scholarly journals Identifying a New Mechanism of Sarcopenia by Autophagy

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.

Abstract 1186: Overexpression Of Endothelial Lipase In The Liver Promotes The Clearance Of Plasma Lipids But Accelerates Liver Steatosis In A Mouse Model Of Metabolic Syndrome

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Tomoyuki Yasuda ◽  
Tatsuro Ishida ◽  
Yoko Kojima ◽  
Hanayo Tanaka ◽  
Takeaki Okada ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Fatty Acid ◽  
Mouse Model ◽  
Fatty Acid Synthase ◽  
Plasma Lipids ◽  
Recombinant Adenovirus ◽  
Mrna Level ◽  
Liver Steatosis ◽  
Endothelial Lipase ◽  
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.

scholarly journals Hyperadiponectinemia protects against premature death in metabolic syndrome model mice by inhibiting AKT signaling and chronic inflammation

2012 ◽  
Vol 213 (1) ◽  
pp. 67-76 ◽  
Author(s):  
S Otabe ◽  
N Wada ◽  
T Hashinaga ◽  
X Yuan ◽  
I Shimokawa ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Accelerated Aging ◽  
Premature Death ◽  
Akt Signaling ◽  
Gene Expressions ◽  
Glucose Levels ◽  
Reactive Protein ◽  
The Metabolic Syndrome ◽  
Daily Food ◽  
Phosphorylated Akt

We previously reported that transgenic (Tg) expression of adiponectin significantly prolonged the lifespan of normal mice. The aim of this study was to elucidate the mechanism involved in the longevity effects of adiponectin using KK/Ta mice, a murine model of metabolic syndrome. We established a Tg line of KK/Ta (Tg-KK/Ta) mice expressing human adiponectin in the liver, and assessed their lifespan. The cause of death was determined by macroscopic and microscopic examinations immediately after death. The expressions of SIRT1, C-reactive protein (CRP), inflammatory cytokines, AMPK, and AKT were measured by quantitative real-time PCR, ELISAs, and/or western blotting. KK/Ta mice had lower serum adiponectin levels and shorter lifespan (57.6±13.9 vs 106.5±18.3 weeks, P<0.0001) than C57BL/6N mice. Tg adiponectin expression significantly extended the lifespan of KK/Ta mice (73.6±16.6 weeks, P<0.001) without affecting body weight, daily food consumption, or plasma glucose levels. Neoplasms were observed in only three of 22 KK/Ta mice that died spontaneously because of tumors. Atherosclerotic lesions were not detected in any mice. SIRT1 levels were not significantly different between KK/Ta and Tg-KK/Ta mice. Gene expressions of Crp, Tnfα, Il6, and Nfκb were increased in KK/Ta mice, but they were significantly attenuated in Tg-KK/Ta mice. Phosphorylated AMPK levels were increased and phosphorylated AKT levels were decreased in Tg-KK/Ta mice. The anti-inflammatory effects of adiponectin, achieved by inhibiting the AKT signaling pathway, may explain how adiponectin slows the accelerated aging process associated with the metabolic syndrome.

scholarly journals The Niemann-Pick C1 Like 1 (NPC1L1) Inhibitor Ezetimibe Improves Metabolic Disease Via Decreased Liver X Receptor (LXR) Activity in Liver of Obese Male Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (8) ◽  
pp. 2810-2819 ◽  
Author(s):  
Taichi Sugizaki ◽  
Mitsuhiro Watanabe ◽  
Yasushi Horai ◽  
Nao Kaneko-Iwasaki ◽  
Eri Arita ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Insulin Signaling ◽  
Metabolic Diseases ◽  
In Vitro Study ◽  
Liver X Receptor ◽  
Gene Expressions ◽  
The Metabolic Syndrome ◽  
Increased Risk

Dyslipidemic patients with diabetes mellitus, including metabolic syndrome, are at increased risk of coronary heart disease. It has been reported that ezetimibe, a cholesterol absorption inhibitor, improves metabolic diseases in mice and humans. However, the underlying mechanism has been unclear. Here we explored the effects of ezetimibe on lipid and glucose homeostasis. Male KK-Ay mice were fed a high-fat diet, which is the mouse model of metabolic syndrome, with or without ezetimibe for 14 weeks. Ezetimibe improved dyslipidemia, steatosis, and insulin resistance. Ezetimibe decreased hepatic oxysterols, which are endogenous agonists of liver X receptor (LXR), to decrease hepatic lipogenic gene expressions, especially in stearoyl-CoA desaturase-1 (SCD1), leading to a remarkable reduction of hepatic oleate content that would contribute to the improvement of steatosis by reducing triglycerides and cholesterol esters. Simultaneously, hepatic β-oxidation, NADPH oxidase and cytochrome P450 2E1 (CYP2E1) were reduced, and thus reactive oxygen species (ROS) and inflammatory cytokines were also decreased. Consistent with these changes, ezetimibe diminished c-Jun N-terminal kinase (JNK) phosphorylation and improved insulin signaling in the liver. In vitro study using primary hepatocytes obtained from male SD rats, treated with oleate and LXR agonist, showed excess lipid accumulation, increased oxidative stress and impaired insulin signaling. Therefore, in obese subjects, ezetimibe reduces hepatic LXR activity by reducing hepatic oxysterols to lower hepatic oleate content. This improves steatosis and reduces oxidative stress, and this reduction improves insulin signaling in the liver. These results provide insight into pathogenesis and strategies for treatment of the metabolic syndrome.

Characterising a novel mouse model of the metabolic syndrome

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

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

Diabetologia ◽  
2011 ◽  
Vol 54 (10) ◽  
pp. 2660-2668 ◽  
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

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

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
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.

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

Nutrients ◽  
2017 ◽  
Vol 9 (7) ◽  
pp. 722 ◽  
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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