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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), Regaldo, 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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(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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Translational characterization of the temporal dynamics of metabolic dysfunctions in liver, adipose tissue and the gut during diet-induced NASH development in Ldlr-/-.Leiden mice

Gart, E. (author), van Duyvenvoorde, W. (author), Snabel, J. (author), de Ruiter, C. (author), Attema, J. (author), Caspers, M.P.M. (author), Lek, S. (author), van Heuven, B.J. (author), Speksnijder, A.G.C.L. (author), Giera, M. (author), Menke, A. (author), Salic, K. (author), Bence, K.K. (author), Tesz, G.J. (author), Keijzer, J. (author), Kleemann, R. (author), Morrison, M.C. (author)

Background: NAFLD progression, from steatosis to inflammation and fibrosis, results from an interplay of intra- and extrahepatic mechanisms. Disease drivers likely include signals from white adipose tissue (WAT) and gut. However, the temporal dynamics of disease development remain poorly understood. Methods: High-fat-diet (HFD)-fed Ldlr-/-...

article 2023

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Impact of White Adipose Tissue on Brain Structure, Perfusion, and Cognitive Function in Patients With Severe Obesity: The BARICO Study

Vreeken, D. (author), Seidel, F. (author), de La Roij, G. (author), Vening, W. (author), den Hengst, W.A. (author), Verschuren, L. (author), Özsezen, S. (author), Kessels, R.P.C. (author), Duering, M. (author), Mutsaerts, H.J.M.M. (author), Kleemann, R. (author), Wiesmann, M. (author), Hazebroek, E.J. (author), Kiliaan, A.J. (author)

BACKGROUND AND OBJECTIVE: While underlying pathophysiology linking obesity to brain health is not completely understood, white adipose tissue (WAT) is considered a key player. In obesity, WAT becomes dysregulated, showing hyperplasia, hypertrophy, and eventually inflammation. This disbalance leads to dysregulated secretion of adipokines...

article 2023

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Sex differences in skeletal muscle-aging trajectory: same processes, but with a different ranking

de Jong, J.C.B.C. (author), Attema, B.J. (author), van der Hoek, M.D. (author), Verschuren, L. (author), Caspers, M.P.M. (author), Kleemann, R. (author), van der Leij, F.R. (author), van den Hoek, A.M. (author), Nieuwenhuizen, A.G. (author), Keijer, J. (author)

Sex differences in muscle aging are poorly understood, but could be crucial for the optimization of sarcopenia-related interventions. To gain insight into potential sex differences in muscle aging, we recruited young (23 ± 2 years, 13 males and 13 females) and old (80 ± 3.5 years, 28 males and 26 females) participants. Males and females in both...

article 2023

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Caloric Restriction Combined with Immobilization as Translational Model for Sarcopenia Expressing Key-Pathways of Human Pathology

de Jong, J.C.B.C. (author), Attema, B.J. (author), van der Hoek, M.D. (author), Verschuren, L. (author), Caspers, M.P.M. (author), Kleemann, R. (author), van der Leij, F.R. (author), van den Hoek, A.M. (author), Nieuwenhuizen, A.G. (author), Keijer, J. (author)

The prevalence of sarcopenia is increasing while it is often challenging, expensive and time-consuming to test the effectiveness of interventions against sarcopenia. Translational mouse models that adequately mimic underlying physiological pathways could accelerate research but are scarce. Here, we investigated the translational value of three...

article 2023

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Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles

Martínez-Arranz, I. (author), Bruzzone, C. (author), Noureddin, M. (author), Gil-Redondo, R. (author), Mincholé, I. (author), Bizkarguenaga, M. (author), Arretxe, E. (author), Iruarrizaga-Lejarreta, M. (author), Fernández-Ramos, D. (author), Lopitz-Otsoa, F. (author), Mayo, R. (author), Embade, N. (author), Newberry, E. (author), Mittendorf, B. (author), Izquierdo-Sánchez, L. (author), Smid, V. (author), Arnold, J. (author), Iruzubieta, P. (author), Pérez Castaño, Y. (author), Krawczyk, M. (author), Marigorta, U.M. (author), Morrison, M.C. (author), Kleemann, R. (author), Martín-Duce, A. (author), Hayardeny, L. (author), Vitek, L. (author), Bruha, R. (author), Aller de la Fuente, R. (author), Crespo, J. (author), Romero-Gomez, M. (author), Banales, J.M. (author), Arrese, M. (author), Cusi, K. (author), Bugianesi, E. (author), Klein, S. (author), Lu, S.C. (author), Anstee, Q.M. (author), Millet, O. (author), Davidson, N.O. (author), Alonso, C. (author), Mato, J.M. (author)

Background and Aims: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. Approach and Results: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD...

article 2022

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Sex difference in skeletal muscle-ageing trajectory: same processes, but with different magnitudes: poster

Jong, J.C.B.C. (author), Attema, B.J. (author), van der Hoek, M.D. (author), Verschuren, L. (author), Caspers, M.P.M. (author), Kleemann, R. (author), van der Leij, F.R. (author), van den Hoek, A.M. (author), Nieuwenhuizen1, A.G. (author), Keijer, J. (author)

Sex differences in muscle‐ageing are incompletely understood and could be crucial for the optimalisation of sarcopenia‐related interventions. • Therefore, we performed an observational trial to gain insight in potential sex differences in processes involved in human muscle‐ageing.

public lecture 2022

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Therapeutic Intervention with Anti-Complement Component 5 Antibody Does Not Reduce NASH but Does Attenuate Atherosclerosis and MIF Concentrations in Ldlr-/-.Leiden Mice

Seidel, F. (author), Kleemann, R. (author), van Duyvenvoorde, W. (author), van Trigt, N. (author), Keijzer, N. (author), van der Kooij, S. (author), van Kooten, C. (author), Verschuren, L. (author), Menke, A. (author), Kiliaan, A.J. (author), Winter, J. (author), Hughes, T.R. (author), Morgan, P. (author), Baas, F. (author), Fluiter, K. (author), Morrison, M.C. (author)

Background: Chronic inflammation is an important driver in the progression of non-alcoholic steatohepatitis (NASH) and atherosclerosis. The complement system, one of the first lines of defense in innate immunity, has been implicated in both diseases. However, the potential therapeutic value of complement inhibition in the ongoing disease remains...

article 2022

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Lipid profiling analyses from mouse models and human infants

Olga, L. (author), Bobeldijk-Pastorova, I. (author), Bas R.C., (author), Seidel, F. (author), Snowden, S.G. (author), Furse, S. (author), Ong, K.K. (author), Kleemann, R. (author), Koulman, A. (author)

This protocol outlines a translational lipidomic approach to discover lipid biomarkers that could predict morphometric body and histological organ measurements (e.g., weight and adiposity gains) during specific stages of life (e.g., early life). We describe procedures ranging from animal experimentation and histological analyses to downstream...

article 2022

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High fat diet-induced obesity prolongs critical stages of the spermatogenic cycle in a Ldlr-/-.Leiden mouse model

Komninos, D. (author), Ramos, L. (author), van der Heijden, G.W. (author), Morrison, M.C. (author), Kleemann, R. (author), van Herwaarden, A.E. (author), Kiliaan, A.J. (author), Arnoldussen, I.A.C. (author)

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...

article 2022

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Neuroimmune cardiovascular interfaces control atherosclerosis

Mohanta, S.K. (author), Peng, L. (author), Li, Y. (author), Lu, S. (author), Sun, T. (author), Carnevale, L. (author), Perrotta, M. (author), Ma, Z. (author), Förstera, B. (author), Stanic, K. (author), Carnevale, R. (author), Hu, D. (author), Nosalski, R. (author), Pallente, F. (author), Beer, M. (author), Santovito, D. (author), Ertürk, A. (author), Mettenleiter, T.C. (author), Klupp, B.G. (author), Megens, R.T.A. (author), Steffens, S. (author), Pelisek, J. (author), Eckstein, H.H. (author), Kleemann, R. (author), Habenicht, L. (author), Mallat, Z. (author), Michel, J.B. (author), Bernhagen, J. (author), Dichgans, M. (author), D'Agostino, G. (author), Guzik, T.J. (author), Olofsson, P.S. (author), Yin, C. (author), Weber, C. (author), Lembo, G. (author), Carnevale, D. (author), Habenicht, A.J.R. (author)

Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes1. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries (the...

article 2022

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Milk fat globule membrane attenuates high fat diet-induced neuropathological changes in obese Ldlr−/−.Leiden mice

Arnoldussen, I.A.C. (author), Morrison, M.C. (author), Wiesmann, M. (author), van Diepen, J.A. (author), Worms, N. (author), Voskuilen, M. (author), Verweij, V. (author), Greenen, B. (author), Pujol Gauldo, N. (author), van der Logt, L. (author), Gross, G. (author), Verschuren, L. (author), Kleemann, R. (author), Kiliaan, A.J. (author)

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...

article 2022

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The effect of transdermal gender-affirming hormone therapy on markers of inflammation and hemostasis

Schutte, M.H. (author), Kleemann, R. (author), Nota, N.M. (author), Wiepjes, C.M. (author), Snabel, J.M. (author), T'Sjoen, G. (author), Thijs, A. (author), den Heijer, M. (author)

Background: Cardiovascular risk is increased in transgender persons using gender-affirming hormone therapy. To gain insight into the mechanism by which sex hormones affect cardiovascular risk in transgender persons, we investigated the effect of hormone therapy on markers of inflammation and hemostasis. Methods: In this exploratory study, 48...

article 2022

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The Human Milk Oligosaccharide 2'-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice

Gart, E. (author), Salic, K. (author), Morrison, M.C. (author), Giera, M. (author), Attema, J. (author), de Ruiter, C. (author), Caspers, M.P.M. (author), Schuren, F. (author), Bobeldijk-Pastorova, I. (author), Heer, M. (author), Qin, Y. (author), Kleemann, R. (author)

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 human milk oligosaccharide 2'-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant...

article 2022

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Intervention with isoleucine or valine corrects hyperinsulinemia and reduces intrahepatic diacylglycerols, liver steatosis, and inflammation in Ldlr-/-.Leiden mice with manifest obesity-associated NASH

Gart, E. (author), van Duyvenvoorde, W. (author), Caspers, M.P.M. (author), van Trigt, N. (author), Snabel, J. (author), Menke, A. (author), Keijer, J. (author), Salic, K. (author), Morrison, M.C. (author), Kleemann, R. (author)

Non-alcoholic steatohepatitis (NASH) is associated with a disturbed metabolism in liver, insulin resistance, and excessive accumulation of ectopic fat. Branched-chain amino acids (BCAAs) may beneficially modulate hepatic lipids, however, it remains unclear whether individual BCAAs can attenuate already established NASH and associated oxidative...

article 2022

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Heat-Inactivated Akkermansia muciniphila Improves Gut Permeability but Does Not Prevent Development of Non-Alcoholic Steatohepatitis in Diet-Induced Obese Ldlr-/-.Leiden Mice

Morrison, M.C. (author), Gart, E. (author), van Duyvenvoorde, W. (author), Snabel, J. (author), Nielsen, M.J. (author), Leeming, D.J. (author), Menke, A. (author), Kleemann, R. (author)

The development of non-alcoholic steatohepatitis (NASH) has been associated with alterations in gut microbiota composition and reduced gut barrier function. Akkermansia muciniphila is a gut microbe that is thought to have health-promoting properties, including the ability to improve gut barrier function and host metabolism, both when...

article 2022

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Lipid ratios representing SCD1, FADS1, and FADS2 activities as candidate biomarkers of early growth and adiposity

Olga, L. (author), van Diepen, J.A. (author), Bobeldijk-Pastorova, I. (author), Gross, G. (author), Prentice, S.M. (author), Snowden, S.G. (author), Furse, S. (author), Kooistra, T. (author), Hughes, I.A. (author), Schoemaker, M.H. (author), van Tol, E.A.F. (author), van Duyvenvoorde, W. (author), Wielinga, P.Y. (author), Ong, K.K. (author), Dunger, D.B. (author), Kleemann, R. (author), Koulman, A. (author)

Background: Altered lipid metabolism in early life has been associated with subsequent weight gain and predicting this could aid in obesity prevention and risk management. Here, a lipidomic approach was used to identify circulating markers for future obesity risk in translational murine models and validate in a human infant cohort. Methods:...

article 2021

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Extra virgin olive oil improved body weight and insulin sensitivity in high fat diet-induced obese LDLr-/-.Leiden mice without attenuation of steatohepatitis

Álvarez-Amor, L. (author), Sierra, A.L. (author), Cárdenas, A. (author), López-Bermudo, L. (author), López-Beas, J. (author), Andújar, E. (author), Pérez-Alegre, M. (author), Gallego-Durán, R. (author), Varela, L.M. (author), Martin-Montalvo, A. (author), Berná, G. (author), Rojas, A. (author), Robles-Frías, J. (author), Hmadcha, A. (author), Romero-Gómez, M. (author), Kleemann, R. (author), Martín, F. (author)

Dietary fatty acids play a role in the pathogenesis of obesity-associated non-alcoholic fatty liver disease (NAFLD), which is associated with insulin resistance (IR). Fatty acid composition is critical for IR and subsequent NAFLD development. Extra-virgin olive oil (EVOO) is the main source of monounsaturated fatty acids (MUFA) in Mediterranean...

article 2021

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Cholesterol Accumulation as a Driver of Hepatic Inflammation Under Translational Dietary Conditions Can Be Attenuated by a Multicomponent Medicine

Mueller, A.M. (author), Kleemann, R. (author), Gart, E. (author), van Duyvenvoorde, W. (author), Verschuren, L. (author), Caspers, M. (author), Menke, A. (author), Krömmelbein, N. (author), Salic, K. (author), Burmeister, Y. (author), Seilheimer, B. (author), Morrison, M.C. (author)

Background: Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is characterised by dysfunctional lipid metabolism and cholesterol homeostasis, and a related chronic inflammatory response. NAFLD has become the most common cause of chronic liver disease in many countries, and its prevalence continues to rise in...

article 2021