Background: Altered lipid metabolism in early life has been associated with subsequent weight gain and predicting this could aid in obesity prevention and risk management. Here, a lipidomic... Show moreBackground: Altered lipid metabolism in early life has been associated with subsequent weight gain and predicting this could aid in obesity prevention and risk management. Here, a lipidomic approach was used to identify circulating markers for future obesity risk in translational murine models and validate in a human infant cohort.Methods: Lipidomics was performed on the plasma of APOE*3 Leiden, Ldlr-/-.Leiden, and the wild-type C57BL/6J mice to capture candidate biomarkers predicting subsequent obesity parameters after exposure to high-fat diet. The identified candidate biomarkers were mapped onto corresponding lipid metabolism pathways and were investigated in the Cambridge Baby Growth Study. Infants' growth and adiposity were measured at 0-24 months. Capillary dried blood spots were sampled at 3 months for lipid profiling analysis.Findings: From the mouse models, cholesteryl esters were correlated with subsequent weight gain and other obesity parameters after HFD period (Spearman's r >= 0.5, FDR p values <0.05) among APOE*3 Leiden and Ldlr-/-.Leiden mice, but not among the wild-type C57BL/6J. Pathway analysis showed that those identified cholesteryl esters were educts or products of desaturases activities: stearoyl-CoA desaturase-1 (SCD1) and fatty acid desaturase (FADS) 1 and 2. In the human cohort, lipid ratios affected by SCD1 at 3 months was inversely associated with 3-12 months weight gain (BSE=-0.31 +/- 0.14, p=0.027), but positively with 12-24 months weight and adiposity gains (0.17 +/- 0.07, p=0.02 and 0.17 +/- 0.07, 0.53 +/- 0.26, p=0.04, respectively). Lipid ratios affected by SCD1 and FADS2 were inversely associated with adiposity gain but positively with height gain between 3-12 months.Interpretation: From murine models to human setting, the ratios of circulating lipid species indicating key desaturase activities in lipid metabolism were associated with subsequent body size increase, providing a potential tool to predict early life weight gain. (C) 2021 The Authors. Published by Elsevier B.V. Show less
OBJECTIVE Inflammation plays an important role in all stages of atherosclerosis, but little is known about the therapeutic effects of quenching inflammation in already existing atherosclerotic... Show moreOBJECTIVE Inflammation plays an important role in all stages of atherosclerosis, but little is known about the therapeutic effects of quenching inflammation in already existing atherosclerotic lesions. Putative beneficial effects of salicylate, an inhibitor of NF-κB activation, were studied in mice with established lesions. METHODS ApoE*3-Leiden mice received a high-cholesterol diet (HC) to establish atherosclerotic lesions. Reference mice (REF) were sacrificed to determine the lesion area at the start of two interventions. In one intervention group HC diet feeding was continued, but the diet contained salicylate (HC+SAL). As salicylate not only quenches inflammation but also reduces plasma cholesterol, a second intervention group was fed a low-cholesterol diet (LC) resulting in cholesterol levels comparable to HC+SAL. The effects of these interventions on lesion area and composition were assessed after 8 and 16 weeks. RESULTS HC+SAL markedly reduced hepatic NF-κB activity compared to REF, and was significantly more effective than LC diet feeding. HC+SAL and LC also quenched aortic NF-κB activity. While continuing HC diet typically further increases total lesion area, 16 weeks of intervention with HC+SAL and LC halted further disease progression and resulted in lesion sizes comparable to that of REF. At the same time, lesion composition was significantly improved, particularly with salicylate. Strikingly, HC+SAL resulted in a lower lesional macrophage content and a greater plaque stability index (ratio of collagen to macrophage area) than LC. CONCLUSION Anti-inflammatory salicylate reduces atherosclerotic macrophage content and increases lesion stability of pre-existing plaques through quenching of NF-κB activity and reducing plasma cholesterol. Show less
Vries-van der Weij, J. de; Toet, K.; Zadelaar, S.; Wielinga, P.Y.; Kleemann, R.; Rensen, P.C.N.; Kooistra, T. 2010
Objective: Inflammation plays an important role in all stages of atherosclerosis, but little is known about the therapeutic effects of quenching inflammation in already existing atherosclerotic... Show moreObjective: Inflammation plays an important role in all stages of atherosclerosis, but little is known about the therapeutic effects of quenching inflammation in already existing atherosclerotic lesions. Putative beneficial effects of salicylate, an inhibitor of NF-kappa B activation, were studied in mice with established lesions. Methods: ApoE*3-Leiden mice received a high-cholesterol diet (HC) to establish atherosclerotic lesions. Reference mice (REF) were sacrificed to determine the lesion area at the start of two interventions. In one intervention group HC diet feeding was continued, but the diet contained salicylate (HC + SAL). As salicylate not only quenches inflammation but also reduces plasma cholesterol, a second intervention group was fed a low-cholesterol diet (LC) resulting in cholesterol levels comparable to HC + SAL. The effects of these interventions on lesion area and composition were assessed after 8 and 16 weeks. Results: HC + SAL markedly reduced hepatic NF-kappa B activity compared to REF, and was significantly more effective than LC diet feeding. HC + SAL and LC also quenched aortic NF-kappa B activity. While continuing HC diet typically further increases total lesion area, 16 weeks of intervention with HC + SAL and LC halted further disease progression and resulted in lesion sizes comparable to that of REF. At the same time, lesion composition was significantly improved, particularly with salicylate. Strikingly, HC + SAL resulted in a lower lesional macrophage content and a greater plaque stability index (ratio of collagen to macrophage area) than LC. Conclusion: Anti-inflammatory salicylate reduces atherosclerotic macrophage content and increases lesion stability of pre-existing plaques through quenching of NF-kappa B activity and reducing plasma cholesterol. (C) 2010 Elsevier Ireland Ltd. All rights reserved. Show less
