Associations of fatty acids in cerebrospinal fluid with peripheral glucose concentrations and energy metabolism

Abstract

Rodent experiments have emphasized a role of central fatty acid (FA) species, such as oleic acid, in regulating peripheral glucose and energy metabolism. Thus, we hypothesized that central FAs are related to peripheral glucose regulation and energy expenditure in humans. To test this we measured FA species profiles in cerebrospinal fluid (CSF) and plasma of 32 individuals who stayed in our clinical inpatient unit for 6 days. Body composition was measured by dual energy X-ray absorptiometry and glucose regulation by an oral glucose test (OGTT) followed by measurements of 24 hour (24EE) and sleep energy expenditure (SLEEP) as well as respiratory quotient (RQ) in a respiratory chamber. CSF was obtained via lumbar punctures; FA concentrations were measured by liquid chromatography/mass spectrometry. As expected, FA concentrations were higher in plasma compared to CSF. Individuals with high concentrations of CSF very-long-chain saturated FAs had lower rates of SLEEP. In the plasma moderate associations of these FAs with higher 24EE were observed. Moreover, CSF monounsaturated long-chain FA (palmitoleic and oleic acid) concentrations were associated with lower RQs and lower glucose area under the curve during the OGTT. Thus, FAs in the CSF strongly correlated with peripheral metabolic traits. These physiological parameters were most specific to long-chain monounsaturated (C16:1, C18:1) and very-long-chain saturated (C24:0, C26:0) FAs.

Conclusions: Together with previous animal experiments these initial cross-sectional human data indicate that central FA species are linked to peripheral glucose and energy homeostasis.

Figure 1. Plasma and CSF fatty acid fractions by race.

Percentual abundance of saturated (SAFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids in plasma (a.) and CSF (b.) are shown for Caucasian (C) and American Indian (AI) individuals in plasma and CSF. Diamonds (♦) represent least squared means adjusted for age, sex, and body fat and error bars indicate 95% confidence interval. *P = 0.01.

Figure 2. Correlation heatmap of fatty acid species with metabolic traits.

Spearman Correlation Coefficients are represented by color codes as illustrated in the side panel. CSF: cerebrospinal fluid; 24EE: 24 hour energy expenditure measured in a metabolic chamber; SLEEP: energy expenditure measured during the sleep phase; RQ: respiratory quotient; GAUC: glucose area under the curve during the oral glucose tolerance test; *p<0.05, †p<0.01, ‡p<0.001, #significant after Bonferroni correction.

Figure 3. Scatter plots of fatty acids in CSF and metabolic factors.

Erucic acid (C26∶0, panel a.) and Lignoceric acid (C24∶0, panel b.) are negatively associated with residuals of energy expenditure during sleep (SLEEP). SLEEP was adjusted for known confounders as described in the Statistical analyses section of the Materials and methods. Panel c. shows the association of palmitoleic acid (C16∶1) with residuals of glucose area under the curve (GAUC). GAUC was adjusted for age, sex and percent body fat. Bonferroni-corrected p-values were a) 0.004, b) 0.004 and c) 0.02.

Figure 4. Glucose and insulin levels during the OGTT.

Glucose (a.) and insulin (b.) levels are shown over the time course of the OGTT. Dashed lines and open bars represent individuals with high palmitoleic acid (PA) in the CSF, full lines and closed bars represent low PA in the CSF. Groups were defined as PA>0.63 (high) and PA<0.63 (low), where 0.63 is the median of central PA representation. Error bars depict standard deviation. AUC: area under the curve; *p<0.05; †p<0.01.