Author: B Lee Peterlin

Migraine, Obesity, and Calcitonin Gene-Related Peptide (CGRP): is there a link?

The risk of migraine increases in people who are overweight or obese. Now, there is emerging evidence that Calcitonin Gene-Related Peptide (CGRP) may mediate this link. Professor B. Lee Peterlin, Director of Johns Hopkins Headache Research, Johns Hopkins School of Medicine, Baltimore, USA discusses this issue. 

People who are overweight or obese are more likely to suffer from migraine.1  While early epidemiological studies into the association between migraine and obesity appeared conflicting, more recent studies over the past decade have clearly shown that the risk of migraine is increased by approximately 30% in individuals who are obese.1,2 Furthermore, the risk of migraine increases with increasing obesity status, i.e. from normal weight to overweight to obese to morbidly obese.2

The mechanisms underpinning this association between migraine and obesity are not fully known. It has been hypothesized, however, that adipose tissue and the bioactive signaling molecules secreted by adipocytes may play an important role.3-7 In support, experimental studies show that obese rodents exhibit an augmented baseline and acute trigeminovascular response to stimulation, and that the presence of such obese states are capable of priming the trigeminovascualr system to be responsive to otherwise non-painful stimuli.4,5

Additionally, it is known that changes in body composition lead to modulation in the production and secretion of several proteins and molecules from adipocytes.1,7 In particular, levels of several molecules that that are predominantly secreted from adipocytes (e.g. adiponectin, resistin), as well as proinflammatory cytokines, that are increased in obese states although not secreted predominantly from adipocytes (e.g. tumor necrosis factor-alpha and interleukin-6), are increased in people with migraine.3,6 More recently, it has been hypothesized that the peptide, calcitonin gene-related peptide (CGRP), also contributes to the association between obesity and migraine.7

CGRP is a bioactive peptide that is largely distributed in the nervous system as well as adipose tissue.8 Human studies have shown that CGRP levels are increased in both obese individuals and those with migraine.8 Additionally, experimental studies demonstrate that both basal and transient receptor potential vanilloid 1 (TRPV1)-induced CGRP release is increased from trigeminal afferents in obese rats.5 It has been suggested that the increased sensitivity in CGRP release in those with migraine may be due to differences in the expression of the CGRP receptor subunit, the receptor activity modifying protein 1 (RAMP1).7,9 There is accumulating evidence that CGRP may be an important link between the migraine-obesity association.4,5,7,9 At least in part, this may be due to obesity increasing CGRP levels and causing increased sensitivity of the mechanisms that trigger attacks and changes in molecules and receptors that are modulated by obesity status and which activate pathways that regulate CGRP activity.5,7,9

For the clinician, it is important to be aware of the association between migraine and obesity, and to consider lifestyle and medication choices in management. Further research evaluating the role of CGRP in the migraine-obesity association may help in advancing our understanding of migraine pathophysiology and the identification of novel therapeutic targets.

References

  1. Gelaye B, Sacco S, Brown WJ, Nichie HL, Ornello R, Peterlin BL. Body composition status and the risk of migraine – a meta-analysis. Neurology 2017; PUBMED https://www.ncbi.nlm.nih.gov/pubmed/28404807
  2. Chai NC, Scher AI, Moghekar A et al. Obesity and headache: Part I – A systematic review of the epidemiology of obesity and headache. Headache 2014;54:219-34 PUBMED https://www.ncbi.nlm.nih.gov/pubmed/24512574
  3. Chai NC, Bond DS, Moghekar A et al. Obesity and headache: Part II – Potential mechanism and treatment considerations. Headache 2014;54:459-71 PUBMED https://www.ncbi.nlm.nih.gov/pubmed/24511882
  4. Rossi HL, Lara O, Recober A. Female sex and obesity increase photophobic behavior in mice. Neuroscience 2016;331:99–108. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/27328418
  5. Marics B, Peitl B, Varga A et al. Diet-induced obesity alters dural CGRP release and potentiates TRPA1-mediated trigeminovascular responses. Cephalalgia 2016 pii: 0333102416654883. [Epub ahead of print]. PUBMED https://www.ncbi.nlm.nih.gov/pubmed/27301459
  6. Peterlin BL, Bigal ME, Tepper SJ et al. Migraine and adiponectin: Is there a connection? Cephalalgia 2007;435-46 PUBMED https://www.ncbi.nlm.nih.gov/pubmed/17448181
  7. Recober A, Goadsby PJ. Calcitonin gene-related peptide (CGRP): a molecular link between obesity and migraine? Drug News Perspect 2010;23:112-7 PUBMED https://www.ncbi.nlm.nih.gov/pubmed/20369076
  8. Liu T, Kamiyoshi A, Sakurai T et al. Endogenous calcitonin gene-related peptide regulates lipid metabolism and energy homeostasis in male mice. Endocrinology 2017; doi: 10.1210/en.2016-1510. [Epub ahead of print] PUBMED https://www.ncbi.nlm.nih.gov/pubmed/28324021
  9. Zhang Z, Winborn CS, Marquez de Prado B, Russo AF. Sensitization of calcitonin gene-relatedpeptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J Neurosci 2007;27:2693–703 PUBMED https://www.ncbi.nlm.nih.gov/pubmed/17344407