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
Pouwer, M.; Pieterman, E.; Verschuren, L.; Caspers, M.; Kluft, K.; Garcia, R.; ... ; Princen, H. 2017
Different aspects of androgenesis induction have been studied in detail, but little is known about the molecular mechanisms associated with this developmental switch. We have employed macroarrays... Show moreDifferent aspects of androgenesis induction have been studied in detail, but little is known about the molecular mechanisms associated with this developmental switch. We have employed macroarrays containing 1421 expressed sequence tags covering the early stages of barley zygotic embryogenesis to compare the gene expression profiles of stress-induced androgenic microspores with those of uninucleate microspores as they progressed into binucleate stage during pollen development. Principal component analysis defined distinct sets of gene expression profiles that were associated with androgenesis induction and pollen development. During pollen development, uninucleate microspores were characterized by the expression of cell division-related genes and transcripts involved in lipid biosynthesis. Progress into binucleate stage resulted in the significant increase in the level of transcripts associated with starch biosynthesis and energy production. These transcripts were downregulated in androgenic microspores. These results indicate that stress blocks the expression of pollen-related genes. The induction of androgenesis by stress was marked by the upregulation of transcripts involved in sugar and starch hydrolysis, proteolysis, stress response, inhibition of programmed cell death, and signaling. Further expression analysis revealed that the induction of genes encoding alcohol dehydrogenase 3, metalloprotease FtsH, cysteine protease 1 precursor, phytepsin precursor (aspartic protease), and a 26S proteasome regulatory subunit was associated with the androgenic potential of microspores, whereas the induction of transcripts involved in signaling and cytoprotection was associated with stress responses. Taken together, these expression profiles represent ‘bio-markers’ associated with the androgenic switch in microspores, providing a substantial contribution toward understanding the molecular events underlying stress-induced androgenesis. Show less
