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(Pro)Renin Receptor Antagonism Attenuates High-Fat-Diet–Induced Hepatic Steatosis

Gayban, A.J.B. (author), Souza, L.A.C. (author), Cooper, S.G. (author), Regalado, E. (author), Kleemann, R. (author), Earley, Y.F. (author)

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we test the hypothesis that the PRR regulates the development of diet-induced hepatic...

article 2023

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Mechanism-Based Biomarker Prediction for Low-Grade Inflammation in Liver and Adipose Tissue

van Bilsen, J.H.M. (author), van den Brink, W. (author), van den Hoek, A.M. (author), Dulos, R. (author), Caspers, M.P.M. (author), Kleeman, R. (author), Wopereis, S. (author), Verschuren, L. (author)

Metabolic disorders, such as obesity and type 2 diabetes have a large impact on global health, especially in industrialized countries. Tissue-specific chronic low-grade inflammation is a key contributor to complications in metabolic disorders. To support therapeutic approaches to these complications, it is crucial to gain a deeper understanding...

article 2021

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Key Inflammatory Processes in Human NASH Are Reflected in Ldlr-/-.Leiden Mice: A Translational Gene Profiling Study

Morrison, M.C. (author), Kleemann, R. (author), van Koppen, A. (author), Hanemaaijer, R. (author), Verschuren, L. (author)

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...

article 2018

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Plasticity of lifelong calorie-restricted C57BL/6J mice in adapting to a medium-fat diet intervention at old age

Rusli, F. (author), Boekschoten, M.V. (author), Borelli, V. (author), Sun, C. (author), Lute, C. (author), Menke, A.L. (author), van den Heuvel, J. (author), Salvioli, S. (author), Franceschi, C. (author), Müller, M. (author), Steegenga, W.T. (author)

Calorie restriction (CR) is a dietary regimen that supports healthy aging. In this study, we investigated the systemic and liver-specific responses caused by a diet switch to a medium-fat (MF) diet in 24-month-old lifelong, CR-exposed mice. This study aimed to increase the knowledge base on dietary alterations of gerontological relevance. Nine...

article 2018

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A casein hydrolysate based formulation attenuates obesity and associated non-alcoholic fatty liver disease and atherosclerosis in LDLr-/-.Leiden mice

Schoemaker, M.H. (author), Kleemann, R. (author), Morrison, M.C. (author), Verheij, J. (author), Salic, K. (author), van Tol, E.A.F. (author), Kooistra, T. (author), Wielinga, P.Y. (author)

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...

article 2017

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Effects of anthocyanin and flavanol compunds on lipid metabolism and adipose tissue associated systemic inflammation in diet-induced obesity

van der Heijden, R.A. (author), Morrison, M.C. (author), Sheedfar, F. (author), Mulder, P. (author), Schreurs, M. (author), Hommelberg, P.P.H. (author), Hofker, M.H. (author), Schalkwijk, C. (author), Kleemann, R. (author), Tietge, U.J.F. (author), Koonen, D.P.Y. (author), Heeringa, P. (author)

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....

article 2016

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Network-based integration of molecular and physiological data elucidates regulatory mechanisms underlying adaptation to high-fat diet

Derous, D. (author), Kelder, T. (author), van Schothorst, E.M. (author), van Erk, M. (author), Voigt, A. (author), Klaus, S. (author), Keijer, J. (author), Radonjic, M. (author)

Health is influenced by interplay of molecular, physiological and environmental factors. To effectively maintain health and prevent disease, health-relevant relations need to be understood at multiple levels of biological complexity. Network-based methods provide a powerful platform for integration and mining of data and knowledge characterizing...

article 2015

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Drugs that reverse disease transcriptomic signatures are more effective in a mouse model of dyslipidemia

Wagner, A. (author), Cohen, N. (author), Kelder, T. (author), Amit, U. (author), Liebman, E. (author), Steinberg, D.M. (author), Radonjic, M. (author), Ruppin, E. (author)

High-throughput omics have proven invaluable in studying human disease, and yet day-to-day clinical practice still relies on physiological, non-omic markers. The metabolic syndrome, for example, is diagnosed and monitored by blood and urine indices such as blood cholesterol levels. Nevertheless, the association between the molecular and the...

article 2015

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Identification of prognostic and diagnostic biomarkers of glucose intolerance in ApoE3Leiden mice

Wopereis, S. (author), Radonjic, M. (author), Rubingh, C. (author), van Erk, M. (author), Smilde, A. (author), van Duyvenvoorde, W. (author), Cnubben, N. (author), Kooistra, T. (author), van Ommen, B. (author), Kleemann, R. (author)

The prevalence of diabetes mellitus Type 2 could be significantly reduced by early identification of subjects at risk, allowing for better prevention and earlier treatment. Glucose intolerance (GI) is a hallmark of the prediabetic stage. This study aims at identifying 1) prognostic biomarkers predicting the risk of developing GI later in life...

article 2012

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Aspirin reduces hypertriglyceridemia by lowering VLDL-triglyceride production in mice fed a high-fat diet

van Diepen, J.A. (author), Vroegrijk, I.O.C.M. (author), Berbée, J.F.P. (author), Shoelson, S.E. (author), Romijn, J.A. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), Voshol, P.J. (author)

Systemic inflammation is strongly involved in the pathophysiology of the metabolic syndrome, a cluster of metabolic risk factors that includes hypertriglyceridemia. Aspirin treatment lowers inflammation via inhibition of NF-?B activity but also reduces hypertriglyceridemia in humans. The aim of this study was to investigate the mechanism by...

article 2011

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A combined transcriptomics and lipidomics analysis of subcutaneous, epididymal and mesenteric adipose tissue reveals marked functional differences

TNO Kwaliteit van Leven (author), Caesar, R. (author), Manieri, M. (author), Kelder, T. (author), Boekschoten, M. (author), Evelo, C. (author), Müller, M. (author), Kooistra, T. (author), Cinti, S. (author), Kleemann, R. (author), Drevon, C.A. (author)

Depot-dependent differences in adipose tissue physiology may reflect specialized functions and local interactions between adipocytes and surrounding tissues. We combined time-resolved microarray analyses of mesenteric- (MWAT), subcutaneous- (SWAT) and epididymal adipose tissue (EWAT) during high-fat feeding of male transgenic ApoE3Leiden mice...

article 2010

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CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice

Parlevliet, E.T. (author), Schröder-van der Elst, J.P. (author), Corssmit, E.P.M. (author), Picha, K. (author), O'Neil, K. (author), Stojanovic-Susulic, V. (author), Ort, T. (author), Havekes, L.M. (author), Romijn, J.A. (author), Pijl, H. (author), TNO Kwaliteit van Leven (author)

CNTO736 is a glucagon-like peptide (GLP) 1 receptor agonist that incorporates a GLP-1 peptide analog linked to the Mimeti-body platform. We evaluate the potential of acute and chronic CNTO736 treatment on insulin sensitivity and very low-density lipoprotein (VLDL) metabolism. For acute studies, diet-induced insulin-resistant C57BL76 mice...

article 2009

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Sustained activation of the mammalian target of rapamycin nutrient sensing pathway is associated with hepatic insulin resistance, but not with steatosis, in mice

Korsheninnikova, E. (author), van der Zon, G.C.M. (author), Voshol, P.J. (author), Janssen, G.M. (author), Havekes, L.M. (author), Grefhorst, A. (author), Kuipers, F. (author), Reijngoud, D.-J. (author), Romijn, J.A. (author), Ouwens, D.M. (author), Maassen, J.A. (author), TNO Kwaliteit van Leven (author)

Aims/hypothesis: Activation of nutrient sensing through mammalian target of rapamycin (mTOR) has been linked to the pathogenesis of insulin resistance. We examined activation of mTOR-signalling in relation to insulin resistance and hepatic steatosis in mice. Materials and methods: Chronic hepatic steatosis and hepatic insulin resistance were...

article 2006

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Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue

den Boer, M.A.M. (author), Berbée, J.F.P. (author), Reiss, P. (author), van der Valk, M. (author), Voshol, P.J. (author), Kuipers, F. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), Romijn, J.A. (author), Gaubius Instituut TNO (author)

Objective - The use of the HIV protease inhibitor ritonavir (RTV) is frequently associated with hypertriglyceridemia and lipodystrophy. The aim of our study was to determine the mechanism underlying the observed hypertriglyceridemia. Methods and Results - Feeding female APOE*3-Leiden transgenic mice a Western-type diet supplemented with RTV (35...

article 2006

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Endogenous interleukin-10 protects against hepatic steatosis but does not improve insulin sensitivity during high-fat feeding in mice

den Boer, M.A.M. (author), Voshol, P.J. (author), Schröder-van Der Elst, J.P. (author), Korsheninnikova, E. (author), Ouwens, D.M. (author), Kuipers, F. (author), Havekes, L.M. (author), Romijn, J.A. (author), TNO Kwaliteit van Leven (author)

Several studies have demonstrated an association in humans between plasma levels or production capacity of the antiinflammatory cytokine IL-10 and insulin sensitivity. The aim of our study was to investigate the protective role of endogenous IL-10 availability in the development of diet-induced insulin resistance. We compared parameters of...

article 2006

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Subchronic (13-week) oral toxicity study, preceded by an in utero exposure phase, with arachidonate-enriched triglyceride oil (SUNTGA40S) in rats

Lina, B.A.R. (author), Wolterbeek, A.P.M. (author), Suwa, Y. (author), Fujikawa, S. (author), Ishikura, Y. (author), Tsuda, S. (author), Dohnalek, M. (author), TNO Kwaliteit van Leven (author)

Polyunsaturated fatty acids (PUFAs), such as arachidonic acid (ARA) and docosahexaenoic acid (DHA) are natural constituents found in human milk, fish oil or egg yolk. Until recently, infant formulas, though providing the essential fatty acid precursors for these PUFAs, did not contain preformed ARA or DHA. In this study the safety of SUNTGA40S...

article 2006

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Rosuvastatin reduces plasma lipids by inhibiting VLDL production and enhancing hepatobiliary lipid excretion in ApoE*3-Leiden mice

Delsing, D.J.M. (author), Post, S.M. (author), Groenendijk, M. (author), Solaas, K. (author), van der Boom, H. (author), van Duyvenvoorde, W. (author), de Wit, E.C.M. (author), Bloks, V.W. (author), Kuipers, F. (author), Havekes, L.M. (author), Princen, H.M.G. (author), TNO Kwaliteit van Leven (author)

The present study was designed to investigate the lipid-lowering properties and mechanisms of action of a new HMG-CoA reductase inhibitor, rosuvastatin, in female ApoE*3-Leiden transgenic mice. Mice received a high fat/cholesterol (HFC) diet containing either rosuvastatin (O [control], 0.00125%, 0.0025%, or 0.005% [w/w]) or 0.05% (w/w)...

article 2005

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Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice

TNO Kwaliteit van Leven (author), Espirito Santo, S.M.S. (author), Rensen, P.C.N. (author), Goudriaan, J.R. (author), Bensadoun, A. (author), Bovenschen, N. (author), Voshol, P.J. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author)

The very low density lipoprotein receptor (VLDLR), low density lipoprotein receptor (LDLR), and low density lipoprotein receptor-related protein (LRP) are the three main apolipoprotein E-recognizing endocytic receptors involved in the clearance of triglyceride (TG)-rich lipoproteins from plasma. Whereas LDLR deficiency in mice results in the...

article 2005

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Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production

Post, S.M. (author), Groenendijk, M. (author), Solaas, K. (author), Rensen, P.C.N. (author), Princen, H.M.G. (author), TNO Preventie en Gezondheid (author)

Objective-Cholesterol 7α-hydroxylase (cyp7a1) catalyzes the rate-limiting step in conversion of cholesterol to bile acids. To study the relationship between bile acid biosynthesis and triglyceride metabolism, we cross-bred mice lacking cyp7a1 on a hyperlipidemic APOE*3-Leiden background. Methods and Results-Female mice received a chow or...

article 2004

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Sensory-specific satiety in obese and normal-weight women

Snoek, H.M. (author), Huntjens, L. (author), van Gemert, L.J. (author), de Graaf, C. (author), Weenen, H. (author), TNO Voeding (author)

Background: Sensory-specific satiety has been found to play an important role in food choice and meal termination, and it might be a factor contributing to obesity. Objective: We hypothesized that obese and normal-weight people have different sensitivities to sensory-specific satiety for high-fat foods. Design: Sensory-specific satiety was...

article 2004