Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as... Show moreNon-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2 '-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant organs. This study investigates whether 2 '-fucosyllactose can alleviate NAFLD development in manifest obesity. Obese hyperinsulinemic Ldlr-/-.Leiden mice, after an 8 week run-in on a high-fat diet (HFD), were treated with 2 '-fucosyllactose by oral gavage until week 28 and compared to HFD-vehicle controls. 2 '-fucosyllactose did not affect food intake, body weight, total fat mass or plasma lipids. 2 '-fucosyllactose altered the fecal microbiota composition which was paralleled by a suppression of HFD-induced gut permeability at t = 12 weeks. 2 '-fucosyllactose significantly attenuated the development of NAFLD by reducing microvesicular steatosis. These hepatoprotective effects were supported by upstream regulator analyses showing that 2 '-fucosyllactose activated ACOX1 (involved in lipid catabolism), while deactivating SREBF1 (involved in lipogenesis). Furthermore, 2 '-fucosyllactose suppressed ATF4, ATF6, ERN1, and NUPR1 all of which participate in endoplasmic reticulum stress. 2 '-fucosyllactose reduced fasting insulin concentrations and HOMA-IR, which was corroborated by decreased intrahepatic diacylglycerols. In conclusion, long-term supplementation with 2 '-fucosyllactose can counteract the detrimental effects of HFD on gut dysbiosis and gut permeability and attenuates the development of liver steatosis. The observed reduction in intrahepatic diacylglycerols provides a mechanistic rationale for the improvement of hyperinsulinemia and supports the use of 2 '-fucosyllactose to correct dysmetabolism and insulin resistance. Show less
Gart, E.; Salic, K.; Morrison, M.C.; Caspers, M.; Duyvenvoorde, W. van; Heijnk, M.; ... ; Kleemann, R. 2021
The development of obesity is characterized by the metabolic overload of tissues and subsequent organ inflammation. The health effects of krill oil (KrO) on obesity-associated inflammation remain... Show moreThe development of obesity is characterized by the metabolic overload of tissues and subsequent organ inflammation. The health effects of krill oil (KrO) on obesity-associated inflammation remain largely elusive, because long-term treatments with KrO have not been performed to date. Therefore, we examined the putative health effects of 28 weeks of 3% (w/w) KrO supplementation to an obesogenic diet (HFD) with fat derived mostly from lard. The HFD with KrO was compared to an HFD control group to evaluate the effects on fatty acid composition and associated inflammation in epididymal white adipose tissue (eWAT) and the liver during obesity development. KrO treatment increased the concentrations of EPA and DHA and associated oxylipins, including 18-HEPE, RvE(2) and 14-HDHA in eWAT and the liver. Simultaneously, KrO decreased arachidonic acid concentrations and arachidonic-acid-derived oxylipins (e.g., HETEs, PGD(2), PGE(2), PGF(2)alpha, TXB2). In eWAT, KrO activated regulators of adipogenesis (e.g., PPAR gamma, CEBP alpha, KLF15, STAT5A), induced a shift towards smaller adipocytes and increased the total adipocyte numbers indicative for hyperplasia. KrO reduced crown-like structures in eWAT, and suppressed HFD-stimulated inflammatory pathways including TNF alpha and CCL2/MCP-1 signaling. The observed eWAT changes were accompanied by reduced plasma leptin and increased plasma adiponectin levels over time, and improved insulin resistance (HOMA-IR). In the liver, KrO suppressed inflammatory signaling pathways, including those controlled by IL-1 beta and M-CSF, without affecting liver histology. Furthermore, KrO deactivated hepatic REL-A/p65-NF-kappa B signaling, consistent with increased PPAR alpha protein expression and a trend towards an increase in IkB alpha. In conclusion, long-term KrO treatment increased several anti-inflammatory PUFAs and oxylipins in WAT and the liver. These changes were accompanied by beneficial effects on general metabolism and inflammatory tone at the tissue level. The stimulation of adipogenesis by KrO allows for safe fat storage and may, together with more direct PPAR-mediated anti-inflammatory mechanisms, attenuate inflammation. Show less
Olga, L.; Diepen, J.A. van; Bobeldijk-Pastorova, I.; Gross, G.; Prentice, P.M.; Snowden, S.G.; ... ; Koulman, A. 2021
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
