Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Aug 31:14:691733.
doi: 10.3389/fnmol.2021.691733. eCollection 2021.

Plasma Lipolysis and Changes in Plasma and Cerebrospinal Fluid Signaling Lipids Reveal Abnormal Lipid Metabolism in Chronic Migraine

Katherine Castor  1 , Jessica Dawlaty  1 , Xianghong Arakaki  1   2 , Noah Gross  1 , Yohannes W Woldeamanuel  3 , Michael G Harrington  1   2   4 , Robert P Cowan  3 , Alfred N Fonteh  1   2
Affiliations

Plasma Lipolysis and Changes in Plasma and Cerebrospinal Fluid Signaling Lipids Reveal Abnormal Lipid Metabolism in Chronic Migraine

Katherine Castor et al. Front Mol Neurosci. .

Abstract

Background: Lipids are a primary storage form of energy and the source of inflammatory and pain signaling molecules, yet knowledge of their importance in chronic migraine (CM) pathology is incomplete. We aim to determine if plasma and cerebrospinal fluid (CSF) lipid metabolism are associated with CM pathology.

Methods: We obtained plasma and CSF from healthy controls (CT, n = 10) or CM subjects (n = 15) diagnosed using the International Headache Society criteria. We measured unesterified fatty acid (UFA) and esterified fatty acids (EFAs) using gas chromatography-mass spectrometry. Glycerophospholipids (GP) and sphingolipid (SP) levels were determined using LC-MS/MS, and phospholipase A2 (PLA2) activity was determined using fluorescent substrates.

Results: Unesterified fatty acid levels were significantly higher in CM plasma but not in CSF. Unesterified levels of five saturated fatty acids (SAFAs), eight monounsaturated fatty acids (MUFAs), five ω-3 polyunsaturated fatty acids (PUFAs), and five ω-6 PUFAs are higher in CM plasma. Esterified levels of three SAFAs, eight MUFAs, five ω-3 PUFAs, and three ω-6 PUFAs, are higher in CM plasma. The ratios C20:4n-6/homo-γ-C20:3n-6 representative of delta-5-desaturases (D5D) and the elongase ratio are lower in esterified and unesterified CM plasma, respectively. In the CSF, the esterified D5D index is lower in CM. While PLA2 activity was similar, the plasma UFA to EFA ratio is higher in CM. Of all plasma GP/SPs detected, only ceramide levels are lower (p = 0.0003) in CM (0.26 ± 0.07%) compared to CT (0.48 ± 0.06%). The GP/SP proportion of platelet-activating factor (PAF) is significantly lower in CM CSF.

Conclusions: Plasma and CSF lipid changes are consistent with abnormal lipid metabolism in CM. Since plasma UFAs correspond to diet or adipose tissue levels, higher plasma fatty acids and UFA/EFA ratios suggest enhanced adipose lipolysis in CM. Differences in plasma and CSF desaturases and elongases suggest altered lipid metabolism in CM. A lower plasma ceramide level suggests reduced de novo synthesis or reduced sphingomyelin hydrolysis. Changes in CSF PAF suggest differences in brain lipid signaling pathways in CM. Together, this pilot study shows lipid metabolic abnormality in CM corresponding to altered energy homeostasis. We propose that controlling plasma lipolysis, desaturases, elongases, and lipid signaling pathways may relieve CM symptoms.

Keywords: chronic migraine; insulin resistance; lipases; lipid signaling; lipolysis; metabolic syndrome; phospholipase A2; platelet-activating factor.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Plasma and CSF unesterified (UFA) and esterified fatty acids (EFA). Lipids were extracted from plasma/CSF, and the levels of the sum of all unesterified or esterified fatty acids > C14:0 were quantified for CT and CM. The violin plots show plasma UFA (A), plasma EFA (B), CSF UFA (C), and CSF EFA (D). In the violin plots, the lower dotted line is the first quartile, the middle line is the median, and the top dotted line is the third quartile. The p values were determined using a Mann–Whitney U test.
FIGURE 2
FIGURE 2
Saturated fatty acid (SAFA) changes in plasma of CT and CM. Box and Whisker plots of unesterified even chain SAFAs (eSAFA) (A), unesterified odd chain SAFAs (oSAFAs) (B), esterified eSAFAs (C), and esterified oSAFAs (D). Fatty acid levels (ng/mL) were normalized using globalized logarithmic transformation and mean-centered. Unpaired multiple t-tests with correction for multiple comparisons (False Discovery Rate, FDR) using the two-state step-up method (Benjamini, Krieger, and Yekutieli). ∗ denote adjusted p (q) < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.005.
FIGURE 3
FIGURE 3
Monounsaturated fatty acid (MUFA) changes in plasma of CT versus CM. We quantified MUFAs in plasma and plotted the normalized (glog/mean-centered) levels for unesterified even chain MUFAs (eMUFA) (A), unesterified odd chain MUFAs (oMUFAs) (B), esterified eMUFAs (C), and esterified oMUFAs (D). Multiple unpaired t-tests with correction for multiple comparisons (False Discovery Rate, FDR) using the two-state step-up method (Benjamini, Krieger, and Yekutieli) were used to compare MUFA levels in CT versus CM. One (∗), two (∗∗), or three asterisks (∗∗∗) denote adjusted p (q) < 0.05, q < 0.01, and q < 0.005, respectively.
FIGURE 4
FIGURE 4
Polyunsaturated fatty acid (PUFA) changes in plasma of CT versus CM. Box and Whisker plots of unesterified n-3 PUFAs (A), unesterified n-6 PUFAs (B), esterified n-3 PUFAs (C), and esterified n-6 PUFAs (D). PUFA levels (ng/mL) were normalized using globalized logarithmic transformation and mean-centered. Unpaired multiple t-tests with correction for multiple comparisons (False Discovery Rate, FDR) used the two-state step-up method of Benjamini, Krieger, and Yekutieli. ∗ denote adjusted p (q) < 0.05, ∗∗ p < 0.01.
FIGURE 5
FIGURE 5
Desaturase and elongase changes in plasma and CSF – Box and Whisker plots of plasma unesterified AA/DGLA (A), plasma esterified AA/DGLA (B), CSF unesterified AA/DGLA (C), and CSF esterified AA/DGLA (D). Violin plots of plasma unesterified elongase index [uElongase, (E)], plasma esterified elongase index [eElongase, (F)], CSF unesterified uElongase (G), and CSF eElongase (H). The p values were determined using a Mann–Whitney U test.
FIGURE 6
FIGURE 6
Glycerophospholipid (GP) and SP changes in CT versus CM. (A) ROC curve of plasma Cer. (B) Heat map of the hierarchical clustering of plasma GPs (LPAF, PAF, LPC, and PC) and SPs (SM, Cer, and dhCer). We used Euclidean for distance measure and Ward for the clustering algorithm for the heatmap. (C) ROC curve of CSF PAF. (D) Heat map of the hierarchical cluster of CSF GPs and SPs. The distance measure and clustering algorithm for the heatmap used Euclidean for Ward, respectively. (E) ROC curve of CSF/plasma of Cer and PAF. (F) Heat map of the hierarchical clustering of CSF/plasma ratio of GPs and SPs using Euclidean for distance measure and Ward for the clustering algorithm.
FIGURE 7
FIGURE 7
Schematic overview of the major sites of lipogenesis and lipolysis and their potential roles in generating unesterified fatty acids–The brain regulates the body’s physiologic state and is involved in energy homeostasis via hunger-stimulating (ghrelin) or hunger-suppressing (leptin) peptides. Dietary fats or fatty acids synthesized in cells are packaged into triacylglycerol-rich lipids (TAG-RL) or are associated with lipoproteins (VLDL, LDL, chylomicrons, and HDL) for transport to tissues. Extra TAG-RL is stored in adipose tissues. Studies show the expression of several neurotransmitters and hormone receptors in adipose tissue, suggesting an interaction of the brain and adipose tissue via the hypothalamic-pituitary-adipose axis or the Brain-Fat-Axis. In times of high energy demands or low blood glucose, sympathetic pathways may stimulate the release of fatty acids through receptor signaling pathways involving PKA/PKG, PKC, tyrosine kinase, and ERK1/ERK2. Unesterified fatty acids (UFA) are released from adipose tissues by lipoprotein lipase (LPL) or a combination of other lipases [adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MAGL)] that are regulated by neurotransmitters, hormones, and neuropeptides. The final lipolysis products are a glycerol molecule and three fatty acids. The released fatty acids are utilized by organs (heart, muscle, and renal cortex) for energy or modified in the liver (lipogenesis) or used to form ketone bodies. Lipolysis is stimulated by adrenergic signaling and glucagon and is inhibited by insulin. Thus, insulin resistance associated with migraines may result in the buildup of unesterified fatty acids in plasma.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Abdelmagid S. A., Clarke S. E., Roke K., Nielsen D. E., Badawi A., El-Sohemy A., et al. (2015). Ethnicity, sex, FADS genetic variation, and hormonal contraceptive use influence delta-5- and delta-6-desaturase indices and plasma docosahexaenoic acid concentration in young Canadian adults: a cross-sectional study. Nutr. Metab. 12:14. - PMC - PubMed
    1. Akerman S., Holland P. R., Lasalandra M. P., Goadsby P. J. (2013). Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and “triptan” receptors: implications in migraine. J. Neurosci. 11 14869–14877. 10.1523/jneurosci.0943-13.2013 - DOI - PMC - PubMed
    1. Alarcon G., Roco J., Medina A., Van Nieuwenhove C., Medina M., Jerez S. (2016). Stearoyl-CoA desaturase indexes and n-6/n-3 fatty acids ratio as biomarkers of cardiometabolic risk factors in normal-weight rabbits fed high fat diets. J. Biomed. Sci. 20:13. - PMC - PubMed
    1. Alcock J., Lin H. C. (2015). Fatty acids from diet and microbiota regulate energy metabolism. F1000Res. 4:738. - PMC - PubMed
    1. Al-Hilal M., Alsaleh A., Maniou Z., Lewis F. J., Hall W. L., Sanders T. A., et al. (2013). Genetic variation at the FADS1-FADS2 gene locus influences delta-5 desaturase activity and LC-PUFA proportions after fish oil supplement. J. Lipid Res. 54 542–551. 10.1194/jlr.p032276 - DOI - PMC - PubMed

LinkOut - more resources