Obesity, migraine, and chronic migraine : Possible mechanisms of

interaction
Marcelo E. Bigal, Richard B. Lipton, Philip R. Holland, et al.
Neurology 2007;68;1851
DOI 10.1212/01.wnl.0000262045.11646.b1

This information is current as of August 4, 2012

The online version of this article, along with updated information and services, is
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously
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VIEWS & REVIEWS

Obesity, migraine, and chronic migraine

Possible mechanisms of interaction

Marcelo E. Bigal, MD, ABSTRACT Migraine and obesity are associated in several ways. First, both are prevalent and dis-
PhD abling disorders influenced by genetic and environmental risk factors. Second, migraine with aura, as
Richard B. Lipton, MD obesity, seems to be a risk factor for cardiovascular events. Finally, large population-based studies
Philip R. Holland, PhD suggest that obesity is a risk factor for chronic migraine after adjusting for comorbidities. In this
Peter J. Goadsby, MD, article, we discuss plausible mechanisms that may account for this association. Several of the inflam-
PhD matory mediators that are increased in obese individuals are important in migraine pathophysiology,
including interleukins and calcitonin gene-related peptide (CGRP). These mediators may increase the
Address correspondence and
reprint requests to Dr. Marcelo frequency, severity, and duration of migraine attacks per se, which in turn would cause central sensi-
E. Bigal, Albert Einstein College tization. Repeated central sensitization may be associated with permanent neuronal damage close to
of Medicine, 1300 Morris Park
Avenue, Rousso Bldg., Room
the periaqueductal gray area, with poor modulation to pain. Obesity is also a state of sympathetic
330, Bronx, NY 10461 activation, which may contribute to increase in headache frequency. Furthermore, the levels of adi-
mbigal@aecom.yu.edu
ponectin are decreased in obesity. At low but not normal levels, adiponectin is nociceptive. Shared
biologic predisposition may also play a major role. Orexins modulate both pain and metabolism. Dys-
function in the orexins pathways seems to be a risk factor for both conditions. Finally, conditions that
are comorbid to both states (e.g., depression, sleep apnea) may also make the relationship between
both diseases more complex. NEUROLOGY 2007;68:1851–1861

Headache and obesity are prevalent and disabling disorders influenced by genetic and environmental risk
factors.1,2 A longitudinal population study showed that persons with episodic headache and obesity develop
chronic daily headache (CDH) at more than five times the rate of normal weighted individuals.3 Subse-
quently, a large population study confirmed that obesity was a risk factor for CDH, and suggested that this
association occurs primarily with chronic migraine (CM) and not with chronic tension-type headache.4 The
prevalence of episodic migraine, however, does not vary significantly with the body mass index (BMI),
suggesting that obesity is not a risk factor for migraine.5 However, among migraineurs, high BMI was
associated with more frequent headache attacks.5 In the three studies, obesity emerged as an independent
risk factor, after adjustments for several comorbidities and demographic variables.
Identifying factors and mechanisms that contribute to the onset of CDH, particularly to frequent mi-
graine, now referred to as CM,6 has emerged as a priority in headache research. Exploring the links between
headache and obesity may make a substantial contribution to this effort, and in this article we review those
links. We start by highlighting some of the mechanisms of migraine and obesity. We describe the epidemio-
logic association between the two disorders. Then we provide a framework for understanding the linkages
and review overlapping neurochemical mechanisms in both diseases. We stress that many of the putative
mechanisms between frequent headaches and obesity are speculative or supported only by animal studies.
Finally, although we emphasize the biochemical relations between both conditions, we do not want to
suggest that the biobehavioral links are less important. We mention some of these links under the comorbid-
ity section of our article and consider that the behavioral relations between headaches and obesity are
beyond the scope of this article.

MIGRAINE AND CHRONIC MIGRAINE: AN OVERVIEW Migraine is a common and often severe disease
globally.7-11 The burden of migraine impacts affected individuals, their family, and society.12,13 Furthermore,
migraine is a disease that sometimes progresses and CM is the result of migraine progression. The former
nomenclature of CM was transformed migraine (TM), and both, with different criteria, refer to the same

From the Departments of Neurology (M.E.B., R.B.L.) and Epidemiology and Population Health (R.B.L.), Albert Einstein College of Medicine,
Bronx; The Montefiore Headache Center (M.E.B., R.B.L.), Bronx, NY; The New England Center for Headache (M.E.B.), Stamford, CT; and
Headache Group (P.R.H., P.J.G.), Institute of Neurology, Queen Square, London, UK.
Disclosure: Drs. Bigal and Lipton have received research support from Ortho-McNeil Pharmaceutical, Inc., which markets Topamax®, a drug that
can cause weight loss. The remaining authors have nothing to disclose.

Copyright © 2007 by AAN Enterprises, Inc. 1851

 entity. Since some studies used the TM definition 64% of adults are either overweight or obese.26 Obe-
and some studies used the CM definition, herein we sity and its associated health problems have a con-
refer to CM and TM synonymously. In the United siderable economic impact on the health care
States, the prevalence of CM is 2%.14 system, accounting for 9.1% of total US medical ex-
Migraine is best understood as a primary disor- penditures in 1998 and reaching as high as $92.6 bil-
der of the brain1,15,16 with peripheral consequences.17 lion in 2002.29
There is abundant evidence that migraine is a famil- Obesity is comorbid with a number of chronic
ial disorder with genetic foundation.18 Primary pain syndromes. In fibromyalgia, it is associated
brain dysfunction may drive peripheral neurovascu- with increased pain severity and refractoriness to
lar events with consequent activation of the trigemi- treatment, while weight loss is followed by im-
novascular system.17,19,20 proved physical functioning.30 Obesity is also asso-
The first neurologic event of migraine is a point ciated with arthritis, as well as with prevalent and
of controversy and two non-mutually exclusive hy- severe back and neck pain in the population.31
potheses exist. Migraine may result from a dysfunc- Discussing the mechanisms of obesity is beyond
tion of an area of the brainstem that is involved in the scope of this article. Findings that are relevant to
the modulation of pain, sensory processing, and headache are discussed below.
craniovascular afferents and has also been shown to
control trigeminocervical nociceptive inputs.20,21 Ac- CLINICAL RELATIONSHIP BETWEEN MIGRAINE
cording to this view, the pain is understood as a AND OBESITY The link between obesity and the
combination of altered perception (due to periph- frequency of primary headaches was first demon-
eral or central sensitization) of stimuli, as well as the strated by Scher and colleagues.3 In a longitudinal
activation of a feed-forward neurovascular dilator population study, over the course of 1 year, 3% of
mechanism in the first division of the trigeminal individuals with episodic headache progressed to
nerve.1 An alternative theory proposes cortical CDH. Among the risk factors for progression, obe-
spreading depression as the first neurologic event, sity figured prominently; the relative odds of CDH
which would explain the migraine aura and would were five times higher in individuals with a BMI
then activate trigeminovascular afferents and in- !30 than in the normal weighted subjects. Over-
duces a series of cortical meningeal and brainstem weight individuals (BMI ranging from 25 to 29) had
events consistent with the development of the head- a threefold increased risk of developing CDH. In the
ache and the associated symptoms.17,19 cross-sectional component of the study they found
The pathophysiology of migraine progression is that obesity was particularly associated with CDH
less understood. An imaging study identified with migraine features vs with CDH without mi-
changes on MRI consistent with iron deposition in graine features. Obesity emerged as a risk factor af-
the periaqueductal gray (PAG) area in subjects with ter adjusting for other comorbidities and
episodic and CM.21 The PAG is a crucial component demographics.
in the modulation of descending inhibitory path- Following the first study,3 two large epidemio-
ways. It receives input from the trigeminal nucleus logic studies further investigated the relationship
caudalis (TNC).22 Allodynia, perception of pain between BMI, episodic migraine, and CM. The first
when a usually nonpainful stimulus is applied, has study focused on the relationship between BMI and
been reported in about two-thirds of migraineurs episodic migraine.5 A total of 30,215 participants
during the attack.23,24 It may be suggested, in a sub- were interviewed, and 3,791 had migraine. Migraine
set of patients, that repeated central sensitization, or prevalence, frequency of headache attacks, and
alternatively, repetitive activation at the level of the headache features were modeled as a function of
PAG, is associated with high metabolic activity, hy- BMI, adjusting by covariates (age, sex, marital sta-
peroxia, high iron turnover, and a progressive free- tus, income, medical treatment, depressive symp-
radical mediated permanent neuronal damage at the toms, medication use). BMI was not associated with
level of, or close to, the PAG, with poor modulation the prevalence of migraine. It was, however, associ-
to pain and disease progression.25 ated with the frequency of headache attacks. In the
normal weighted group, just 4.4% of migraine suf-
OBESITY: AN OVERVIEW Obesity is a highly prev- ferers had 10 to 14 headache days per month. This
alent disorder that severely affects health-related increased to 5.8% of the overweight group (OR "
quality of life and is a risk factor for hypertension, 1.3, 95% CI " 0.6, 2.8), 13.6% of the obese (OR "
metabolic syndrome, diabetes, myocardial infarc- 2.9, 95% CI " 1.9, 4.4), and 20.7% of the severely
tion, and stroke.26 It has reached epidemic propor- obese (OR 5.7, 95% CI " 3.6, 8.8). Although 6% of
tions globally27,28 and in the United States, where the underweight had high frequency of headache at-

1852 Neurology 68 May 22, 2007

 Figure 1 Prevalence of chronic migraine according to the body mass index Figure 2 Possible links between obesity and
chronic migraine

From Bigal and Lipton,

2006.4 Analyses adjusted by tacks, due to the small sample size in this group, the
age, gender, socioeconomic
income, and depression. OR
differences were not significant (OR " 1.4, 95%
and CI are described in the CI " 0.7, 2.5). In adjusted analyses, obesity corre-
text. lated with frequency of attacks among migraineurs.
In the obesity-CDH study, similar methods were
used to assess the relationship between BMI and
CDH, as well as its subtypes, CM and chronic
tension-type headache (CTTH).4 The study con-
firmed that obesity and CDH are comorbid, after
adjusting for several comorbidities and for demo-
graphics. It also suggested that obesity is a much
stronger risk factor for CM than for CTTH. For the impact on the overall frequency of attacks
CM, the prevalence ranged from 0.9% of the nor- should be small.
mal weighted (reference group) to 1.2% of the over-
weight (OR " 1.4 [1.1, 1.8]), 1.6% of the obese
POSSIBLE LINKS OF MIGRAINE AND OBESITY
(OR " 1.7 [1.2, 2.43]), and 2.5% of the severely Possible reasons for the association between obesity
obese (OR " 2.2 [1.5, 3.2]). Underweight subjects and frequent migraine/CM are summarized in fig-
(prevalence " 1.06%, OR " 1.13 [0.6, 2.1]) did not ure 2 and briefly discussed below.
differ from normal weight (figure 1). The effects of
BMI on the prevalence of CTTH were not signifi- Spurious interaction. It could be that obesity and fre-
cant, except in the severely obese group. quent headaches appeared to be related as a conse-
Because of the increase in the prevalence of over- quence of biased ascertainment. If persons with
weight over the past decades,32 a parallel increment obesity or migraine/CM were more likely to be in
in the prevalence of CM over time could be pre- the health care system, individuals with both disor-
dicted. However, studies on the prevalence of CM ders may be over-represented in clinic-based sam-
are recent.3,33 Obesity does not seem comorbid to ples. Another potential source of spurious
migraine, just a risk factor to frequent migraine at- interaction is the fact that both migraine and obesity
tacks.5 Furthermore, none of the large prevalence are common disorders, potentially leading to a sta-
studies conducted in the United States assessed the tistically but not pathophysiologically relevant asso-
proportion of migraineurs with frequent attacks as ciation between the two.
an individualized category.8,34,35 Nonetheless, most Since the association is supported by two large
migraineurs in the population have few migraine at- cross-sectional population studies and a longitudi-
tacks and even considering that the proportion of nal analyses adjusted by gender, age, and sociode-
individuals with frequent attacks may be increasing mographic status, spurious interactions seem to be
following the increase in the prevalence of obesity, unlikely.3,5,6

Neurology 68 May 22, 2007 1853

 Unidirectional causal relationships. Herein, one dis- flex activation of the cranial parasympathetic
ease would lead to the other. CM may be a risk fac- outflow.42
tor for obesity, since individuals with daily pain Other inflammatory promoters are also altered
may live more sedentary lives and may use preven- in migraineurs, including several cytokines, and
tive medications that increase weight. Obesity could some of these markers are normalized after
increase the risk of CM if proinflammatory media- sumatriptan.43,44 Transient increase in soluble intra-
tors contribute to headache progression. In the only cellular adhesion molecule (sICAM-1), interleukin
available longitudinal study,3 obesity was a risk fac- (IL)-6, and tumor necrosis factor (TNF)-alpha can
tor for incident CM. CM has not been studied as a be induced by sensory neuropeptides released from
risk factor for obesity. activated trigeminal endings and are seen during mi-
As detailed in the next section, unidirectional graine attacks.44
causal relationships may explain some of the rela- Migraine is also comorbid to a number of vascu-
tionship between both conditions (e.g., inflamma- lar diseases. Migraineurs with aura seem to be at
tory mediators that are elevated in obesity and may risk of silent cerebellar infarcts.45 It has been dem-
be of importance in migraine). onstrated that cortical spreading depression (CSD)
Shared environmental risk factors. Comorbid rela- alters blood– brain barrier (BBB) permeability by
tionships might be explained by shared environ- activating brain matrix metalloproteinases
mental risks. A sedentary and stressful occupation (MMPs), especially MMP-9.46 MMP-9 regulates
might contribute to the co-occurrence of these dis- perfusion at the level of the BBB. CSD induces up-
orders. There is no direct evidence to support this regulation of MMP-9 which, in turn, opens the BBB
hypothesis. and promotes sustained leakage of serum proteins.
Barrier disruption may contribute to changes in
Shared genetic risk factors. Migraine and obesity
brain permeability during migraine attacks, as well
may share a common genetic underpinning. Shared
as neuronal death and an increase in infarct volume
genetic risk factors explain several of the comor-
in the already compromised brain.46 It must be
bidities of migraine.36,37 Some of the relationship be-
borne in mind that most aura is visual, and there
tween obesity and migraine may be explained by
seems to be no evidence that this region suffers an
this model. As discussed below, some neurochemi-
undue burden of brain lesions.47
cals, including orexins, are responsible for modulat-
ing a number of metabolic and nociceptive Studies also investigated the presence of genetic
processes. Genetic risk factors that lead to dys- abnormalities of the protein C system in subjects
modulation in the orexin pathways could lead to with migraine, contrasted with controls. In one
both refractory pain and obesity. study, migraineurs had an increased frequency of
In the next section we discuss specific linkage activated protein C resistance due to Arg506Gln
points between both conditions. Although we can- factor V mutation and of protein S deficiency.48 Ad-
not completely exclude shared environmental risk ditionally, C-reactive protein (CRP) was increased
factors as important, we focus on unidirectional and in individuals with migraine with aura in a clinic-
shared biologic interactions. based study.49
Obesity, inflammation, and vascular mediators. Adi-
POSSIBLE MECHANISMS OF MIGRAINE AND
OBESITY RELATIONSHIP Migraine, inflammation
pose tissue, previously considered a passive storage
and vascular mediators. The source of pain in mi- depot for fat, is now known to play an active role in
graine headache may involve neurogenic plasma ex- metabolism.50 Adipocytes produce and release in-
travasation and consequent vascular meningeal flammatory cytokines, and obesity is considered by
inflammation.38 Structural changes in the dura ma- some experts as a permanent state of low-grade in-
ter following trigeminal ganglion stimulation have flammation.51 In a population study, overweight
been demonstrated in animals, specifically mast cell and obese individuals were more likely to have ele-
degranulation and changes in post-capillary venules vated CRP levels than their normal-weight counter-
including platelet aggregation.39 Electrical stimula- parts. After adjustment for potential confounders,
tion of the trigeminal ganglion leads to increases in the odds for elevated CRP were 2.13 for obese men
extracerebral blood flow and local release of both and 6.21 for obese women. Obesity, as well as high
calcitonin gene-related peptide (CGRP) and sub- levels of CRP, are independent risk factors for leu-
stance P (SP).40 SP release is likely to be proinflam- kocytosis.52 Additionally, adipocytes secrete a wide
matory.41 Trigeminal ganglion stimulation also range of inflammatory molecules including TNF-
causes release of a powerful vasodilator peptide, va- alpha and IL-6. The adipose tissue is estimated to
soactive intestinal polypeptide (VIP), through a re- produce about 25% of the systemic IL-6 in vivo.51

1854 Neurology 68 May 22, 2007

 Table 1 Selective inflammatory events of importance in obesity and migraine

Biomarker Obesity Migraine Potential linkage

C-reactive protein Increased Increased CRP is one of the acute phase proteins that
(CRP) increase during systemic inflammation

CRP is also associated with cardiovascular

disease risk

Since obesity is a proinflammatory state,

it may be associated with enhancement in
the inflammatory response in migraine

Tumor necrosis Secreted by adipocytes Elevated at the onset of migraine TNF causes allodynia in animals
factor (TNF)-! attacks

Administration of TNF increases pain states

in several models

Interleukin (IL)-6 Secreted by adipocytes Transient elevation in the onset IL-6 induces pain in several models
of migraine attacks

Mast cells One of major secretory Mast cells can be activated by Activated mast cells secrete proinflammatory
compartment of trigeminal nerve stimulation. Mast and neurosensitizing mediators
adipose tissue cells are also activated by peptides,
such as CGRP and substance P

Brain mast cells can also secrete

proinflammatory and vasodilatory molecules
such as IL-6

Macrophages The fat tissue is infiltrated Macrophage iNOS upregulation Macrophages are a major source of locally
by macrophages and edema formation follow GTN produced proinflammatory cytokines
infusion in human models of migraine pain

iNOS is implicated in the vasodilatation that

happens in migraine pain

CGRP " calcitonin gene-related peptide.

Additionally, the adipose tissue is infiltrated by main unchanged. It was suggested that CGRP levels
macrophages, which may also be a major source of may be genetically determined in obese individuals,
locally produced proinflammatory cytokines.53 and that fat intake may be associated with increased
Weight loss is associated with a reduction in the CGRP secretion.59
macrophage infiltration of adipose tissue.53 Other Amylin (AM) and adrenomedullin (ADM) are
substances produced by the adipocytes with inflam- two peptides that share between 25 and 50% se-
matory properties include adiponectin, leptin, and quence homology with CGRP.60,61 The levels of
reistin, and are discussed below. AM are elevated in obese individuals, probably
Table 1 summarizes some of the inflammatory leading to downregulation of the amylin recep-
abnormalities that happen in obesity and migraine, tors which, in turn, would lessen the impact of
discussing some of the possible points of postprandial AM secretion on satiety and gastric
interaction. emptying.62 Null amylin mutant mice have re-
Calcitonin gene-related peptide (CGRP) and other duced pain response in the paw formalin test, sug-
peptides. CGRP is released into the cranial circula- gesting that amylin is pro-nociceptive in primary
tion of humans during acute migraine, and is an sensory neurons.63
important postsynaptic modulator of the trigemi- AM is a potent, long-lasting vasoactive peptide.
novascular neurotransmission.54 CGRP receptors Considerable evidence exists for a wide range of au-
in the trigeminocervical complex can be inhibited tocrine, paracrine, and endocrine mechanisms for
by CGRP receptor blockade.55 In models of medi- AM which include vasodilatory, antiapoptotic, an-
cation overuse, morphine tolerance in spinal neu- giogenic, antifibrotic, natriuretic, diuretic, and pos-
rons can be reversed by CGRP receptor itive inotropic.63 The adipose tissue, especially
antagonists.56 Finally, experimental CGRP recep- mature adipocytes, is a major source of AM in the
tor antagonists are effective in the acute treat- body, and AM might play a pathophysiologic role
ment of migraine.57,58 in obesity.63
Plasma levels of CGRP are elevated in obese indi- As with CGRP, ADM is a potent dilatator of hu-
viduals, and fat intake may also be associated with man arteries. The vasodilation induced by ADM is
CGRP secretion.59 In a clinic-based study, CGRP mediated through a CGRP1 receptor, suggesting the
was significantly higher in obese subjects relative to presence of functional ADM receptors in human as-
controls. After fat intake, the CGRP levels further troglial cells.64 This may be of importance in the
increased, and after weight loss, concentrations re- pathophysiology of migraine.

Neurology 68 May 22, 2007 1855

 Table 2 Calcitonin gene-related peptide (CGRP) and analogous molecules: Importance in obesity and migraine

Biomarker Obesity Migraine Potential linkage

CGRP Plasmatic CGRP is elevated Postsynaptic mediator of CGRP is one of the most important
in obese individuals. Fat intake the migraine trigemino-vascular peripheral migraine mediators and
is associated with increased inflammation one target for development of new
CGRP secretion migraine treatments

Amylin Elevated in obese individuals Not tested Amylin mutant mice display a reduced
pain response in the paw formalin test

Amylin has a pro-nociceptive function

in primary sensory neurons

Adrenomedullin (AM) Adipocytes are a major source Not tested ADM is a potent dilatator of human
of AM in the body arteries

The effects of ADM happen trough

CGRP1 receptors

ADM " adrenomedullin.

Table 2 summarizes the importance of CGRP sy,70 and 90% of narcoleptic patients demonstrating
and analogous molecules in obesity and migraine. a decreased level of orexin A in their CSF.71 A link
Substances and pathways important in the regulation
between orexin and migraine can be indirectly pos-
of food intake and weight control. Orexins. Several tulated by the increased prevalence of migraine in
peptides have been reported recently to be involved narcoleptic patients.72 Narcoleptic patients also
in the modulation of appetite and energy homeosta- demonstrate an increased BMI,73 as do first-degree
sis, including the orexins (orexin A and B)65-67 (table relatives, suggesting a possible genetic link.74
3). The orexins bind to two G-protein coupled re- The orexinergic influence on feeding is depen-
ceptors, termed OX1R and OX2R. Orexin A has an dent on circadian processes, with the effect of
equal affinity for both receptors, whereas orexin B orexin A administration on feeding varying depend-
has a 10-fold higher affinity for the OX2R.68 The ing on time of day.75 Furthermore, the orexins may
broad projections of the orexinergic system have led be important in the modulation of obesity. In a
to its implication in a variety of functions including clinic-based study, plasma orexin A concentrations
feeding, sleep wake cycle, cardiovascular function, were significantly lower in obese women when com-
hormone secretion,67 and more recently the modula- pared to control subjects. Plasma orexin B concen-
tion of nociceptive processing.69 Interestingly the trations did not change as a function of BMI.76
orexinergic system has been linked to the sleep dis- Recent studies have also linked the orexins with
order narcolepsy with the discovery of a mutation at the modulation of nociceptive processing.77,78
the OX2R, being responsible for canine narcolep- Orexin A receptors have been localized to the spinal

Table 3 Substances important in the modulation of food intake and weight control: Relevance in migraine

Biomarker Obesity Migraine Potential linkage

Orexins Levels of orexin A Injection of orexin A decreased Low levels of orexin, as found in obese
are reduced in obese the A- and C-fiber responses to individuals, may be related to a
individuals painful stimulation. Orexin A proinflammatory state in the trigeminal
inhibits neurogenic induced system
vasodilatation

Orexin plays a key role in regulating

the sleep cycle. Sleep disorders are
known risk factor for migraine progression

Adiponectin Decreases with Not tested Low levels are associated with platelet
increased BMI aggregation, as well as proinflammatory
cytokine release

Adiponectin inhibits IL-6 and TNF-induced

IL-8 formation, as well as induction of the
anti-inflammatory cytokines, IL-10 and IL-1RA

Adiponectin levels are inversely correlated

with CRP, TNF-!, and IL-6 levels

Leptin Increases with BMI Not tested Leptin induces cytokine release
in several models

Resistin Increases with BMI Not tested As leptin, resistin induces cytokine
release in several animal models

BMI " body mass index; IL " interleukin; TNF " tumor necrosis factor.

1856 Neurology 68 May 22, 2007

cord and dorsal root ganglion, and orexin-A was protein, TNF-!, and IL-6 levels.85,86 At lower levels,
shown to be analgesic when given IV and intrathe- adiponectin induces a proinflammatory state.85,86
cally.79 In animals, the efficacy of orexin-A was sim- Beyond their effects on central metabolic func-
ilar to that of morphine. However, involvement of tions, leptin, resistin, and adiponectin have pro-
the opiate system was discounted as the effects were found effects on a number of other physiologic
blocked by the OX1R antagonist SB-334867 but not processes, including inflammation.87 It has been
naloxone.80 demonstrated that leptin and adiponectin activate
The orexins have only very recently been linked proinflammatory cytokine release and phospholipid
with a possible role in migraine. In an animal model metabolism in the adipose tissue, and that antiin-
of trigeminovascular pain, activation of the OX1R flammatory agents counteract the induced inflam-
and OX2R in the posterior hypothalamus has been mation.88 Adiponectin is upregulated in vivo and in
shown to differentially modulate nociceptive dural vitro in response to inflammatory stimuli. The un-
input to the TNC.79 Activation of the OX1R elicits derlying mechanisms seem to involve a NO-
an antinociceptive effect whereas OX2R activation dependent pathway.89 Finally, it is worth noting
elicits a pro-nociceptive effect. This is of impor- that low levels of adiponectin have been recently
tance, since regulation of autonomic and neuroen- reported to be associated with platelet
docrine functions as well as nociceptive processing aggregation.89,90
are closely coupled in the hypothalamus,80 probably
mediated by orexinergic mechanisms.81 Thus, the IMPORTANCE OF COMORBID ASSOCIATIONS
orexinergic could be a possible link between the The relationship between chronic migraine and
pain of primary neurovascular headaches and obesity may be at least partially explained by both
the possible hypothalamic dysfunction seen in diseases sharing comorbidities that are also known
migraine.82 In a further study, the effects of orexin A risk factors for migraine transformation.
and B on neurogenic dural vasodilation were inves- Depression and stressful life events have been
tigated. Inhibition of neurogenic dural vasodilation identified as risk factors for CDH and exemplify
has proved successful in predicting antimigraine ef- this issue.3 A recent population study showed that,
ficacy with numerous compounds including the in the United States, obesity was associated with sig-
triptans.83 Orexin A, but not orexin B, was able to nificant increases in lifetime diagnosis of major de-
inhibit neurogenic dural vasodilation, resulting in pression, bipolar disorder, and panic disorder or
inhibition of prejunctional release of CGRP from agoraphobia.90 Sleep apnea is also a risk factor for
trigeminal neurons. The response was reversed by migraine progression,3 and with increased daytime
pretreatment with the OX1R antagonist sleepiness in migraineurs.91
SB-334867.84 Medication overuse is a third condition that may
Adipocytokines. Adipocytes also act as endocrine be used as an example. It is a known risk factor for
cells, secreting substances called adipocytokines. CDH.92 There is increasing evidence that dysfunc-
Some of the adipocytokines have hormonal proper- tioning of the reward and drive circuitry (the fronto-
ties, including adiponectin, resistin, and leptin. striatal-amygdala-midbrain circuit) may play a
They seem to be exclusively produced in the fat cells pivotal role in obesity.93 The same circuit may also
and placenta.85 be involved in substance abuse.94
The better studied of the adipocytokines is adi- It is clear that some of these common comorbidi-
ponectin, a substance that has endocrine effects in ties may contribute to the process of migraine trans-
the liver, muscle, and vasculature. Adiponectin formation. In two of the studies that found obesity
modulates a number of metabolic processes impor- and CDH comorbid,5,6 analyses were partially ad-
tant in the control of glycemia, as well as fatty acid justed for depression (depression scales were not
catabolism. Levels of the hormone are inversely cor- used, but questions on depression were) and were
related with BMI,86 which plays a key role in meta- fully adjusted for acute and preventive medication
bolic disorders such as type 2 diabetes, obesity, and use and for demographics. In the third3 analyses
atherosclerosis. Plasma concentrations are higher in were adjusted for stressful life events, sleep apnea,
females than in males.86 Weight reduction signifi- and snoring. In the three studies, obesity emerged as
cantly increases circulating levels. At normal levels, an independent risk factor for transformation.
the anti-inflammatory activities of adiponectin in- However, it has been suggested that depression may
clude inhibition of IL-6 and TNF-induced IL-8 at least partially explain the influence of BMI on
formation, as well as induction of the anti- CDH prevalence,95 and none of the mentioned stud-
inflammatory cytokines, IL-10 and IL-1. Adiponec- ies used a validated depression scale.
tin levels are inversely correlated with C-reactive The importance of comorbid associations is ex-

Neurology 68 May 22, 2007 1857

 hypothesized that, due to sympathetic hypofunc-
Figure 3 Algorithm summarizing the relationship between obesity and migraine
progression tion, obese migraineurs are less able to cope with
the increased sympathetic tone associated with obe-
sity, and thus would be at a greater risk for frequent
headaches.

CONCLUSION In this article, we discussed several

hypothetical mechanisms that may account for the
association between obesity and frequent migraines,
including chronic migraine in epidemiologic studies.
Figure 3 summarizes many of these relationships.
We propose that unidirectional causality as well as
shared biologic mechanisms are important. Obesity
increases the levels of several markers that are im-
portant in migraine pathophysiology, including in-
terleukins and CGRP. These mediators may
increase the frequency, severity, and duration of mi-
graines per se. Increase in the frequency of migraine
is associated with central sensitization, which
emplified by what is seen in the underweight group. would contribute to self-perpetuating the process.
In three population studies (Bigal et al., data in Obesity is also a state of sympathetic activation,
preparation),4,5 underweight individuals had a which may contribute to increase in headache fre-
higher prevalence of CDH and higher frequency of quency. The levels of adiponectin are decreased in
headache attacks overall. However, after adjusting obesity, and, as exposed, at normal levels, adiponec-
for covariates (questions on depression and anxiety, tin has anti-inflammatory properties.99 Finally,
for example), the relationship remained true for shared biologic predisposition may play a relevant
obesity but not for underweight, suggesting that in role. Orexins are important, modulating both pain
the underweight, psychiatric comorbidities mediate and metabolic pathways. Dysfunction in the orexins
at least in part the relationship. pathways seems to be a risk factor for both
conditions.
ROLE OF THE AUTONOMIC NERVOUS SYSTEM A recent large population in which we inter-
Obesity may be explained as a disturbance of energy viewed 160,000 individuals supported that obesity
balance, with energy intake exceeding energy ex- was an exacerbating factor for migraine and proba-
penditure. As the autonomic nervous system has a ble migraine but not for episodic tension-type head-
role in the regulation of both these variables, it has ache. Therefore it was a risk factor for CM but not
become a major focus of investigation in the fields for CTTH (Bigal et al., data in preparation). This
of obesity pathogenesis.96 A prospective study in specificity of association creates opportunity to gen-
8,000 obese and nonobese patients revealed a high erate mechanistic hypothesis. Future research
relative risk to develop type 2 diabetes if autonomic should explore the several hypothetical mechanisms
dysfunction is present.97 It may be suggested that an of relationship between obesity and CM, as well as
unbalanced autonomic output develops in obese in- the interaction between obesity and other risk fac-
dividuals with increased parasympathetic domi- tors for migraine progression. For example, based
nance in the visceral compartment and increased on the obesity data alone, CM should be more fre-
sympathetic tone in the thoracic compartment and quent in the United States than in Europe, since obe-
muscles. Finally, it is also speculated that the in- sity is more prevalent in the former, which is not the
crease in the sympathetic tone, happening under case.33 It is possible that other known risk factors to
fasting conditions in obesity, may be associated migraine transformation (depression, stressful life
with high cardiovascular morbidity and mortality. events, income, head trauma, sleep apnea, fre-
At least partially, this dysmodulation is driven by quency of headache attacks, medication overuse)
leptin, a proinflammatory molecule. counterbalance the stronger influence of obesity
Autonomic dysfunction has been suggested in that would be expected in the United States.
migraine.98 Obesity leads to activation of the sym-
pathetic nervous system, as well as changes in cen- ACKNOWLEDGMENT
tral serotonergic responsiveness (a reduction in Dr. Bigal thanks Dr. B. Lee Peterlin, for sharing her thoughts on
central “serotonin tone”), and this might increase adiponectin, and Dr. David Biondi, on the role of the auto-
the chance of migraine transformation. It may be nomic nervous system on migraine progression.

1858 Neurology 68 May 22, 2007

Received October 6, 2006. Accepted in final form January 10, graine with and without aura. Dutch Migraine Genetics
2007. Research Group. Headache 1997;37:479–485.
19. Moskowitz MA. Neurogenic inflammation in the patho-
physiology and treatment of migraine. Neurology 1993;
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 Obesity, migraine, and chronic migraine : Possible mechanisms of interaction
Marcelo E. Bigal, Richard B. Lipton, Philip R. Holland, et al.
Neurology 2007;68;1851
DOI 10.1212/01.wnl.0000262045.11646.b1
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