The Role of Adiponectin in Migraine
B. Lee Peterlin, DO
Assistant Professor of Neurology and
Assistant Professor of Pharmacology & Physiology
Director DUCOM Headache Clinic
Drexel University College of Medicine
The opinions contained within this commentary are solely those of B. Lee Peterlin, DO and are not supported or endorsed by MediCom Worldwide, Inc. or Endo Pharmaceuticals.
Migraine is a common neurovascular disorder. Although the full pathophysiology underlying migraine has not been fully defined, recent data suggests a link to feeding and adipose tissue. Adipose tissue is an active participant in physiological and pathological processes associated with insulin sensitivity, immunity, atherosclerosis, and inflammation. Centrally, the role and function of feeding and adipose tissue is modulated by the hypothalamus, a structure also shown to be activated during acute migraine attacks. Peripherally, adipose tissue has been shown to secrete or modulate several proinflammatory cytokines and adipocytokines, which are involved in feeding and play a role in inflammation. This review will focus on one such adipocytokine, adiponectin, and its link to migraine pathophysiology.
Adipose tissue is an active participant in physiological and pathological processes associated with insulin sensitivity, immunity, atherosclerosis, and inflammation. Centrally, the role and function of feeding and adipose tissue is modulated by the system involving the arcuate nucleus of the hypothalamus and its connections. Peripherally, adipose tissue has been shown to secrete or modulate several proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, as well as adipocytokines, which are involved in feeding as well as play a role in inflammation. Recent research has linked one such adipocytokine, adiponectin, to migraine.[4,5] This review will discuss the peripheral and central mechanism of adiponectin in inflammation and its link to migraine.
The Peripheral Mechanisms of Adiponectin and Migraine
The Basics of Adiponectin
Adiponectin (ADP) is a multifunctional protein which plays a role in energy homeostasis, modulates inflammatory properties, and has protective roles against the development of insulin resistance, dyslipidemia, and atherosclerosis. It was discovered in 1995 by Scherer, et al., and independently cloned by three other groups in 1996.[6-9] Structurally, ADP is a serum protein which belongs to the complement 1q family; and it is also a structural homologue of the TNF family of cytokines.[10,11] ADP is primarily secreted by adipocytes, although the placenta, cardiomyocytes, and hepatocytes do as well.12-14 It is the adipocytokines found in highest concentration in the circulation.12 Plasma levels have been reported to range from 1.9-30 mcg/ml, with levels being higher in the lean as compared to the obese, and in females as compared to males.[11,15,16] Animal data support brain transport of ADP from the circulation. And cerebrospinal fluid (CSF) concentrations of ADP have been reported to be 1-4% of that in the serum.
ADP can exist as a full-length or smaller, globular fragment or as one of several characteristic units including trimers, hexamers, and high molecular weight multimers. The basic unit of adiponectin is the trimer or low molecular weight (LMW) adiponectin. Middle molecular weight (MMW) adiponectin is a hexamer, composed of two trimers; and MMW is the building block to compose high molecular weight (HMW) adiponectin.[4,10]
The different units of adiponectin appear to activate different pathways and have distinct functions. Human globular adiponectin (gADP) activates the proinflammatory nuclear factor kappa β (NF-κβ) pathways as well as induces the secretion of nitric oxide and the proinflammatory cytokines, IL-6 and TNF-α. Similarly, it has been reported that HMW and MMW adiponectin activate the proinflammatory NF-κβ pathways and that in addition to being the most active form in causing depression of blood glucose levels, HMW adiponectin induces the secretion of IL-6. In contrast, LMW adiponectin can inhibit endotoxin-mediated release of IL-6.
Adiponectin in Migraine
Abnormalities in cytokine levels have been noted in the blood of migraine sufferers. Specifically, NF-κβ and the proinflammatory cytokines, TNF-α, IL-1β, and IL-6, have all been shown to be increased ictally in the serum of episodic migraineurs (EM) taken from the internal jugular vein.[20,21]
Given that NF-κβ and similar proinflammatory cytokines which are modulated by adiponectin are increased in migraine sufferers during acute attacks, our lab evaluated the serum levels of adiponectin in migraine sufferers. As both sex and race have been shown to effect adipose tissue distribution and quantity, we limited our participants to Caucasian women who were matched based on age and total body obesity, as estimated utilizing body mass index (BMI). A total of 37 normotensive, nondiabetic participants were included and divided into three groups. Group 1 consisted of chronic daily headache (CDH) participants who fulfilled ICDH-2 criteria for probable medication overuse headache (MOH) or chronic migraine (CM). Group 2 consisted of episodic migraineurs with or without aura. Group 3 consisted of healthy women without pain. All participants had body mass indices (including BMI, waist to hip ratio [WHR]) and serum adiponectin levels measured.
Although the women were BMI matched, the percentage of CDH sufferers with abdominal obesity, (based on a WHR > 0.85) was greater as compared to the episodic migraineurs and controls. And after adjusting for WHR, serum T-ADP levels were significantly higher in CDH sufferers (10.1±4.0 mcg/ml) than in both EM (8.6±3.5 mcg/ml) and controls (7.5±2.4 mcg/ml), P=.024. In addition, HMW-ADP was higher in CDH (6.1±2.8 mcg/ml) as compared to EM (4.2±1.7 mcg/ml) and controls (3.9±1.5 mcg/ml), P=.003. MMW-ADP was also higher in CDH (2.0±1.2 mcg/ml) as compared to EM (1.5±0.7 mcg/ml) and controls (1.1±0.4 mcg/ml), P=.009. However no significant difference was found for LMW-ADP.
Our findings support that it is predominantly the HMW adiponectin unit that is responsible for the increase in T-ADP seen in the CDH sufferers and the trend toward elevation seen in the episodic migraineurs. This is also consistent with data showing that HMW adiponectin activates the NF-κβ pathways and increases IL-6, and that NF-κβ and IL-6 are increased during acute migraine attacks. Given these results, it is possible that adiponectin, and more specifically HMW adiponectin, could serve as a biomarker for chronic daily headache. However, given the small sample size, it is also possible that adiponectin is elevated in episodic migraineurs as well. Larger studies are needed to help determine this.
It is also important to note that by puberty, adult females have higher T-ADP and HMW-ADP levels than males. And in parallel with the puberty-related increases in T-ADP and HMW-ADP, migraine occurs in three times as many women as men following puberty. In addition, menstrually related migraine has been shown to occur at the time in the menstrual cycle when estrogen levels are significantly declining, ie, two days before to three days after the onset of menses. As estrogen has been shown to suppress adiponectin, it would suggest that adiponectin may significantly rise at this time and contribute to neurogenic inflammation through stimulation of NF-κβ pathways and release of cytokines. In addition to estrogen, testosterone also modulates adiponectin levels. And testosterone replacement (which would cause a decrease in serum adiponectin levels) in refractory, male cluster headache sufferers, has been shown to effectively resolve headache. Thus, larger studies which control for sex hormones and evaluate all the units of adiponectin are needed.
The Hypothalamus, Adiponectin and Migraine
In addition to their peripheral link, migraine and adiponectin may also be linked centrally through the hypothalamus. Adiponectin receptor (AdipoR)-1 and AdipoR2 are two receptors for adiponectin which have been identified and shown to be expressed in the hypothalamus as well as adipose tissue.28 While AdipoR1 is expressed diffusely in both the anterior and posterior hypothalamus, AdipoR2 has been shown to be concentrated in the paraventricular nucleus of the hypothalamus. Consistent with their expression in the hypothalamus, both receptors have been shown to exhibit a circadian periodicity, with the lowest synthesis occurring between 8 PM and 6 AM. In addition, fasting and obesity are associated with a reduction in their expression, while treatment with insulin restores expression in fasting hypoinsulinemic mice.
It is possible that adiponectin receptors may be altered during migraine attacks, as both functional imaging and clinical observations support hypothalamic involvement in migraine. In addition to activation of various brainstem regions, including the periaqueductal grey region (PAG), positron emission tomography of spontaneous migraine attacks in humans have shown activation of the hypothalamus.[30-32] And the PAG region has extensive connections with the hypothalamus in addition to modulating the trigeminal nociceptive system. Finally, hypothalamic activation during migraine attacks has long been supported by clinical observations of premonitory symptoms in migraineurs, which are attributed to the hypothalamus including changes in alertness, food cravings, mood and sleep disturbances. Future studies evaluating changes of adiponectin receptors utilizing animal modes of chronic migraine may shed further light on the potential involvement of adiponectin receptors in migraine
Adipose tissue is an important endocrine organ modulated centrally by the hypothalamus and its connection and which peripherally produces several cytokines as well as adipocytokines, such as adiponectin. The knowledge of the various mechanisms that regulate the different functions of adiponectin and its receptors may broaden both our understanding of disease states and our potential therapeutic options for a variety of medical disorders. Specifically, the modulation of adiponectin may affect not just obesity and diabetes, but also migraine and other pain syndromes. Future research focusing on how and why adiponectin and its receptors are altered during migraine attacks may provide further insight into the pathophysiology of migraine, as well as to help uncover adiponectin’s utility as a possible biomarker or therapeutic drug target for migraine.
Glossary of Terms
ADP = adiponectin
AdipoR = adiponectin receptor
BMI = body mass index
CDH = chronic daily headache
CM = chronic migraine
CSF = cerebrospinal fluid
EM = episodic migraineurs
gADP = globular adiponectin
HMW-ADP = high molecular weight adiponectin
IL = interleukin
LMW-ADP = low molecular weight adiponectin
MOH = medication overuse headache
MMW-ADP = middle molecular weight adiponectin
NF-κβ= nuclear factor kappa B
TNF-α = tumor necrosis factor alpha
WHR = waist to hip ratio
Competing Interests Statement
Dr. Peterlin has applied for a patent in regards to the use of adiponectin in headaches.
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Address all correspondence to B. Lee Peterlin, DO, 245 N. 15th Street MS 423, Philadelphia, PA 19102,
The Role of Adiponectin in Migraine
provided by RS Widmer
How do we interpret these study results for use in the clinical environment?
Although obesity is not a direct risk factor for migraine, it has been linked to increased frequency and severity of migraine. Recent advances in obesity research have led to the recognition that adipose tissue functions not only as an energy storage medium, a thermal regulator and insulator, but also as an active endocrine organ.
White abdominal fat secretes a host of bioactive protein signaling agents, collectively termed adipokines, and other chemical messengers and bioactivators such as sex steroids (ie, estradiol) and other hormones. It also expresses receptors for most of these substances, contributing to the potential of protective or injurious anatomical and/or physiologic effects. Obesity contributes to dysregulation of these chemical messengers, associated receptors, and bioactive proteins; and therefore, obesity may be considered an independent endocrine disease.4] As Dr. Peterlin’s commentary states, data reported from a study that looked at adiponectin revealed a suggested connection between this protein and increased occurrence of chronic daily headache in obese Caucasian women. Obesity is considered a risk factor for chronic daily headache in women.
These findings are important clinically, as implementation of a weight-reduction program in this population may help to reduce chronic daily headache and possibly minimize frequency and severity of migraine attacks. Successful weight loss and weight control elicits a lower body mass index (BMI), and this result has also been reported as beneficial in reducing the risk of diabetes, non-alcoholic fatty liver disease, cardiovascular disease, and other hypoxic and inflammatory-based disease processes.6 Diagnosis and effective management of obesity may be considered important measures in the effective comprehensive management of chronic daily headache and migraine.
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