433 results on '"Kleemann R"'
Search Results
2. Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought
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Kozijn, A.E., Gierman, L.M., van der Ham, F., Mulder, P., Morrison, M.C., Kühnast, S., van der Heijden, R.A., Stavro, P.M., van Koppen, A., Pieterman, E.J., van den Hoek, A.M., Kleemann, R., Princen, H.M.G., Mastbergen, S.C., Lafeber, F.P.J.G., Zuurmond, A.-M., Bobeldijk, I., Weinans, H., and Stoop, R.
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- 2018
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3. The Preventive Effect of Exercise and Oral Branched-Chain Amino Acid Supplementation on Obesity-Induced Brain Changes in Ldlr-/-.Leiden Mice.
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Lohkamp, K.J., Hoek, A.M. van den, Solé Guardia, G., Lisovets, M., Alves Hoffmann, T., Velanaki, K., Geenen, B., Verweij, V.G.M., Morrison, M.C., Kleemann, R., Wiesmann, M., Kiliaan, A.J., Lohkamp, K.J., Hoek, A.M. van den, Solé Guardia, G., Lisovets, M., Alves Hoffmann, T., Velanaki, K., Geenen, B., Verweij, V.G.M., Morrison, M.C., Kleemann, R., Wiesmann, M., and Kiliaan, A.J.
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Item does not contain fulltext, Exercise and dietary interventions are promising approaches to tackle obesity and its obesogenic effects on the brain. We investigated the impact of exercise and possible synergistic effects of exercise and branched-chain amino acids (BCAA) supplementation on the brain and behavior in high-fat-diet (HFD)-induced obese Ldlr-/-.Leiden mice. Baseline measurements were performed in chow-fed Ldlr-/-.Leiden mice to assess metabolic risk factors, cognition, and brain structure using magnetic resonance imaging. Thereafter, a subgroup was sacrificed, serving as a healthy reference. The remaining mice were fed an HFD and divided into three groups: (i) no exercise, (ii) exercise, or (iii) exercise and dietary BCAA. Mice were followed for 6 months and aforementioned tests were repeated. We found that exercise alone changed cerebral blood flow, attenuated white matter loss, and reduced neuroinflammation compared to non-exercising HFD-fed mice. Contrarily, no favorable effects of exercise on the brain were found in combination with BCAA, and neuroinflammation was increased. However, cognition was slightly improved in exercising mice on BCAA. Moreover, BCAA and exercise increased the percentage of epididymal white adipose tissue and muscle weight, decreased body weight and fasting insulin levels, improved the circadian rhythm, and transiently improved grip strength. In conclusion, BCAA should be supplemented with caution, although beneficial effects on metabolism, behavior, and cognition were observed.
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- 2023
4. Ldlr-/-.Leiden mice develop neurodegeneration, age-dependent astrogliosis and obesity-induced changes in microglia immunophenotype which are partly reversed by complement component 5 neutralizing antibody.
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Seidel, F., Fluiter, K., Kleemann, R., Worms, N., Nieuwkoop, A. van, Caspers, M.P.M., Grigoriadis, N., Kiliaan, A.J., Baas, F., Michailidou, I., Morrison, M.C., Seidel, F., Fluiter, K., Kleemann, R., Worms, N., Nieuwkoop, A. van, Caspers, M.P.M., Grigoriadis, N., Kiliaan, A.J., Baas, F., Michailidou, I., and Morrison, M.C.
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Contains fulltext : 294954.pdf (Publisher’s version ) (Open Access), INTRODUCTION: Obesity has been linked to vascular dysfunction, cognitive impairment and neurodegenerative diseases. However, experimental models that recapitulate brain pathology in relation to obesity and vascular dysfunction are still lacking. METHODS: In this study we performed the histological and histochemical characterization of brains from Ldlr-/-.Leiden mice, an established model for obesity and associated vascular disease. First, HFD-fed 18 week-old and 50 week-old Ldlr-/-.Leiden male mice were compared with age-matched C57BL/6J mice. We then assessed the effect of high-fat diet (HFD)-induced obesity on brain pathology in Ldlr-/-.Leiden mice and tested whether a treatment with an anti-complement component 5 antibody, a terminal complement pathway inhibitor recently shown to reduce vascular disease, can attenuate neurodegeneration and neuroinflammation. Histological analyses were complemented with Next Generation Sequencing (NGS) analyses of the hippocampus to unravel molecular pathways underlying brain histopathology. RESULTS: We show that chow-fed Ldlr-/-.Leiden mice have more severe neurodegeneration and show an age-dependent astrogliosis that is not observed in age-matched C57BL/6J controls. This was substantiated by pathway enrichment analysis using the NGS data which showed that oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction pathways, all associated with neurodegeneration, were significantly altered in the hippocampus of Ldlr-/-.Leiden mice compared with C57BL/6J controls. Obesity-inducing HFD-feeding did not aggravate neurodegeneration and astrogliosis in Ldlr-/-.Leiden mice. However, brains from HFD-fed Ldlr-/-.Leiden mice showed reduced IBA-1 immunoreactivity and increased CD68 immunoreactivity compared with chow-fed Ldlr-/-.Leiden mice, indicating alteration of microglial immunophenotype by HFD feeding. The systemic administration of an anti-C5 treatment partially restored the HFD effect on microglial immunophenotype. In ad
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- 2023
5. Cognitive Performance during the Development of Diabetes in the Zucker Diabetic Fatty Rat.
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Spoelder, M., Bright, Y., Morrison, M.C., Kempen, V. van, Groodt, L.P.M.T. de, Begalli, M., Schuijt, N., Kruiger, E., Bulthuis, R., Gross, G., Kleemann, R., Diepen, J.A. van, Homberg, J.R., Spoelder, M., Bright, Y., Morrison, M.C., Kempen, V. van, Groodt, L.P.M.T. de, Begalli, M., Schuijt, N., Kruiger, E., Bulthuis, R., Gross, G., Kleemann, R., Diepen, J.A. van, and Homberg, J.R.
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Contains fulltext : 299982.pdf (Publisher’s version ) (Open Access), Increased insulin levels may support the development of neural circuits involved in cognition, while chronic mild inflammation may also result in cognitive impairment. This study aimed to gain more insight into whether cognition is already impacted during adolescence in a genetic rat model for obesity and type 2 diabetes. Visual discrimination learning throughout adolescence and the level of motivation during early adulthood were investigated in Zucker Diabetic Fatty (ZDF) obese and ZDF lean rats using operant touchscreens. Blood glucose, insulin, and lipids were longitudinally analyzed. Histological analyses were performed in the liver, white adipose tissues, and the prefrontal cortex. Prior to the experiments with the genetic ZDF research model, all experimental assays were performed in two groups of outbred Long Evans rats to investigate the effect of different feeding circumstances. Adolescent ZDF obese rats outperformed ZDF lean rats on visual discrimination performance. During the longitudinal cognitive testing period, insulin levels sharply increased over weeks in ZDF obese rats and were significantly enhanced from 6 weeks of age onwards. Early signs of liver steatosis and enlarged adipocytes in white adipose tissue were observed in early adult ZDF obese rats. Histological analyses in early adulthood showed no group differences in the number of prefrontal cortex neurons and microglia, nor PSD95 and SIRT1 mRNA expression levels. Together, our data show that adolescent ZDF obese rats even display enhanced cognition despite their early diabetic profile.
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- 2023
6. Temporal dynamics and nutritional targeting of multi-organ metabolic dysfunctions in non-alcoholic fatty liver disease
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Keijer, J., Morrison, M.C., Kleemann, R., Gart, Eveline, Keijer, J., Morrison, M.C., Kleemann, R., and Gart, Eveline
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- 2023
7. Factors associated with cognitive improvement after bariatric surgery among patients with severe obesity in the Netherlands
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Vreeken, D., Seidel, F., Custers, E.M., Olsthoorn, L., Cools, S., Aarts, E.O., Kleemann, R., Kessels, R.P.C., Wiesmann, M., Hazebroek, E.J., and Kiliaan, A.J.
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All institutes and research themes of the Radboud University Medical Center ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,Neuro- en revalidatiepsychologie ,Neuropsychology and rehabilitation psychology - Abstract
Contains fulltext : 293119.pdf (Publisher’s version ) (Open Access) Importance: Bariatric surgery-induced weight loss is often associated with improved cognitive function. However, improvement in cognitive function is not always exhibited by all patients, and the mechanisms behind cognitive improvement remain unknown. Objective: To investigate the association of changes in adipokines, inflammatory factors, mood, and physical activity with alterations in cognitive function after bariatric surgery among patients with severe obesity. Design, setting, and participants: This cohort study included 156 patients with severe obesity (body mass index [calculated as weight in kilograms divided by height in meters squared], >35) eligible for Roux-en-Y gastric bypass, aged between 35 and 55 years, who were enrolled in the BARICO (Bariatric Surgery Rijnstate and Radboudumc Neuroimaging and Cognition in Obesity) study between September 1, 2018, and December 31, 2020. Follow-up was completed July 31, 2021; 146 participants completed the 6-month follow-up and were included in the analysis. Intervention: Roux-en-Y gastric bypass. Main outcomes and measures: Overall cognitive performance (based on a 20% change index of the compound z score), inflammatory factors (eg, C-reactive protein and interleukin 6 levels), adipokines (eg, leptin and adiponectin levels), mood (assessed via the Beck Depression Inventory), and physical activity (assessed with the Baecke questionnaire). Results: A total of 146 patients (mean [SD] age, 46.1 [5.7] years; 124 women [84.9%]) completed the 6-month follow-up and were included. After bariatric surgery, all plasma levels of inflammatory markers, including C-reactive protein (median change, -0.32 mg/dL [IQR, -0.57 to -0.16 mg/dL]; P < .001) and leptin (median change, -51.5 pg/mL [IQR, -68.0 to -38.4 pg/mL]; P < .001), were lower, whereas adiponectin levels were higher (median change, 0.15 μg/mL [IQR, -0.20 to 0.62 µg/mL]; P < .001), depressive symptoms were (partly) resolved (median change in Beck Depression Inventory score, -3 [IQR, -6 to 0]; P < .001), and physical activity level was higher (mean [SD] change in Baecke score, 0.7 [1.1]; P < .001). Cognitive improvement was observed in 43.8% (57 of 130) of the participants overall. This group had lower C-reactive protein (0.11 vs 0.24 mg/dL; P = .04) and leptin levels (11.8 vs 14.5 pg/mL; P = .04) and fewer depressive symptoms at 6 months (4 vs 5; P = .045) compared with the group of participants who did not show cognitive improvement. Conclusions and relevance: This study suggests that lower C-reactive protein and leptin levels, as well as fewer depressive symptoms, might partly explain the mechanisms behind cognitive improvement after bariatric surgery. 13 p.
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- 2023
8. Butyrate restores HFD-induced adaptations in brain function and metabolism in mid-adult obese mice
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Arnoldussen, I A C, Wiesmann, M, Pelgrim, C E, Wielemaker, E M, van Duyvenvoorde, W, Amaral-Santos, P L, Verschuren, L, Keijser, B J F, Heerschap, A, Kleemann, R, Wielinga, P Y, and Kiliaan, A J
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- 2017
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9. Intervention with a caspase-1 inhibitor reduces obesity-associated hyperinsulinemia, non-alcoholic steatohepatitis and hepatic fibrosis in LDLR-/-.Leiden mice
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Morrison, M C, Mulder, P, Salic, K, Verheij, J, Liang, W, van Duyvenvoorde, W, Menke, A, Kooistra, T, Kleemann, R, and Wielinga, P Y
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- 2016
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10. Milk fat globule membrane attenuates high fat diet-induced neuropathological changes in obese Ldlr-/-.Leiden mice
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Arnoldussen, I.A.C., Morrison, M.C., Wiesmann, M., Diepen, J.A. van, Worms, N., Voskuilen, M., Verweij, V.G.M., Geenen, B., Pujol Gualdo, Natalia, Logt, Lonneke van der, Gross, Gabriele, Kleemann, R., Kiliaan, A.J., Arnoldussen, I.A.C., Morrison, M.C., Wiesmann, M., Diepen, J.A. van, Worms, N., Voskuilen, M., Verweij, V.G.M., Geenen, B., Pujol Gualdo, Natalia, Logt, Lonneke van der, Gross, Gabriele, Kleemann, R., and Kiliaan, A.J.
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Item does not contain fulltext, BACKGROUND: Milk-fat globule membrane (MFGM) is a complex structure secreted by the mammary gland and present in mammalian milk. MFGM contains lipids and glycoproteins as well as gangliosides, which may be involved in myelination processes. Notably, myelination and thereby white matter integrity are often altered in obesity. Furthermore, MFGM interventions showed beneficial effects in obesity by affecting inflammatory processes and the microbiome. In this study, we investigated the impact of a dietary MFGM intervention on fat storage, neuroinflammatory processes and myelination in a rodent model of high fat diet (HFD)-induced obesity. METHODS: 12-week-old male low density lipoprotein receptor-deficient Leiden mice were exposed to a HFD, a HFD enriched with 3% whey protein lipid concentrate (WPC) high in MFGM components, or a low fat diet. The impact of MFGM supplementation during 24-weeks of HFD-feeding was examined over time by analyzing body weight and fat storage, assessing cognitive tasks and MRI scanning, analyzing myelinization with polarized light imaging and examining neuroinflammation using immunohistochemistry. RESULTS: We found in this study that 24 weeks of HFD-feeding induced excessive fat storage, increased systolic blood pressure, altered white matter integrity, decreased functional connectivity, induced neuroinflammation and impaired spatial memory. Notably, supplementation with 3% WPC high in MFGM components restored HFD-induced neuroinflammation and attenuated the reduction in hippocampal-dependent spatial memory and hippocampal functional connectivity. CONCLUSIONS: We showed that supplementation with WPC high in MFGM components beneficially contributed to hippocampal-dependent spatial memory, functional connectivity in the hippocampus and anti-inflammatory processes in HFD-induced obesity in rodents. Current knowledge regarding exact biological mechanisms underlying these effects should be addressed in future studies.
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- 2022
11. High fat diet-induced obesity prolongs critical stages of the spermatogenic cycle in a Ldlr(-/-).Leiden mouse model
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Komninos, D., Ramos, L., Heijden, G.W. van der, Morrison, M.C., Kleemann, R., Herwaarden, A.E. van, Kiliaan, A.J., Arnoldussen, I.A.C., Komninos, D., Ramos, L., Heijden, G.W. van der, Morrison, M.C., Kleemann, R., Herwaarden, A.E. van, Kiliaan, A.J., and Arnoldussen, I.A.C.
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Item does not contain fulltext
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- 2022
12. Inflammatory lipid sphingosine-1-phosphate upregulates C-reactive protein via C/EBPβ and potentiates breast cancer progression
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Kim, E-S, Cha, Y, Ham, M, Jung, J, Kim, S G, Hwang, S, Kleemann, R, and Moon, A
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- 2014
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13. Surgical removal of inflamed epididymal white adipose tissue attenuates the development of non-alcoholic steatohepatitis in obesity
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Mulder, P, Morrison, M C, Wielinga, P Y, van Duyvenvoorde, W, Kooistra, T, and Kleemann, R
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- 2016
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14. 2283P Assessing the replicative potential of the oncolytic virus VSV-GP in patient-derived tumor biopsies ex vivo
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Schoeps, B., Mayr, M., Glatz, M., Estermann, S., Tort, A. Guerrero, Scheidl, S., Knobbe-Thomsen, C., Nolden, T., Schneeberger, S., Elbers, K., Lauer, U., Kloker, L., Berchtold, S., Beil, J., Yurttas, C., Kleemann, R., and Petersson, M.
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- 2023
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15. Propionic acid and not caproic acid, attenuates nonalcoholic steatohepatitis and improves (cerebro) vascular functions in obese Ldlr−/−.Leiden mice
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Tengeler, A.C., Gart, E., Wiesmann, M., Arnoldussen, I.A.C., Verschuren, L., Duyvenvoorde, W. van, Hoogstad, M., Dederen, P.J., Verweij, V., Geenen, B., Kozicz, T., Kleemann, R., Morrison, M.C., and Kiliaan, A.J.
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Mice ,nutritional and metabolic diseases ,food and beverages ,Caproic acid ,Nonalcoholic steatohepatitis ,Propionic acid ,Obese - Abstract
The obesity epidemic increases the interest to elucidate impact of short‐chain fatty acids on metabolism, obesity, and the brain. We investigated the effects of propionic acid (PA) and caproic acid (CA) on metabolic risk factors, liver and adipose tissue pathology, brain function, structure (by MRI), and gene expression, during obesity development in Ldlr−/−.Leiden mice. Ldlr−/−.Leiden mice received 16 weeks either a high‐fat diet (HFD) to induce obesity, or chow as reference group. Next, obese HFD‐fed mice were treated 12 weeks with (a) HFD + CA (CA), (b) HFD + PA (PA), or (c) a HFD‐control group. PA reduced the body weight and systolic blood pressure, lowered fasting insulin levels, and reduced HFD‐induced liver macrovesicular steatosis, hypertrophy, inflammation, and collagen content. PA increased the amount of glucose transporter type 1‐positive cerebral blood vessels, reverted cerebral vasoreactivity, and HFD‐induced effects in microstructural gray and white matter integrity of optic tract, and somatosensory and visual cortex. PA and CA also reverted HFD‐induced effects in functional connectivity between visual and auditory cortex. However, PA mice were more anxious in open field, and showed reduced activity of synaptogenesis and glutamate regulators in hippocampus. Therefore, PA treatment should be used with caution even though positive metabolic, (cerebro) vascular, and brain structural and functional effects were observed.The obesity epidemic increases the interest to elucidate impact of short‐chain fatty acids on metabolism, obesity, and the brain. We investigated the effects of propionic acid (PA) and caproic acid (CA) on metabolic risk factors, liver and adipose tissue pathology, brain function, structure (by MRI), and gene expression, during obesity development in Ldlr−/−.Leiden mice. Ldlr−/−.Leiden mice received 16 weeks either a high‐fat diet (HFD) to induce obesity, or chow as reference group. Next, obese HFD‐fed mice were treated 12 weeks with (a) HFD + CA (CA), (b) HFD + PA (PA), or (c) a HFD‐control group. PA reduced the body weight and systolic blood pressure, lowered fasting insulin levels, and reduced HFD‐induced liver macrovesicular steatosis, hypertrophy, inflammation, and collagen content. PA increased the amount of glucose transporter type 1‐positive cerebral blood vessels, reverted cerebral vasoreactivity, and HFD‐induced effects in microstructural gray and white matter integrity of optic tract, and somatosensory and visual cortex. PA and CA also reverted HFD‐induced effects in functional connectivity between visual and auditory cortex. However, PA mice were more anxious in open field, and showed reduced activity of synaptogenesis and glutamate regulators in hippocampus. Therefore, PA treatment should be used with caution even though positive metabolic, (cerebro) vascular, and brain structural and functional effects were observed.
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- 2020
16. Propionic acid and not caproic acid, attenuates nonalcoholic steatohepatitis and improves (cerebro) vascular functions in obese Ldlr(-/-) .Leiden mice
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Tengeler, A.C., Gart, E., Wiesmann, M., Arnoldussen, I.A.C., Duyvenvoorde, W. van, Hoogstad, M., Dederen, P.J.W.C., Verweij, V.G.M., Geenen, B., Kozicz, T., Kleemann, R., Morrison, M.C., Kiliaan, A.J., Tengeler, A.C., Gart, E., Wiesmann, M., Arnoldussen, I.A.C., Duyvenvoorde, W. van, Hoogstad, M., Dederen, P.J.W.C., Verweij, V.G.M., Geenen, B., Kozicz, T., Kleemann, R., Morrison, M.C., and Kiliaan, A.J.
- Abstract
Contains fulltext : 225913.pdf (Publisher’s version ) (Open Access), The obesity epidemic increases the interest to elucidate impact of short-chain fatty acids on metabolism, obesity, and the brain. We investigated the effects of propionic acid (PA) and caproic acid (CA) on metabolic risk factors, liver and adipose tissue pathology, brain function, structure (by MRI), and gene expression, during obesity development in Ldlr(-/-) .Leiden mice. Ldlr(-/-) .Leiden mice received 16 weeks either a high-fat diet (HFD) to induce obesity, or chow as reference group. Next, obese HFD-fed mice were treated 12 weeks with (a) HFD + CA (CA), (b) HFD + PA (PA), or (c) a HFD-control group. PA reduced the body weight and systolic blood pressure, lowered fasting insulin levels, and reduced HFD-induced liver macrovesicular steatosis, hypertrophy, inflammation, and collagen content. PA increased the amount of glucose transporter type 1-positive cerebral blood vessels, reverted cerebral vasoreactivity, and HFD-induced effects in microstructural gray and white matter integrity of optic tract, and somatosensory and visual cortex. PA and CA also reverted HFD-induced effects in functional connectivity between visual and auditory cortex. However, PA mice were more anxious in open field, and showed reduced activity of synaptogenesis and glutamate regulators in hippocampus. Therefore, PA treatment should be used with caution even though positive metabolic, (cerebro) vascular, and brain structural and functional effects were observed.
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- 2020
17. Lipid ratios representing SCD1, FADS1, and FADS2 activities as candidate biomarkers of early growth and adiposity
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Olga, L., primary, van Diepen, J.A., additional, Bobeldijk-Pastorova, I., additional, Gross, G., additional, Prentice, P.M., additional, Snowden, S.G., additional, Furse, S., additional, Kooistra, T., additional, Hughes, I.A., additional, Schoemaker, M.H., additional, van Tol, E.A.F., additional, van Duyvenvoorde, W., additional, Wielinga, P.Y., additional, Ong, K.K., additional, Dunger, D.B., additional, Kleemann, R., additional, and Koulman, A., additional
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- 2021
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18. Metabolic stress–induced inflammation plays a major role in the development of osteoarthritis in mice
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Gierman, L. M., van der Ham, F., Koudijs, A., Wielinga, P. Y., Kleemann, R., Kooistra, T., Stoop, R., Kloppenburg, M., van Osch, G. J. V. M., Stojanovic-Susulic, V., Huizinga, T. W., and Zuurmond, A.-M.
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- 2012
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19. GENOME-WIDE HEPATIC TRANSCRIPTOME EFFECTS OF ANTI-DIABETIC DRUGS AND A LIFESTYLE INTERVENTION IN MOUSE MODELS OF METABOLIC SYNDROME
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Radonjic, M., van Erk, M., Verschuren, L., Wielinga, P. Y., Kooistra, T., van Ommen, B., and Kleemann, R.
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- 2011
20. MIF-DEFICIENCY REDUCES CHRONIC INFLAMMATION IN ADIPOSE TISSUE AND IMPAIRS INSULIN RESISTANCE, GLUCOSE INTOLERANCE AND ASSOCIATED ATHEROSCLEROSIS
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Verschuren, L., Kooistra, T., Bernhagen, J., Ouwens, M., Erk, van M., Voshol, P. J., der Weij, Vries-van J. de, Bockel, van J.H., Dijk, van K.W., Fingerle-Rowson, G., Bucala, R., and Kleemann, R.
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- 2009
21. High fat diet-induced obesity prolongs critical stages of the spermatogenic cycle in a Ldlr−/−.Leiden mouse model.
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Komninos, D., Ramos, L., van der Heijden, G. W., Morrison, M. C., Kleemann, R., van Herwaarden, A. E., Kiliaan, A. J., and Arnoldussen, I. A. C.
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HIGH-fat diet ,LABORATORY mice ,SERTOLI cells ,ANIMAL disease models ,LIPOPROTEIN receptors ,LEPTIN ,LEPTIN receptors - Abstract
Obesity can disturb spermatogenesis and subsequently affect male fertility and reproduction. In our study, we aim to elucidate at which cellular level of adult spermatogenesis the detrimental effects of obesity manifest. We induced high fat diet (HFD) obesity in low-density lipoprotein receptor knock-out Leiden (Ldlr
−/− .Leiden) mice, and studied the morphological structure of the testes and histologically examined the proportion of Sertoli cells, spermatocytes and spermatids in the seminiferous tubules. We examined sperm DNA damage and chromatin condensation and measured plasma levels of leptin, testosterone, cholesterol and triglycerides. HFD-induced obesity caused high plasma leptin and abnormal testosterone levels and induced an aberrant intra-tubular organisation (ITO) which is associated with an altered spermatids/spermatocytes ratio (2:1 instead of 3:1). Mice fed a HFD had a higher level of tubules in stages VII + VIII in the spermatogenic cycle. The stages VII + VII indicate crucial processes in spermatogenic development like initiation of meiosis, initiation of spermatid elongation, and release of fully matured spermatids. In conclusion, HFD-induced obese Ldlr−/− .Leiden mice develop an aberrant ITO and alterations in the spermatogenic cycle in crucial stages (stages VII and VII). Thereby, our findings stress the importance of lifestyle guidelines in infertility treatments. [ABSTRACT FROM AUTHOR]- Published
- 2022
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22. Oral insulin for diabetes prevention in NOD mice: potentiation by enhancing Th2 cytokine expression in the gut through bacterial adjuvant
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Hartmann, B., Bellmann, K., Ghiea, I., Kleemann, R., and Kolb, H.
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- 1997
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23. Cytokine gene expression in the BB rat pancreas: natural course and impact of bacterial vaccines
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Kolb, H., Wörz-Pagenstert, U., Kleemann, R., Rothe, H., Rowsell, P., and Scott, F. W.
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- 1996
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24. Study rationale and protocol of the BARICO study: A longitudinal, prospective, observational study to evaluate the effects of weight loss on brain function and structure after bariatric surgery
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Vreeken, D., Wiesmann, M., Deden, L.N., Arnoldussen, I.A.C., Aarts, E., Kessels, R.P.C., Kleemann, R., Hazebroek, E.J., Aarts, E.O., and Kiliaan, A.J.
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Bariatric surgery ,Weight loss ,Ccognition ,Neuroimaging ,Obesity ,Biology - Abstract
Introduction Weight loss after bariatric surgery (BS) is often associated with improved cognition and structural brain recovery. However, improved cognition after BS is not always exhibited by patients, in fact, in some cases there is even a decline in cognition. Long-term consequences of BS weight loss, in terms of obesity and related diseases, can be hard to determine due to studies having short follow-up periods and small sample sizes. The aim of the BARICO study (BAriatric surgery Rijnstate and Radboudumc neuroImaging and Cognition in Obesity) is to determine the long-term effect of weight loss after BS on brain function and structure, using sensitive neuropsychological tests and (functional) MRI ((f)MRI). Secondary study endpoints are associated with changes in metabolic and inflammation status of adipose tissue, liver and gut, in relation to brain structure and function. Also, the possible correlation between weight loss, gut microbiota composition change and neuropsychological outcomes will be investigated. Methods and analysis Data from 150 Dutch BS patients (ages between 35 and 55, men and women) will be collected at various time points between 2 months before and up to 10 years after surgery. Neuropsychological tests, questionnaires, blood, faeces and tissue samples will be collected before, during and after surgery to measure changes in cognition, microbiota, metabolic activity and inflammation over time. A subgroup of 75 participants will undergo (f)MRI in relation to executive functioning (determined by the Stroop task), grey and white matter volumes and cerebral blood flow. Regression analyses will be used to explore associations between weight loss and outcome measures. Ethics and dissemination This study has been approved by the medical review ethics committee CMO Region Arnhem and Nijmegen (NL63493.091.17). Research findings will be published in peer-reviewed journals and at conferences. Trial registration number NTR7288. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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- 2019
25. A novel nutritional supplement prevents muscle loss and accelerates muscle mass recovery in caloric-restricted mice
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Hoek, A.M. van den, Zondag, G.C.M., Verschuren, L., Ruiter, C. de, Attema, J., Wit, E.C. de, Schwerk, A.M.K., Guigas, B., Rietman, A., Strijker, R., and Kleemann, R.
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Medical nutrition ,Sarcopenia ,Life ,Malnutrition ,Biomedical Innovation ,Muscle atrophy ,ELSS - Earth, Life and Social Sciences ,MHR - Metabolic Health Research ,Healthy Living - Abstract
BACKGROUND: Muscle atrophy is defined as decreased muscle mass, associated with aging as well as with various chronic diseases and is a fundamental cause of frailty, functional decline and disability. Frailty represents a huge potential public health issue worldwide with high impact on healthcare costs. A major clinical issue is therefore to devise new strategies preventing muscle atrophy. In this study, we tested the efficacy of Vital01, a novel oral nutritional supplement (ONS), on body weight and muscle mass using a caloric restriction-induced mouse model for muscle atrophy. METHODS: Mice were calorically restricted for 2 weeks to induce muscle atrophy: one control group received 60% kcal of the normal chow diet and one intervention group received 30% kcal chow and 30 kcal% Vital01. The effects on body weight, lean body mass, muscle histology and transcriptome were assessed. In addition, the effects of Vital01, in mice with established muscle atrophy, were assessed and compared to a standard ONS. To this end, mice were first calorically restricted on a 60% kcal chow diet and then refed with either 100 kcal% chow, a mix of Vital01 (receiving 60% kcal chow and 40 kcal% Vital01) or with a mix of standard, widely prescribed ONS (receiving 60 kcal% chow and 40 kcal% Fortisip Compact). RESULTS: Vital01 attenuated weight loss (-15% weight loss for Vital01 vs. -25% for control group, p
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- 2019
26. Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis
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Salic, K., Gart, E., Verschuren, L., Duyvenvoorde, W. van, Wong, K.E., Keijer, J., Bobeldijk-Pastorova, I., Wielinga, P.Y., and Kleemann, R.
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Lipid peroxidation ,Metabolomics ,β-oxidation ,Obesity ,Transcriptomics ,Acylcarnitines ,Mitochondria ,Non-alcoholic fatty liver disease - Abstract
Obesity characterized by adiposity and ectopic fat accumulation is associated with the development of non-alcoholic fatty liver disease (NAFLD). Treatments that stimulate lipid utilization may prevent the development of obesity and comorbidities. This study evaluated the potential anti-obesogenic hepatoprotective effects of combined treatment with L-carnitine and nicotinamide riboside, i.e., components that can enhance fatty acid transfer across the inner mitochondrial membrane and increase nicotinamide adenine nucleotide (NAD+) levels, which are necessary for β-oxidation and the TCA cycle, respectively. Ldlr −/−.Leiden mice were treated with high-fat diet (HFD) supplemented with L-carnitine (LC; 0.4% w/w), nicotinamide riboside (NR; 0.3% w/w) or both (COMBI) for 21 weeks. L-carnitine plasma levels were reduced by HFD and normalized by LC. NR supplementation raised its plasma metabolite levels demonstrating effective delivery. Although food intake and ambulatory activity were comparable in all groups, COMBI treatment significantly attenuated HFD-induced body weight gain, fat mass gain (−17%) and hepatic steatosis (−22%). Also, NR and COMBI reduced hepatic 4-hydroxynonenal adducts. Upstream-regulator gene analysis demonstrated that COMBI reversed detrimental effects of HFD on liver metabolism pathways and associated regulators, e.g., ACOX, SCAP, SREBF, PPARGC1B, and INSR. Combination treatment with LC and NR exerts protective effects on metabolic pathways and constitutes a new approach to attenuate HFD-induced obesity and NAFLDObesity characterized by adiposity and ectopic fat accumulation is associated with the development of non-alcoholic fatty liver disease (NAFLD). Treatments that stimulate lipid utilization may prevent the development of obesity and comorbidities. This study evaluated the potential anti-obesogenic hepatoprotective effects of combined treatment with L-carnitine and nicotinamide riboside, i.e., components that can enhance fatty acid transfer across the inner mitochondrial membrane and increase nicotinamide adenine nucleotide (NAD+) levels, which are necessary for β-oxidation and the TCA cycle, respectively. Ldlr −/−.Leiden mice were treated with high-fat diet (HFD) supplemented with L-carnitine (LC; 0.4% w/w), nicotinamide riboside (NR; 0.3% w/w) or both (COMBI) for 21 weeks. L-carnitine plasma levels were reduced by HFD and normalized by LC. NR supplementation raised its plasma metabolite levels demonstrating effective delivery. Although food intake and ambulatory activity were comparable in all groups, COMBI treatment significantly attenuated HFD-induced body weight gain, fat mass gain (−17%) and hepatic steatosis (−22%). Also, NR and COMBI reduced hepatic 4-hydroxynonenal adducts. Upstream-regulator gene analysis demonstrated that COMBI reversed detrimental effects of HFD on liver metabolism pathways and associated regulators, e.g., ACOX, SCAP, SREBF, PPARGC1B, and INSR. Combination treatment with LC and NR exerts protective effects on metabolic pathways and constitutes a new approach to attenuate HFD-induced obesity and NAFLD.
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- 2019
27. Sex-Specific Differences in Fat Storage, Development of Non-Alcoholic Fatty Liver Disease and Brain Structure in Juvenile HFD-Induced Obese Ldlr-/-.Leiden Mice
- Author
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Jacobs, S.A.H., Gart, E., Vreeken, D., Franx, B.A.A., Wekking, L., Verweij, V.G.M., Worms, N., Schoemaker, M.H., Gross, G., Morrison, M.C., Kleemann, R., Arnoldussen, I.A.C., and Kiliaan, A.J.
- Subjects
Juvenile ,Sex ,Obesity - Abstract
Background: Sex-specific differences play a role in metabolism, fat storage in adipose tissue, and brain structure. At juvenile age, brain function is susceptible to the effects of obesity; little is known about sex-specific differences in juvenile obesity. Therefore, this study examined sex-specific differences in adipose tissue and liver of high-fat diet (HFD)-induced obese mice, and putative alterations between male and female mice in brain structure in relation to behavioral changes during the development of juvenile obesity. Methods: In six-week-old male and female Ldlr-/-.Leiden mice (n = 48), the impact of 18 weeks of HFD-feeding was examined. Fat distribution, liver pathology and brain structure and function were analyzed imunohisto- and biochemically, in cognitive tasks and with MRI. Results: HFD-fed female mice were characterized by an increased perigonadal fat mass, pronounced macrovesicular hepatic steatosis and liver inflammation. Male mice on HFD displayed an increased mesenteric fat mass, pronounced adipose tissue inflammation and microvesicular hepatic steatosis. Only male HFD-fed mice showed decreased cerebral blood flow and reduced white matter integrity. Conclusions: At young age, male mice are more susceptible to the detrimental effects of HFD than female mice. This study emphasizes the importance of sex-specific differences in obesity, liver pathology, and brain function.
- Published
- 2019
28. Cyclophosphamide treatment of female non-obese diabetic mice causes enhanced expression of inducible nitric oxide synthase and interferon-gamma, but not of interleukin-4
- Author
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Rothe, H., Faust, A., Schade, U., Kleemann, R., Bosse, G., Hibino, T., Martin, S., and Kolb, H.
- Published
- 1994
- Full Text
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29. Innovationen
- Author
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Duda, G., primary, Blücher, U., additional, Hoffmann, J.-E., additional, Kleemann, R., additional, Weiler, A., additional, Hinterwimmer, S., additional, Glaser, C., additional, Burgkart, R., additional, Baumgart, R., additional, Englmeier, K.-H., additional, Reiser, M., additional, Eckstein, F., additional, Jerosch, J., additional, Filler, T., additional, Peuker, E., additional, Schunck, J., additional, Riechert, K., additional, Labs, K., additional, Zippel, H., additional, Pokinskyj, P., additional, Sandner, B., additional, Schilke, F., additional, Ignatius, A., additional, Linhart, W., additional, Kock, H.-J., additional, Amlang, M., additional, Heinz, P., additional, Zwipp, H., additional, Mentzel, M., additional, Wachter, N. J., additional, Merk, S. E., additional, Ebinger, T., additional, Kinzl, L., additional, Grass, R., additional, Biewener, A., additional, Rammelt, S., additional, Briem, D., additional, Meenen, N. M., additional, Rueger, J. M., additional, and Müller-Haberstock, S., additional
- Published
- 2001
- Full Text
- View/download PDF
30. HMG-CoA Reductase Inhibitors: Effects on Chronic Subacute Inflammation and Onset of Atherosclerosis Induced by Dietary Cholesterol
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Kleemann, R. and Kooistra, T.
- Published
- 2005
31. Nonresonant Raman spectroscopy of isolated human retina samples complying with laser safety regulations for in vivo measurements.
- Author
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Stiebing, C., Schie, I.W., Knorr, F., Schmitt, M., Keijzer, N., Kleemann, R., Jahn, I.J., Jahn, M., Kiliaan, A.J., Ginner, L., Lichtenegger, A., Drexler, W., Leitgeb, R.A., Popp, J., Stiebing, C., Schie, I.W., Knorr, F., Schmitt, M., Keijzer, N., Kleemann, R., Jahn, I.J., Jahn, M., Kiliaan, A.J., Ginner, L., Lichtenegger, A., Drexler, W., Leitgeb, R.A., and Popp, J.
- Abstract
Contains fulltext : 214852.pdf (publisher's version ) (Open Access), Retinal diseases, such as age-related macular degeneration, are leading causes of vision impairment, increasing in incidence worldwide due to an aging society. If diagnosed early, most cases could be prevented. In contrast to standard ophthalmic diagnostic tools, Raman spectroscopy can provide a comprehensive overview of the biochemical composition of the retina in a label-free manner. A proof of concept study of the applicability of nonresonant Raman spectroscopy for retinal investigations is presented. Raman imaging provides valuable insights into the molecular composition of an isolated ex vivo human retina sample by probing the entire molecular fingerprint, i.e., the lipid, protein, carotenoid, and nucleic acid content. The results are compared to morphological information obtained by optical coherence tomography of the sample. The challenges of in vivo Raman studies due to laser safety limitations and predefined optical parameters given by the eye itself are explored. An in-house built setup simulating the optical pathway in the human eye was developed and used to demonstrate that even under laser safety regulations and the above-mentioned optical restrictions, Raman spectra of isolated ex vivo human retinas can be recorded. The results strongly support that in vivo studies using nonresonant Raman spectroscopy are feasible and that these studies provide comprehensive molecular information of the human retina.
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- 2019
32. Key Inflammatory Processes in Human NASH Are Reflected in Ldlr−/−.Leiden Mice: A Translational Gene Profiling Study
- Author
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Morrison, M.C., Kleemann, R., Koppen, A. van, Hanemaaijer, R., and Verschuren, L.
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Mouse ,Nonalcoholic fatty liver ,Biomedical Innovation ,Life ,Animal model ,Animal experiment ,Human tissue ,Transcriptomics ,Biology ,Cytokine ,Inflammation ,NASH ,Translational ,nutritional and metabolic diseases ,Molecular ,Growth factor ,Extracellular matrix ,Liver biopsy ,Lipid diet ,Nonhuman ,Gene expression profiling ,Lipid metabolism ,Liver ,Gene expression ,ELSS - Earth, Life and Social Sciences ,Transcription factor ,MHR - Metabolic Health Research ,Controlled study ,Healthy Living ,Human - Abstract
Introduction: It is generally accepted that metabolic inflammation in the liver is an important driver of disease progression in NASH and associated matrix remodeling/fibrosis. However, the exact molecular inflammatory mechanisms are poorly defined in human studies. Investigation of key pathogenic mechanisms requires the use of pre-clinical models, for instance for time-resolved studies. Such models must reflect molecular disease processes of importance in patients. Herein we characterized inflammation in NASH patients on the molecular level by transcriptomics and investigated whether key human disease pathways can be recapitulated experimentally in Ldlr−/−.Leiden mice, an established pre-clinical model of NASH. Methods: Human molecular inflammatory processes were defined using a publicly available NASH gene expression profiling dataset (GSE48452) allowing the comparison of biopsy-confirmed NASH patients with normal controls. Gene profiling data from high-fat diet (HFD)-fed Ldlr−/−.Leiden mice (GSE109345) were used for assessment of the translational value of these mice. Results: In human NASH livers, we observed regulation of 65 canonical pathways of which the majority was involved in inflammation (32%), lipid metabolism (16%), and extracellular matrix/remodeling (12%). A similar distribution of pathways across these categories, inflammation (36%), lipid metabolism (24%) and extracellular matrix/remodeling (8%) was observed in HFD-fed Ldlr−/−.Leiden mice. Detailed evaluation of these pathways revealed that a substantial proportion (11 out of 13) of human NASH inflammatory pathways was recapitulated in Ldlr−/−.Leiden mice. Furthermore, the activation state of identified master regulators of inflammation (i.e., specific transcription factors, cytokines, and growth factors) in human NASH was largely reflected in Ldlr−/−.Leiden mice, further substantiating its translational value. Conclusion: Human NASH is characterized by upregulation of specific inflammatory processes (e.g., “Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes,” “PI3K signaling in B Lymphocytes”) and master regulators (e.g., TNF, CSF2, TGFB1). The majority of these processes and regulators are modulated in the same direction in Ldlr−/−.Leiden mice fed HFD with a human-like macronutrient composition, thus demonstrating that specific experimental conditions recapitulate human disease on the molecular level of disease pathways and upstream/master regulators.
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- 2018
33. Extra-Virgin Olive Oil with Natural Phenolic Content Exerts an Anti-Inflammatory Effect in Adipose Tissue and Attenuates the Severity of Atherosclerotic Lesions in Ldlr−/−.Leiden Mice
- Author
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Luque-Sierra, A., Alvarez-Amor, L., Kleemann, R., Martín, F., and Varela, L.M.
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Inflammation ,High-fat diet ,digestive, oral, and skin physiology ,Extra-virgin olive oil ,nutritional and metabolic diseases ,food and beverages ,Obesity ,Healthy for Life ,Atherosclerosis ,Healthy Living ,Nutrition - Abstract
Scope: The present study investigates the effect of olive oils with different phenolic content in high-fat diets (HFDs) on hypertrophy and inflammation in adipose tissue and associated atherosclerosis, in the context of obesity. Methods and results: Ldlr−/−.Leiden mice were fed three different HFDs for 32 weeks and were compared with mice fed the standard low-fat diet (LFD). The different fats provided in the HFDs were lard (HFD-L), extra-virgin olive oil (EVOO; 79 mg kg–1 of phenolic compounds, HFD-EVOO), or EVOO rich in phenolic compounds (OL, 444 mg kg–1 of phenolic compounds, HFD-OL). All HFD-fed mice became obese, but only HFD-L–induced adipocyte hypertrophy. HFD-EVOO mice exhibited the greatest levels of Adiponectin in adipose tissue and presented atherosclerotic lesions similar to the LFD group, with a very low count of monocyte/macrophage compared with HFD-L and HFD-OL mice. Enrichment of the phenolic content of olive oil reduced the secretion of nitrites/nitrates in the aorta, but atherosclerosis was not attenuated in HFD-OL mice compared to other HFD mice. Conclusion: Consumption of olive oil with a natural content of phenolic compounds attenuates adipose tissue hypertrophy and inflammation and exerts antiatherosclerotic effects in mice. A higher phenolic content of olive oil did not provide further benefits in the prevention of atherosclerosis. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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- 2018
34. Cardiovascular effects among workers exposed to multiwalled carbon nanotubes
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Kuijpers, E., Pronk, A., Kleemann, R., Vlaanderen, J., Lan, Q., Rothman, N., Silverman, D., Hoet, P., and Vermeulen, R.
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Multi-walled carbon nanotubes (mwcnts) ,Human biomarkers ,Cardiovascular effects ,Endothelial damage marker Icam-1 - Abstract
Objectives: The increase in production of multiwalled carbon nanotubes (MWCNTs) has led to growing concerns about health risks. In this study, we assessed the association between occupational exposure to MWCNTs and cardiovascular biomarkers. Methods: A cross-sectional study was performed among 22 workers of a company commercially producing MWCNTs (subdivided into lab personnel with low or high exposure and operators), and a gender and age-matched unexposed population (n=42). Exposure to MWCNTs and 12 cardiovascular markers were measured in participants' blood (phase I). In a subpopulation of 13 exposed workers and six unexposed workers, these measures were repeated after 5 months (phase II). We analysed associations between MWCNT exposure and biomarkers of cardiovascular risk, adjusted for age, body mass index, sex and smoking. Results: We observed an upward trend in the concentration of endothelial damage marker intercellular adhesion molecule-1 (ICAM-1), with increasing exposure to MWCNTs in both phases. The operator category showed significantly elevated ICAM-1 geometric mean ratios (GMRs) compared with the controls (phase I: GMR=1.40, P=1.30E-3; phase II: GMR=1.37, P=0.03). The trends were significant both across worker categories (phase I: P=1.50E-3; phase II: P=0.01) and across measured GM MWCNT concentrations (phase I: P=3.00E-3; phase II: P=0.01). No consistent significant associations were found for the other cardiovascular markers. Conclusion: The associations between MWCNT exposure and ICAM-1 indicate endothelial activation and an increased inflammatory state in workers with MWCNT exposure
- Published
- 2018
35. Variable cartilage degradation in mice with diet-induced metabolic dysfunction : food for thought
- Author
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Kozijn, A. E., Gierman, L. M., van der Ham, F., Mulder, P., Morrison, M. C., Kühnast, S., van der Heijden, R. A., Stavro, P. M., van Koppen, A., Pieterman, E. J., van den Hoek, A. M., Kleemann, R., Princen, H. M.G., Mastbergen, S. C., Lafeber, F. P.J.G., Zuurmond, A. M., Bobeldijk, I., Weinans, H., Stoop, R., Kozijn, A. E., Gierman, L. M., van der Ham, F., Mulder, P., Morrison, M. C., Kühnast, S., van der Heijden, R. A., Stavro, P. M., van Koppen, A., Pieterman, E. J., van den Hoek, A. M., Kleemann, R., Princen, H. M.G., Mastbergen, S. C., Lafeber, F. P.J.G., Zuurmond, A. M., Bobeldijk, I., Weinans, H., and Stoop, R.
- Published
- 2018
36. Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought
- Author
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Verpleegafd Orthopaedie D4 west, Regenerative Medicine and Stem Cells, Pathologie Groep Goldschmeding, Lab Reumatologie/Klinische Immunologie, Infection & Immunity, Kozijn, A. E., Gierman, L. M., van der Ham, F., Mulder, P., Morrison, M. C., Kühnast, S., van der Heijden, R. A., Stavro, P. M., van Koppen, A., Pieterman, E. J., van den Hoek, A. M., Kleemann, R., Princen, H. M.G., Mastbergen, S. C., Lafeber, F. P.J.G., Zuurmond, A. M., Bobeldijk, I., Weinans, H., Stoop, R., Verpleegafd Orthopaedie D4 west, Regenerative Medicine and Stem Cells, Pathologie Groep Goldschmeding, Lab Reumatologie/Klinische Immunologie, Infection & Immunity, Kozijn, A. E., Gierman, L. M., van der Ham, F., Mulder, P., Morrison, M. C., Kühnast, S., van der Heijden, R. A., Stavro, P. M., van Koppen, A., Pieterman, E. J., van den Hoek, A. M., Kleemann, R., Princen, H. M.G., Mastbergen, S. C., Lafeber, F. P.J.G., Zuurmond, A. M., Bobeldijk, I., Weinans, H., and Stoop, R.
- Published
- 2018
37. Prolonged high-fat diet induces gradual and fat depot-specific DNA methylation changes in adult mice
- Author
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Slieker, R.C., Mulder, P.C.A., Zoetemelk, I., Verschuren, L., Suchiman, H.E.D., Toet, K.H., Droog, S., Slagboom, P.E., Kooistra, T., Kleemann, R., and Heijmans, B.T.
- Subjects
Life ,digestive, oral, and skin physiology ,food and beverages ,nutritional and metabolic diseases ,Biomedical Innovation ,MHR - Metabolic Health Research MSB - Microbiology and Systems Biology ,ELSS - Earth, Life and Social Sciences ,Biology ,Healthy Living ,hormones, hormone substitutes, and hormone antagonists - Abstract
High-fat diets (HFD) are thought to contribute to the development of metabolism-related diseases. The long-term impact of HFD may be mediated by epigenetic mechanisms, and indeed, HFD has been reported to induce DNA methylation changes in white adipose tissue (WAT) near metabolism related genes. However, previous studies were limited to a single WAT depot, a single time-point and primarily examined the pre-pubertal period. To define dynamic DNA methylation patterns specific for WAT depots, we investigated DNA methylation of Pparg2 and Leptin in gonadal adipose tissue (GAT) and subcutaneous adipose tissue (SAT), at baseline and after 6, 12 and 24 weeks of HFD exposure in adult mice. HFD induced hypermethylation of both the Leptin promoter (max. 19.6% at week 24, P = 2.6·10−3) and the Pparg2 promoter in GAT (max. 10.5% at week 12, P = 0.001). The differential methylation was independent of immune cell infiltration upon HFD exposure. In contrast, no differential methylation in the Pparg2 and Leptin promoter was observed in SAT. Leptin and Pparg2 DNA methylation were correlated with gene expression in GAT. Our study shows that prolonged exposure to HFD in adulthood is associated with a gradually increasing DNA methylation level at the Leptin and Pparg2 promoters in a depot-specific manner.
- Published
- 2017
38. A casein hydrolysate based formulation attenuates obesity and associated non-alcoholic fatty liver disease and atherosclerosis in LDLr-/-.Leiden mice
- Author
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Schoemaker, M.H., Kleemann, R., Morrison, M.C., Verheij, J., Salic, K., Tol, E.A.F. van, Kooistra, T., and Wielinga,P.Y.
- Subjects
Life ,Health ,nutritional and metabolic diseases ,food and beverages ,Biomedical Innovation ,lipids (amino acids, peptides, and proteins) ,ELSS - Earth, Life and Social Sciences ,MHR - Metabolic Health Research ,Healthy Living - Abstract
Background: Obesity frequently associates with the development of non-alcoholic fatty liver disease (NAFLD) and atherosclerosis. Chronic inflammation in white adipose tissue (WAT) seems to be an important driver of these manifestations. Objective: This study investigated a combination of an extensively hydrolyzed casein (eHC), docosahexaenoic acid (DHA), arachidonic acid (ARA), and Lactobacillus Rhamnosus GG (LGG) (together referred to as nutritional ingredients, NI) on the development of obesity, metabolic risk factors, WAT inflammation, NAFLD and atherosclerosis in high-fat diet-fed LDLr-/-.Leiden mice, a model that mimics disease development in humans. Methods: LDLr-/-.Leiden male mice (n = 15/group) received a high-fat diet (HFD, 45 Kcal%) for 21 weeks with or without the NI (23.7% eHC, 0.083% DHA, 0.166% ARA; all w/w and 1x109 CFU LGG gavage 3 times/week). HFD and HFD+NI diets were isocaloric. A low fat diet (LFD, 10 Kcal%) was used for reference. Body weight, food intake and metabolic risk factors were assessed over time. At week 21, tissues were analyzed for WAT inflammation (crown-like structures), NAFLD and atherosclerosis. Effects of the individual NI components were explored in a follow-up experiment (n = 7/group). Results: When compared to HFD control, treatment with the NI strongly reduced body weight to levels of the LFD group, and significantly lowered (P
- Published
- 2017
39. CAT-2003: A Novel Sterol Regulatory Element-Binding Protein Inhibitor That Reduces Steatohepatitis, Plasma Lipids, and Atherosclerosis in Apolipoprotein E*3-Leiden Mice
- Author
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Zimmer, M., Bista, P., Benson, E.L., Lee, D.Y., Liu, F., Picarella, D., Vega, R.B., Vu, C.B., Yeager, M., Ding, M., Liang, G., Horton, J.D., Kleemann, R., Kooistra, T., Morrison, M.C., Wielinga, P.Y., Milne, J.C., Jirousek, M.R., and Nichol, A.J.
- Subjects
Life ,Biomedical Innovation ,lipids (amino acids, peptides, and proteins) ,ELSS - Earth, Life and Social Sciences ,MHR - Metabolic Health Research ,Biology ,Healthy Living - Abstract
CAT-2003 is a novel conjugate of eicosapentaenoic acid (EPA) and niacin designed to be hydrolyzed by fatty acid amide hydrolase to release EPA inside cells at the endoplasmic reticulum. In cultured liver cells, CAT-2003 blocked the maturation of sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 proteins and decreased the expression of multiple SREBP target genes, including HMGCR and PCSK9. Consistent with proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, both low-density lipoprotein receptor protein at the cell surface and low-density lipoprotein particle uptake were increased. In apolipoprotein E*3-Leiden mice fed a cholesterol-containing western diet, CAT-2003 decreased hepatic inflammation and steatosis as evidenced by fewer inflammatory cell aggregates in histopathologic sections, decreased nuclear factor kappa B activity in liver lysates, reduced inflammatory gene expression, reduced intrahepatic cholesteryl ester and triglyceride levels, and decreased liver mass. Plasma PCSK9 was reduced and hepatic low-density lipoprotein receptor protein expression was increased; plasma cholesterol and triglyceride levels were lowered. Aortic root segments showed reduction of several atherosclerotic markers, including lesion size, number, and severity. CAT-2003, when dosed in combination with atorvastatin, further lowered plasma cholesterol levels and decreased hepatic expression of SREBP target genes. Conclusion: SREBP inhibition is a promising new strategy for the prevention and treatment of diseases associated with abnormal lipid metabolism, such as atherosclerosis and nonalcoholic steatohepatitis.
- Published
- 2017
40. P4416The role of CD40 in murine and human arteriogenesis
- Author
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Jansen, M F, primary, Hollander, M R, additional, Hopman, L G A, additional, Kleemann, R, additional, Horrevoets, A J, additional, Van Royen, N, additional, and Lutgens, E, additional
- Published
- 2018
- Full Text
- View/download PDF
41. Targeting the NAFLD metabolome and the shaping of precision medicine for patients with NASH
- Author
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Iruarrizaga-Lejarreta, M., primary, Martínez-Arranz, I., additional, Morrison, M.C., additional, Varela-Rey, M., additional, Ramos, D.F., additional, Delacruz-Villar, L., additional, Noureddin, M., additional, Martínez-Chantar, M.L., additional, Kleemann, R., additional, Alonso, C., additional, Lu, S.C., additional, and Mato, J.M., additional
- Published
- 2018
- Full Text
- View/download PDF
42. Butyrate restores HFD-induced adaptations in brain function and metabolism in mid-adult obese mice
- Author
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Arnoldussen, I.A.C., Wiesmann, M., Pelgrim, C.E., Wielemaker, E.M., Duyvenvoorde, W. van, Amaral-Santos, P.L., Verschuren, L., Keijser, B.J.F., Heerschap, A., Kleemann, R., Wielinga, P.Y., Kiliaan, A.J., Arnoldussen, I.A.C., Wiesmann, M., Pelgrim, C.E., Wielemaker, E.M., Duyvenvoorde, W. van, Amaral-Santos, P.L., Verschuren, L., Keijser, B.J.F., Heerschap, A., Kleemann, R., Wielinga, P.Y., and Kiliaan, A.J.
- Abstract
Item does not contain fulltext, OBJECTIVE: Midlife obesity affects cognition and increases risk of developing dementia. Recent data suggest that intake of the short chain fatty acid butyrate could improve memory function, and may protect against diet-induced obesity by reducing body weight and adiposity. SUBJECTS: We examined the impact of a high-fat diet (HFD) followed by intervention with 5% (w/w) dietary butyrate, on metabolism, microbiota, brain function and structure in the low-density-lipoprotein receptor knockout (LDLr-/-) mouse model in mid and late life. RESULTS: In mid-adult mice, 15 weeks of HFD-induced adiposity, liver fibrosis and neuroinflammation, increased systolic blood pressure and decreased cerebral blood flow, functional connectivity assessed with neuroimaging. The subsequent 2 months butyrate intervention restored these detrimental effects to chow-fed control levels. Both HFD and butyrate intervention decreased variance in fecal microbiota composition. In late-adult mice, HFD showed similar detrimental effects and decreased cerebral white and gray matter integrity, whereas butyrate intervention attenuated only metabolic parameters. CONCLUSION: HFD induces detrimental effects in mid- and late-adult mice, which can be attenuated by butyrate intervention. These findings are consistent with reported associations between midlife obesity and cognitive impairment and dementia in humans. We suggest that butyrate may have potential in prevention and treatment of midlife obesity.
- Published
- 2017
43. Butyrate Reduces HFD-Induced Adipocyte Hypertrophy and Metabolic Risk Factors in Obese LDLr-/-.Leiden Mice
- Author
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Pelgrim, C.E., Franx, B.A., Snabel, J., Kleemann, R., Arnoldussen, I.A.C., Kiliaan, A.J., Pelgrim, C.E., Franx, B.A., Snabel, J., Kleemann, R., Arnoldussen, I.A.C., and Kiliaan, A.J.
- Abstract
Contains fulltext : 178200.pdf (publisher's version ) (Open Access), Adipose tissue (AT) has a modulating role in obesity-induced metabolic complications like type 2 diabetes mellitus (T2DM) via the production of so-called adipokines such as leptin, adiponectin, and resistin. The adipokines are believed to influence other tissues and to affect insulin resistance, liver function, and to increase the risk of T2DM. In this study, we examined the impact of intervention with the short-chain fatty acid butyrate following a high-fat diet (HFD) on AT function and other metabolic risk factors associated with obesity and T2DM in mice during mid- and late life. In both mid- and late adulthood, butyrate reduced HFD-induced adipocyte hypertrophy and elevations in leptin levels, which were associated with body weight, and cholesterol and triglyceride levels. HFD feeding stimulated macrophage accumulation primarily in epididymal AT in both mid- and late life adult mice, which correlated with liver inflammation in late adulthood. In late-adult mice, butyrate diminished increased insulin levels, which were related to adipocyte size and macrophage content in epididymal AT. These results suggest that dietary butyrate supplementation is able to counteract HFD-induced detrimental changes in AT function and metabolic outcomes in late life. These changes underlie the obesity-induced elevated risk of T2DM, and therefore it is suggested that butyrate has potential to attenuate risk factors associated with obesity and T2DM.
- Published
- 2017
44. Intervention with a caspase-1 inhibitor reduces obesity-associated hyperinsulinemia, non-alcoholic steatohepatitis (NASH) and hepatic fibrosis in LDLR-/-.Leiden mice
- Author
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Morrison, M.C., Mulder, P., Salic, K., Verheij, J., Liang, W., Duyvenvoorde, W. van, Menke, A., Kooistra, T., Kleemann, R., and Wielinga, P.Y.
- Subjects
Life ,nutritional and metabolic diseases ,Biomedical Innovation ,ELSS - Earth, Life and Social Sciences ,MHR - Metabolic Health Research ,Biology ,Healthy Living - Abstract
Background/objectives: Non-alcoholic steatohepatitis (NASH) is a serious liver condition, closely associated with obesity and insulin resistance. Recent studies have suggested an important role for inflammasome/caspase-1 in the development of NASH, but the potential therapeutic value of caspase-1 inhibition remains unclear. Therefore, we aimed to investigate the effects of caspase-1 inhibition in the ongoing disease process, to mimic the clinical setting. Subjects/methods: To investigate effects of caspase-1 inhibition under therapeutic conditions, male LDLR-/-.Leiden mice were fed a high-fat diet (HFD) for 9 weeks to induce a pre-diabetic state before start of treatment. Mice were then continued on HFD for another 12 weeks, without (HFD) or with (HFD-YVAD) treatment with the caspase-1 inhibitor Ac-YVAD-cmk (40 mg/kg/day). Results: 9 weeks of HFD feeding resulted in an obese phenotype, with obesity-associated hypertriglyceridemia, hypercholesterolemia, hyperglycemia, and hyperinsulinemia. Treatment with Ac-YVAD-cmk did not affect further body weight gain or dyslipidaemia, but did attenuate further progression of insulin resistance. Histopathological analysis of livers clearly demonstrated prevention of NASH development in HFD-YVAD mice: livers were less steatotic and neutrophil infiltration was strongly reduced. In addition, caspase-1 inhibition had a profound effect on hepatic fibrosis, as assessed by histological quantification of collagen staining and gene expression analysis of fibrosis-associated genes Col1a1, Acta2, and Tnfa. Conclusions: Intervention with a caspase-1 inhibitor attenuated the development of NASH, liver fibrosis and insulin resistance. Our data support the importance of inflammasome/caspase-1 in the development of NASH and demonstrate that therapeutic intervention in the already ongoing disease process is feasible
- Published
- 2016
45. Effects of anthocyanin and flavanol compunds on lipid metabolism and adipose tissue associated systemic inflammation in diet-induced obesity
- Author
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Heijden, R.A. van der, Morrison, M.C., Sheedfar, F., Mulder, P., Schreurs, M., Hommelberg, P.P.H., Hofker, M.H., Schalkwijk, C., Kleemann, R., Tietge, U.J.F., Koonen, D.P.Y., and Heeringa, P.
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Life ,digestive, oral, and skin physiology ,nutritional and metabolic diseases ,food and beverages ,Biomedical Innovation ,lipids (amino acids, peptides, and proteins) ,ELSS - Earth, Life and Social Sciences ,MHR - Metabolic Health Research ,Biology ,Healthy Living - Abstract
Background. Naturally occurring substances from the flavanol and anthocyanin family of polyphenols have been proposed to exert beneficial effects in the course of obesity. We hypothesized that their effects on attenuating obesity-induced dyslipidemia as well as the associated inflammatory sequelae especially have health-promoting potential. Methods. Male C57BL/6J mice (n=13) received a control low-fat diet (LFD; 10 kcal% fat;n=13) for 6 weeks followed by 24 weeks of either LFD (n=13) or high-fat diet (HFD; 45 kcal% fat;n=13) or HFD supplemented with 0.1% w/w of the flavanol compound epicatechin (HFD+E;n=13) or an anthocyanin-rich bilberry extract (HFD+B;n=13). Energy substrate utilization was determined by indirect calorimetry in a subset of mice following the dietary switch and at the end of the experiment. Blood samples were collected at baseline and at 3 days and 4, 12, and 20 weeks after dietary switch and analyzed for systemic lipids and proinflammatory cytokines. Adipose tissue (AT) histopathology and inflammatory gene expression as well as hepatic lipid content were analyzed after sacrifice. Results. The switch from a LFD to a HFD lowered the respiratory exchange ratio and increased plasma cholesterol and hepatic lipid content. These changes were not attenuated by HFD+E or HFD+B. Furthermore, the polyphenol compounds could not prevent HFD-induced systemic rise of TNF-α levels. Interestingly, a significant reduction in Tnf gene expression in HFD+B mice was observed in the AT. Furthermore, HFD+B, but not HFD+E, significantly prevented the early upregulation of circulating neutrophil chemoattractant mKC. However, no differences in AT histopathology were observed between the HFD types. Conclusion. Supplementation of HFD with an anthocyanin-rich bilberry extract but not with the flavanol epicatechin may exert beneficial effects on the systemic early inflammatory response associated with diet-induced obesity. These systemic effects were transient and not observed after prolongation of HFD-feeding (24 weeks). On the tissue level, long-term treatment with bilberry attenuated TNF-α expression in adipose tissue.
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- 2016
46. Early intake of long-chain polyunsaturated fatty acids preserves brain structure and function in diet-induced obesity
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Arnoldussen, I.A.C., Zerbi, V., Wiesmann, M., Noordman, R.H.J., Bolijn, S., Mutsaers, M.P.C., Dederen, P.J.W.C., Kleemann, R., Kooistra, T., Tol, E.A.F. van, Gross, G., Schoemaker, M.H., Wieling, P.Y., and Kilian, A.
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Long-chain polyunsaturated fatty acids ,Life ,Brain structure ,food and beverages ,High-fat and high-carbohydrate diets ,Biomedical Innovation ,lipids (amino acids, peptides, and proteins) ,Neuroimaging ,Obesity ,ELSS - Earth, Life and Social Sciences ,MHR - Metabolic Health Research ,Biology ,Healthy Living - Abstract
orldwide, the incidence of obesity is increasing at an alarming rate, and the number of children with obesity is especially worrisome. These developments raise concerns about the physical, psychosocial and cognitive consequences of obesity. It was shown that early dietary intake of arachidonic acid (ARA) and docosahexaenoic acid (DHA) can reduce the detrimental effects of later obesogenic feeding on lipid metabolism and adipogenesis in an animal model of mild obesity. In the present study, the effects of early dietary ARA and DHA on cognition and brain structure were examined in mildly obesogenic ApoE*3Leiden mouse model. We used cognitive tests and neuroimaging during early and later life. During their early development after weaning (4–13 weeks of age), mice were fed a chow diet or ARA and DHA diet for 8 weeks and then switched to a high-fat and high-carbohydrate (HFHC) diet for 12 weeks (14–26 weeks of age). An HFHC-diet led to increased energy storage in white adipose tissue, increased cholesterol levels, decreased triglycerides levels, increased cerebral blood flow and decreased functional connectivity between brain regions as well as cerebrovascular and gray matter integrity. ARA and DHA intake reduced the HFHC-diet-induced increase in body weight, attenuated plasma triglycerides levels and improved cerebrovasculature, gray matter integrity and functional connectivity in later life. In conclusion, an HFHC diet causes adverse structural brain and metabolic adaptations, most of which can be averted by dietary ARA and DHA intake early in life supporting metabolic flexibility and cerebral integrity later in life.
- Published
- 2016
47. The NuGO proof of principle study package: a collaborative research effort of the European Nutrigenomics Organisation
- Author
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Baccini, M, Bachmaier, EM, Biggeri, A, Boekschoten, MV, Bouwman, FG, Brennan, L, Caesar, R, Cinti, S, Coort, SL, Crosley, K, Daniel, H, Drevon, CA, Duthie, S, Eijssen, L, Elliott, RM, van Erk, M, Evelo, C, Gibney, M, Heim, C, Horgan, GW, Johnson, IT, Kelder, T, Kleemann, R, Kooistra, T, van Iersel, MP, Mariman, EC, Mayer, C, McLoughlin, G, Müller, M, Mulholland, F, van Ommen, B, Polley, AC, Pujos-Guillot, E, Rubio-Aliaga, I, Roche, HM, de Roos, B, Sailer, M, Tonini, G, Williams, LM, de Wit, N, For the NuGO PPS Team, Università degli Studi di Firenze = University of Florence (UniFI), University of Aberdeen, Division of Human Nutrition, Wageningen University and Research [Wageningen] (WUR), Top Institute Food and Nutrition (TIFN), Maastricht University [Maastricht], School of Agriculture, Food Science and Veterinary Medicine, University College Dublin [Dublin] (UCD), University of Oslo (UiO), Università Politecnica delle Marche, Partenaires INRAE, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institute of Food Research [Norwich], Biotechnology and Biological Sciences Research Council (BBSRC), Department of Physiological Genomics, Munich University, University College Dublin (UCD), Netherlands Organisation for Applied Scientific Research, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, TNO Kwaliteit van Leven, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Humane Biologie, Bioinformatica, RS: CARIM School for Cardiovascular Diseases, and RS: NUTRIM - R4 - Gene-environment interaction
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Endocrinology, Diabetes and Metabolism ,[SDV]Life Sciences [q-bio] ,MEDLINE ,030209 endocrinology & metabolism ,Physiological Sciences ,Bioinformatics ,03 medical and health sciences ,Voeding, Metabolisme en Genomica ,0302 clinical medicine ,Voeding ,Genetics ,Network of excellence ,Medicine ,030304 developmental biology ,Nutrition ,VLAG ,0303 health sciences ,business.industry ,Metabolism and Genomics ,Nutrigenomics ,immune-system ,Proof of concept ,Metabolisme en Genomica ,Commentary ,Engineering ethics ,Nutrition, Metabolism and Genomics ,business - Abstract
Acknowledgments This project is funded by the Nutrigenomics Organisation, EC funded Network of Excellence, grant nr.FOOD- 2004-506360.
- Published
- 2008
48. Systems biology approach to identify processes and early markers for fibrosis in metabolically-induced non-alcoholic steatosis hepatitis in mice
- Author
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Van Koppen, A., primary, Verschuren, L., additional, Nagabukuro, H., additional, Costessi, A., additional, Caspers, M., additional, Morrison, M., additional, Salic, K., additional, Stoop, R., additional, Turner, S.M., additional, Li, K., additional, Beysen, C., additional, Hanauer, G., additional, van den Hoek, A.M., additional, Kleemann, R., additional, and Hanemaaijer, R., additional
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- 2017
- Full Text
- View/download PDF
49. The CCR2 inhibitor propagermanium attenuates diet-induced insulin resistance, adipose tissue inflammation and nonalcoholic steatohepatitis
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Mulder, P., primary, Van Koppen, A., additional, van den Hoek, A.M., additional, and Kleemann, R., additional
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- 2017
- Full Text
- View/download PDF
50. Sustainable phosphorus management - a global transdisciplinary roadmap
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Kleemann, R and Morse, S
- Published
- 2015
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