HEPATIC TRANSCRIPTOMIC SIGNATURES IN A MOUSE MODEL OF THE METABOLIC SYNDROME

The metabolic syndrome includes high triglyceride (TG) and low HDL-cholesterol (HDL-C) levels in the plasma, and often accompanies steatosis in the liver. Endothelial lipase (EL) is a phospholipase that regulates HDL metabolism. EL is expressed by hepatocytes, while the function of EL in the liver has not been identified. Here, we examined the role of EL in the liver using a mouse model of metabolic syndrome. The EL expression in the liver was analyzed by real-time PCR. It revealed that liver EL expression was significantly increased in obese and diabetic db/db mice compared to that of control mice. To examine the significance of the EL upregulation in the liver, we injected the recombinant adenovirus encoding human EL into mice. The EL overexpression in the liver resulted in a significant decrease in plasma HDL-C, TG, and free fatty acid levels. Interestingly, the EL overexpression in the liver increased liver weight and liver TG content both in wild-type and db/db mice. In db/db mice, particularly, EL overexression accelerated the formation of steatosis by increasing the mRNA level of fatty acid synthase. These findings indicate that EL expression is increased in the liver in the metabolic syndrome. The upregulation of EL promotes the uptake of plasma lipids by hepatocytes, and accelerates the progression of steatosis in db/db mice. Thus EL may play a role in the genesis of steatosis as well as dyslipidemia in the metabolic syndrome.

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Atherosclerotic plaque volume correlates with arterial elastance in a mouse model of the metabolic syndrome

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2006.03.268 ◽

2006 ◽

Vol 40 (6) ◽

pp. 1012-1013

Author(s):

A. Van den Bergh ◽

P. Holvoet ◽

H. Bernar ◽

W. Flameng ◽

P. Herijgers

Keyword(s):

Metabolic Syndrome ◽

Mouse Model ◽

Atherosclerotic Plaque ◽

Plaque Volume ◽

Arterial Elastance ◽

The Metabolic Syndrome

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Characterising a novel mouse model of the metabolic syndrome

Heart Lung and Circulation ◽

10.1016/j.hlc.2009.05.594 ◽

2009 ◽

Vol 18 ◽

pp. S240

Author(s):

Nicola J.A. Scott ◽

Leigh J. Ellmers ◽

Sara Raudsepp ◽

Evan Simpson ◽

A. Mark Richards ◽

...

Keyword(s):

Metabolic Syndrome ◽

Mouse Model ◽

The Metabolic Syndrome

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Critical role of chemokine (C-C motif) receptor 2 (CCR2) in the KKAy + Apoe −/− mouse model of the metabolic syndrome

Diabetologia ◽

10.1007/s00125-011-2248-8 ◽

2011 ◽

Vol 54 (10) ◽

pp. 2660-2668 ◽

Cited By ~ 10

Author(s):

H. G. Martinez ◽

M. P. Quinones ◽

F. Jimenez ◽

C. A. Estrada ◽

K. Clark ◽

...

Keyword(s):

Metabolic Syndrome ◽

Mouse Model ◽

Critical Role ◽

The Metabolic Syndrome ◽

Apoe Mouse

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ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

Mediators of Inflammation ◽

10.1155/2017/7281986 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Lakshini Weerasekera ◽

Caroline Rudnicka ◽

Qing-Xiang Sang ◽

Joanne E. Curran ◽

Matthew P. Johnson ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Mouse Model ◽

White Adipose Tissue ◽

Mononuclear Cells ◽

Western World ◽

Diet Induced Obesity ◽

The Metabolic Syndrome

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF-α levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF-α levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D.

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Metabolic and Blood Pressure Effects of Walnut Supplementation in a Mouse Model of the Metabolic Syndrome

Nutrients ◽

10.3390/nu9070722 ◽

2017 ◽

Vol 9 (7) ◽

pp. 722 ◽

Cited By ~ 4

Author(s):

Nicola Scott ◽

Leigh Ellmers ◽

Anna Pilbrow ◽

Lotte Thomsen ◽

Arthur Richards ◽

...

Keyword(s):

Blood Pressure ◽

Metabolic Syndrome ◽

Mouse Model ◽

Pressure Effects ◽

The Metabolic Syndrome ◽

Blood Pressure Effects

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Identifying a New Mechanism of Sarcopenia by Autophagy

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.099 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A50-A50

Author(s):

Eijiro Yamada ◽

Ryota Uehara ◽

Yasuyo Nakajima ◽

Kazuhiko Horiguchi ◽

Emi Ishida ◽

...

Keyword(s):

Metabolic Syndrome ◽

Mouse Model ◽

Hind Limb ◽

Tibialis Anterior Muscle ◽

Intraperitoneal Administration ◽

Gene Expressions ◽

The Metabolic Syndrome ◽

Hind Limb Suspension ◽

Stat3 Phosphorylation ◽

Autophagy Activity

Abstract Sarcopenia is one of the critical factors in reducing Activity of Daily Life and associated with morbidity and mortality. Sarcopenia has also been linked to metabolic syndrome. In recent years, it has been reported that autophagy is one of the mechanisms as a cause of sarcopenia. Therefore, we focused on autophagy as a system that can regulate both sarcopenia and metabolic syndrome in skeletal muscle and revealed that non-receptor tyrosine kinase Fyn not only participates in metabolic syndrome but also regulates autophagy regulating sarcopenia through STAT3 regulation, mainly using transgenic mice (Cell metabolism 2010, Cell Rep. 2012). However, since these were non-physiological studies, we proceeded with further studies and demonstrating that Fyn dependent STAT3 phosphorylation by IL6, which is involved in chronic inflammation and metabolic syndrome, was observed in mouse C2C12 myotube cells. Autophagy was decreased in those cells by both IL6 dependent and Fyn dependent mechanisms. Furthermore, in the denervated mouse model, not only both Fyn and IL6 gene expressions as well as the key muscle specific E3 ubiquitin ligases, Atrogin1 and MuRf1 were increased but the expression and phosphorylation levels of STAT3 were also augmented, while the autophagy activity was decreased. We believe that a denervated mouse model alone is not enough as a model for sarcopenia, thus we next introduced a hind limb suspension mouse model that promotes disuse atrophy by suspending the hind limb. Using this model, we found that muscle atrophy was observed mainly in the soleus muscle, tibialis anterior muscle, and the gastrocnemius muscle with Atrogin1 and MuRf1 increased. Increase of both IL6 and STAT3 expression/phosphorylation were also observed in the muscles of hind limb suspension mice. Autophagy activity, examined by intraperitoneal administration of colchicine, was decreased. These results strongly suggest that Fyn is involved not only in the metabolic syndrome but also in the pathogenesis of sarcopenia, and may lead to a better understanding of the pathology of sarcopenia obesity and the development of therapeutic methods.

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