levels have been shown to be higher in females than in males. It is during puberty that the magnitude of total adiponectin increases in females to levels that are much higher than in males. However, females have a relatively lower percentage composition of MMW- and LMW-ADP than males (see Fig. 3). Thus the sexual dimorphism appears to be due primarily to the difference in HMW-ADP levels (11).

Figure 3

Sexual dimorphism of adiponectin with regard to the percentage composition of its different units vs. the total adiponectin (∗P < 0.05) and vs. males (∗∗P < 0.01). Adapated with permission from reference 11. ▪, Male; □, female.

Testosterone treatment has been shown to decrease total adiponectin and, specifically, HMW-ADP but not MMW- or LMW-ADP in humans (11). Lower levels of testosterone have been also associated with cluster headache in the early morning as well as during an acute cluster period (60–62). Furthermore, Stillman recently showed that a subgroup of cluster patients with low testosterone levels had a significant therapeutic response to testosterone replacement (62). As testosterone suppresses total and HMW-ADP, this suggests that adiponectin levels may be lower prior to onset of a cluster attack and are increased during an attack.

Similar to testosterone, oestrogen has been shown to suppress adiponectin in mice. In addition, oestrogen reduced adiponectin in late gestation and in lactating mice and increased adiponectin in anovulatory mice (63). Menstrually related migraine (MRM) has been shown to occur at the time of the greatest fluctuation in oestrogen. Furthermore, Somerville has reported that MRM occurs during or after the fall of oestrogen and that supplemental oestrogen delays the onset of headache (64, 65). Thus, if oestrogen suppresses adiponectin, in the early luteal phase oestrogen levels would be elevated and adiponectin levels low; and, in the late luteal phase, when MRM is most likely to occur, it would be expected that oestrogen levels would decline and adiponectin levels increase. This would correlate with the study by Tsatsanis showing that high levels of adiponectin following exposure to low levels of adiponectin are proinflammatory (17). Similarly, in pregnancy, when levels of oestrogen are continuously elevated without fluctuations, adiponectin levels would not be expected to fluctuate, there would be no proinflammatory response and migraines plummet. Thus, once again, the effects of adiponectin appear to have both positive and negative potential in migraine generation, in this case linked to oestrogen fluctuations.

With advancing age, the levels of oestrogen in women decline (65) and adiponectin levels would be expected to increase. Thus, menopause may be protective against headache for two reasons. First, as with pregnancy, the lack of cyclical fluctuations from low levels to high levels of adiponectin would inhibit the proinflammatory response that would be expected based on the data from Tsantis et al. Second, there is a baseline higher level of adiponectin which exerts anti-inflammatory properties and is potentially protective against headache.

Adiponectin, headache and thyroid dysfunction

As with the sex hormones, adiponectin and migraine are also linked to thyroid-stimulating hormone. Serum adiponectin levels have been shown to be significantly decreased in hypothyroid states compared with hyperthyroid states and correlate positively with both free T4 and free T3 (66). Chronic migraine and new daily persistent headache have also been found to be associated with hypothyroidism (67).

Adiponectin, headache and C-reactive protein

In addition to the modulation of cytokines and hormones, adiponectin has been shown to modulate other acute inflammatory markers, such as C-reactive protein (CRP) (68, 69) (see Fig. 2). CRP, as well as IL-6 and TNF, has been reported to be elevated in obese subjects and individuals at high risk of atherosclerosis (20, 31).

In 2003 Ouchi et al. found that high-sensitivity CRP levels are negatively correlated with plasma adiponectin levels in male patients, with another study finding a similar negative correlation between adiponectin and CRP in women (68, 69). The reciprocal association between adiponectin and CRP levels might regulate the development of atherosclerosis, and alterations in their balance could potentially extend to migraine pathogenesis.

There is also limited evidence suggesting that CRP elevations may be associated with migraine. In a recent retrospective study by Welch et al., elevated high-sensitivity CRP levels were found in 43% of patients with migraine who presented with complex clinical features. In 25% of these patients no other conditions were found that could explain the elevated high-sensitivity CRP levels (70). As the CRP–obesity axis is linked to greater likelihood of migraine progression, it is possible that a part of this association is through adiponectin.

Adiponectin, headache and obesity

In light of the multiple anti-inflammatory cytokines and anti-inflammatory markers that adiponectin modulates, it is not surprising that adiponectin is negatively correlated with obesity. In fact, adiponectin is decreased in obesity and also shows a significant negative correlation with BMI (21). Similarly, an inverse relationship between plasma adioponectin levels and serum triglyceride concentrations has been shown, as well as with adiponectin levels and the presence of CAD or diabetes. Obese diabetic people have been shown to have lower plasma adiponectin levels than non-diabetic obese subjects; and obese diabetic subjects with CAD have even lower plasma levels than obese diabetic people without CAD. Furthermore, weight reduction is associated with significantly elevated plasma adiponectin levels (71).

Obesity has also been identified as a risk factor for headache chronification by Scher et al. (72). In addition, in a recent population-based study, Bigal et al. studied the influence of BMI on the prevalence, attack frequency and clinical features of migraine. Although BMI was not associated with the prevalence of migraine, it was associated with the frequency of headache attacks. In the normal weight group 4.4% had 10–14 headache days per month and this increased to 13.6% of the obese and 20.7% of the morbidly obese. The proportion of subjects with severe headache pain increased with BMI, doubling in the morbidly obese relative to the normally weighted. Furthermore, a similar association was demonstrated with BMI category for disability, photophobia and phonophobia (73). It may be speculated that the influence of obesity on migraine is linked from a biochemical perspective through adiponectin. It is possible that since obesity is associated with lower levels of adiponectin, obese subjects are at greater susceptibility to stimuli which could result in greater changes of adiponectin levels, which may trigger headache. Furthermore, the same stimuli in a non-obese subject, with higher baseline levels of adiponectin, and a smaller delta of change, may not be enough to result in headache.

In a second study, Bigal et al. did not find a significant difference with regard to mean reduction in headache frequency following preventive treatment in different weight groups. However, the reduction of the number of severe headache days was higher in the overweight group compared with the normal weight group, suggesting that obese migraineurs respond better to preventive medication than normal weight patients (74). It is possible this difference would have been even more significant if patients had been separated out based on the class of headache preventive medication used. Specifically, attention to topiramate as used for migraine prevention may be of interest due to the possible weight loss seen with this drug. It is also possible that preventive migraine medications may result in a more significant modulation of adiponectin levels in overweight patients, ultimately resulting in higher sustained levels of adiponectin.

As with obesity, insulin resistance has been shown to be associated with lower serum plasma levels of adiponectin. Furthermore, a recent study by Rainero et al. has shown that insulin sensitivity, independent of obesity, may be impaired in migraineurs. In their study, the insulin sensitivities of 30 non-obese, non-diabetic, normotensive migraine patients were compared with 15 healthy controls with oral glucose tolerance tests. Although fasting-based indices of insulin sensitivity were not significantly different between migraineurs and controls, all of the oral glucose tolerance test-derived data showed a condition of insulin resistance in migraineurs (75). This is consistent with the hypothesis that adiponectin levels are lower in migraineurs than in controls.

In contrast to the negative correlation with obesity and insulin resistance, weight loss, caloric restriction, cold exposure and thiazolidinedione treatment have been shown to increase adiponectin levels. Berg et al. have reported that adiponectin injections transiently decrease plasma glucose levels without increasing plasma insulin concentration in diabetic mice models. The glucose-lowering effect was observed at 4 h after adiponectin injections, with a return to normal levels by 6 h after injection. They also reported that rosiglitazone (a thiazolidinedione used in diabetes) effectively increased adiponectin secretion in vivo in diabetic mice models (10, 76). Based on the above studies, it is possible that a significant adiponectin rise is the stimulus which results in headache in a fasting migraineur (who has baseline lower levels of adiponectin than a non-migraineur) and that sustained elevated levels of adiponectin may inhibit migraine.

Adiponectin, headache and atherogenic processes

Adiponectin may have a role not just in weight maintenance and insulin action, but also in antiatherogenic processes. In 1999, Ouchi et al. demonstrated that an 18-h treatment of human aortic endothelial cells with adiponectin attenuated the induction of adhesion molecule expression by TNF (77). The same group also reported inhibition of phagocytosis and endotoxin induction of TNF production in human macrophages by adiponectin. Furthermore, long-term treatment of human macrophages with adiponectin reduced cholesteryl ester and lipid accumulation (10, 78).

Adiponectin may accelerate fat metabolism. Serum triglyceride levels in adiponectin-treated animals were lower compared with non-treated control animals in one study (76). In a separate study by Yamauchi et al., improved insulin sensitivity and decreased storage of liver and muscle triglycerides in mice were demonstrated with adiponectin treatment. Furthermore, the treatment markedly improved hyperglycaemia, elevated plasma triglyceride and free fatty acid levels (10, 79).

Similarly, there is limited evidence that suggests a decreased dietary fat intake is associated with a decrease in headache frequency. Bic et al. studied 54 migraineurs before and after restricting their diet to 20 g/day of fat. They found a significant reduction in headache frequency and intensity with the decreased dietary fat intervention. However, it is not clear from the article if they adjusted this for weight loss (80).

There are also clinical data to support an association between adiponectin and atherogenic processes. Dzielinska et al. reported that decreased plasma adiponectin levels may be associated with a higher risk of CAD in patients. They showed a significant decrease in plasma adiponectin concentrations in a group of hypertensive men with CAD compared with normotensive healthy subjects (81).

Atherogenic processes have also been associated with migraine. Several studies have suggested a relationship between migraine and stroke, including migraine as a risk factor for stroke, as well as a consequence and cause of stroke (82–84). Although the mechanism of this increased risk of stroke as well as the higher cardiovascular risk profile in migraineurs has not been fully elicited, it is possible that adiponectin modulation through IL-8 induction is involved. Furthermore, it would be consistent with the hypothesis suggesting that baseline levels of adiponectin are lower in migraineurs than in those without migraine.

Adiponectin, headache and circadian rhythms

Although adiponectin levels do not show evidence of a circadian rhythm, Bluher et al. have demonstrated that adiponectin receptors appear to have a circadian rhythm. In their study, both AdipoR1 and AdipoR2 showed the highest synthesis during the daytime between 10.00 h and 18.00 h and a lower gene expression during the night from 20.00 h to 06.00 h (85). Similarly, the greatest frequency of cluster attacks has been shown to occur between 21.00 h and 10.00 h (86).

Mouse studies also suggest a crucial involvement of the melanocortin pathway in the central action of adiponectin (22). This once again suggests a link to headache disorders, as both cluster headache and migraine may exhibit a circadian periodicity; both have also been reported to respond to preventive agents involved in circadian rhythms, such as melatonin (86, 87). Thus, adiponectin could play a role in the circadian periodicity seen in some headache disorders.

Summary

Basics

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Adiponectin is a protein secreted by adipose tissue.

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Full-length adiponectin is composed of different units, which are the HMW, MMW and LMW multimers.

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Mouse studies of adiponectin suggest an involvement of the melanocortin pathway in the central action of adiponectin as well as Fos immunoreactivity in the hypothalamus.

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Adiponectin receptors (AdipoR1/R2) have been identified in muscle, liver and brain endothelium.

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AdipoR1 and FHM have both been mapped to chromosome 1.

Suggestive of adiponectin being proheadache

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Adiponectin gender differences develop during puberty, leading to higher levels in adolescent girls compared with boys. (Migraine is more prevalent in women than in men from adolescence through adulthood.)

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Full-length adiponectin and gADP enhance NO production. (NO has been implicated in migraine pathophysiology.)

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Baseline low levels of gADP, followed by restimulation with proinflammatory stimuli, has been shown to result in a stimulation of TNF and IL-6. (Females have a relatively lower percentage of LMW-ADP than males.)

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Oestrogen and testosterone suppress adiponectin levels in mice. (Oestrogen withdrawal is associated with migraine pathophysiology. Testosterone replacement has been shown to treat cluster headache.)

Suggestive of adiponectin being anti-headache

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Adiponectin induces the anti-inflammatory cytokines, IL-1RA and IL-10. (However, a study found a decrease in IL-10 after acute migraine treatment with a triptan.)

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Adiponectin has been shown to inhibit IL-6, TNF-induced IL-8 formation, VCAM-1, ICAM-1 and E-selectin. (A study has shown a transient increase in IL-6, TNF and ICAM during migraine attacks.)

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Baseline high levels of gADP, stimulated with adiponectin or other cytokines, results in an anti-inflammatory response.

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LMW-ADP reduces IL-6 release and stimulates secretion of IL-10.

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AdipoR1/R2 show a circadian periodicity with lowest synthesis from 20.00 h to 06.00 h. (Migraine and cluster headache have a circadian periodicity. The greatest frequency of cluster headaches has been shown to be between 21.00 h and 10.00 h.)

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Prolactin decreases adiponectin secretion. (Prolactin antagonists have been used to treat migraine.)

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Adiponectin levels decrease with increased hs-CRP levels. (Increased CRP levels have been shown in a subgroup of migraine patients.)

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Adiponectin levels decrease with increasing BMI, insulin resistance and CAD. (Increasing BMI has been shown to be associated with headache frequency.)

Conclusion

The many recent discoveries regarding adipocyte function have helped to elevate the status of adipose tissue from a mere fat storage depot to an important endocrine organ producing several cytokines and hormones, including adiponectin. The knowledge of the various mechanisms that regulate the different functions of adiponectin may broaden both our understanding of disease states and our potential therapeutic options for a variety of medical disorders. Specifically, adiponectin modulation may be involved with not just obesity, diabetes and cardiovascular disorders, but also migraine, other headaches and other pain syndromes. Adiponectin may be both protective and detrimental for headache. Most of the data on adiponectin support the speculation that sustained elevated adiponectin levels are protective and that baseline lower levels of adiponectin, followed by significant rises in adiponectin, may correlate with headache generation. Future research focusing on how and why adiponectin levels are altered during migraine attacks may provide further insight into the pathophysiology of migraine as well as help uncover adiponectin's utility as a possible biomarker or therapeutic drug target for migraine.

Competing interests

B.P. has applied for a patent with regard to the use of adiponectin in headaches.

Acknowledgements

The authors thank Dr Thomas N. Ward and Jeffrey Lidicker for their invaluable advice and support.

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Migraine and Adiponectin: Is There a Connection?

Abstract

Keywords

Introduction

The basics of adiponectin

Adiponectin receptors

The pharmacological properties of adiponectin

Adiponectin and cytokines

Adiponectin, TNF, IL-6 and headache

Adiponectin, headache and IL-8

Adiponectin, headache and IL-1 and IL-10

Adiponectin, nitric oxide and headache

Adiponectin and headache: potentially shared genetic mechanisms

Adiponectin, headache and prolactin

Adiponectin, headache and sex hormones

Adiponectin, headache and thyroid dysfunction

Adiponectin, headache and C-reactive protein

Adiponectin, headache and obesity

Adiponectin, headache and atherogenic processes

Adiponectin, headache and circadian rhythms

Summary

Basics

Suggestive of adiponectin being proheadache

Suggestive of adiponectin being anti-headache

Conclusion

Competing interests

Acknowledgements

References