Cold-induced changes in plasma signaling lipids are associated with a healthier cardiometabolic profile independently of brown adipose tissue

Abstract

Cold exposure activates brown adipose tissue (BAT) and potentially improves cardiometabolic health through the secretion of signaling lipids by BAT. Here, we show that 2 h of cold exposure in young adults increases the levels of omega-6 and omega-3 oxylipins, the endocannabinoids (eCBs) anandamide and docosahexaenoylethanolamine, and lysophospholipids containing polyunsaturated fatty acids. Contrarily, it decreases the levels of the eCBs 1-LG and 2-LG and 1-OG and 2-OG, lysophosphatidic acids, and lysophosphatidylethanolamines. Participants overweight or obese show smaller increases in omega-6 and omega-3 oxylipins levels compared to normal weight. We observe that only a small proportion (∼4% on average) of the cold-induced changes in the plasma signaling lipids are slightly correlated with BAT volume. However, cold-induced changes in omega-6 and omega-3 oxylipins are negatively correlated with adiposity, glucose homeostasis, lipid profile, and liver parameters. Lastly, a 24-week exercise-based randomized controlled trial does not modify plasma signaling lipid response to cold exposure.

Keywords: adiposity; bioactive lipids; brown adipose tissue; cardiometabolic health; cold; endocannabinoids; lipidomics; obesity; oxylipins; polyunsaturated fatty acids.

Graphical abstract

Figure 1

Design of the study investigating the effects of a 2-h cold exposure on the plasma levels of signaling lipids in young adults Abbreviations are as follows: ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; BAT, brown adipose tissue; PET/CT, positron emission tomography/computed tomography.

Figure 2

2-h cold exposure modifies the levels of signaling lipids Effects of 2-h cold exposure on the plasma levels of omega-6 oxylipins (A), omega-3 oxylipins (B), endocannabinoids and analogs (eCBs, C), and lysophospholipids and sphingosine-1-phosphate (D) in young adults. The colors of the squares represent the mean log2 fold change of the area peak ratio of that time point relative to baseline. Red color represents an increase, whereas blue represents a decrease. p values were obtained from repeated measures analyses of variance (ANOVA). Values in brackets represent the percentage of change at 120 min relative to baseline. The name and abbreviations of signaling lipids are detailed in Table S3.

Figure 3

Association between cold-induced changes in the plasma levels of signaling lipids and brown adipose tissue-related outcomes Volcano plots show partial correlation analyses between the 120-min fold change relative to baseline and BAT volume (A), BAT SUVmean (B), BAT SUVpeak (C), and BAT mean radiodensity (D, n = 47). Partial correlation analyses were adjusted for the natural calendar day when the baseline PET/CT scan was performed. The X axis represents Pearson partial correlation coefficients, whereas the Y axis represents the false discovery rate (FDR)-adjusted p values of the correlations. Gray dots represent non-significant correlations, whereas colored dots represent statistically significant correlations (p value < 0.05 after FDR correction). Abbreviations are as follows: BAT, brown adipose tissue; eCBs, endocannabinoids; SUV, standardized uptake value.

Figure 4

Relationship of cold-induced changes on the plasma levels of signaling lipids with cardiometabolic risk factors and brown adipose tissue Bar graphs showing the proportion of cold-induced changes in omega-6 oxylipins (A), omega-3 oxylipins (B), endocannabinoids and analogs (eCBs, C), and lysophospholipids and sphingosine-1-phosphate (D) associated with cardiometabolic risk factors. Associations were determined by Pearson bivariate correlation analyses or partial correlation analyses (for brown adipose tissue). Partial correlation analyses were adjusted for the natural calendar day when the baseline PET/CT scan was performed. Cold-induced changes in plasma lipidome were determined by the 120-min fold change relative to baseline. Significance was set at p value <0.05 after FDR correction. Gray parts represent the proportion of lipids showing non-significant correlations, red parts represent the proportion of lipids showing significant positive correlations, whereas green parts represent the proportion of lipids showing significant negative correlations. Abbreviations are as follows: ALP, alkaline phosphatase; APOA1, apolipoprotein A1; APOB, apolipoprotein B; BAT, brown adipose tissue; BMI, body mass index; CRP, C-reactive protein; eCBs, endocannabinoids; GGT, gamma-glutamyl transferase; GPT, glutamic pyruvic transaminase; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment of insulin resistance index; LDL-C, low-density lipoprotein cholesterol; SUV, standardized uptake value; VAT, visceral adipose tissue; WC, waist circumference.

Figure 5

Effect of 24-week supervised concurrent exercise intervention on the plasma levels of signaling lipids as a response to cold exposure Heatmap shows the changes in 120-min fold change after the intervention in each group. Each square represents the change after the intervention in 120-min fold change (i.e., post-intervention 120-min fold change minus pre-intervention 120-min fold change for each lipid). Blue squares represent a decrease, whereas red squares indicate an increase after the intervention. ∗p value < 0.05, obtained from analyses of variance (ANOVA). The names and abbreviations of signaling lipids are detailed in Table S3. Abbreviations are as follows: CON, control group; MOD-EX, moderate-intensity exercise group; VIG-EX, vigorous-intensity exercise group.