04.06 Alterations to adipose tissue-associated vasculopathology during inflammatory arthritis causes vascular dysfunction in dba/1 mice that is resolved by anti-tnf treatment

Obesity is a risk factor for vascular dysfunction and insulin resistance. The study aim was to demonstrate that adipocyte-specific HO-1 (heme oxygenase-1) gene therapy is a therapeutic approach for preventing the development of obesity-induced metabolic disease in an obese-mice model. Specific expression of HO-1 in adipose tissue was achieved by using a lentiviral vector expressing HO-1 under the control of the adiponectin vector (Lnv-adipo-HO-1). Mice fed a high-fat diet (HFD) developed adipocyte hypertrophy, fibrosis, decreased mitochondrial respiration, increased levels of inflammatory adipokines, insulin resistance, vascular dysfunction, and impaired heart mitochondrial signaling. These detrimental effects were prevented by the selective expression of HO-1 in adipocytes. Lnv-adipo-HO-1-transfected mice on a HFD display increased cellular respiration, increased oxygen consumption, increased mitochondrial function, and decreased adipocyte size. Moreover, RNA arrays confirmed that targeting adipocytes with HO-1 overrides the genetic susceptibility of adiposopathy and correlated with restoration of the expression of anti-inflammatory, thermogenic, and mitochondrial genes. Our data demonstrate that HO-1 gene therapy improved adipose tissue function and had positive impact on distal organs, suggesting that specific targeting of HO-1 gene therapy is an attractive therapeutic approach for improving insulin sensitivity, metabolic activity, and vascular function in obesity.

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Abstract 1123: Critical Role Of Adipose Senescence In Insulin Resistance And Vascular Dysfunction

Circulation ◽

10.1161/circ.116.suppl_16.ii_226-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Masayuki Orimo ◽

Tohru Minamino ◽

Hideyuki Miyauchi ◽

Kaoru Tateno ◽

Sho Okada ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Inflammatory Cytokines ◽

Cellular Senescence ◽

Vascular Dysfunction ◽

Critical Role ◽

Serum Levels ◽

P53 Expression ◽

Deficient Mice ◽

Pro Inflammatory Cytokines

Cellular senescence is originally described as the finite replicative lifespan of human somatic cells in culture. As a consequence of semi-conservative DNA replication, the extreme terminals of the chromosomes are not duplicated completely, resulting in successive shortening of telomeres with each cell division. Telomerase is a ribonucleoprotein that adds telomeres to the ends of chromosomes. Critically short telomeres are thought to trigger DNA damage response, thereby inducing cellular senescence. Accumulating evidence has suggested that senescent cells promote aging phenotypes or age-related pathologies. Here we show that adipose senescence is critically involved in the regulation of insulin resistance that underlies age-associated cardiovascular disease. The later generation of telomerase-deficient mice with short telomeres exhibited insulin resistance and vascular dysfunction when fed on a high-calorie diet. Adipose tissue of these mice revealed senescence-like phenotypes such as an increase in neutral β galactosidase activity and upregulation of p53 and pro-inflammatory cytokines. Serum levels of pro-inflammatory cytokines were markedly elevated in telomerase-deficient mice and treatment of these mice with a neutralizing antibody against TNF-α significantly improved insulin and glucose intolerance. Removal of senescent adipose tissue reduced serum levels of pro-inflammatory cytokines and thereby improved insulin resistance in telomerase-deficient mice. Conversely, implantation of senescent adipose tissue to wild-type mice impaired insulin sensitivity and glucose tolerance in recipients. Introduction of telomere dysfunction to young adipose tissue markedly upregulated p53 expression and increased the production of pro-inflammatory cytokines. Inhibition of p53 activity significantly improved senescence-like phenotypes of adipose tissue, insulin resistance, and vascular dysfunction in telomerase-deficient mice. These results disclose a novel mechanism of insulin resistance and suggest that adipose senescence is a potential therapeutic target for the treatment of diabetes and diabetic vasculopathy.

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Abstract 931: Compensatory Response of Perivascular Adipose Tissue to Vascular Dysfunction in Metabolic Syndrome Rats Involves Apelin

Circulation Research ◽

10.1161/res.125.suppl_1.931 ◽

2019 ◽

Vol 125 (Suppl_1) ◽

Author(s):

Satomi Kagota ◽

Miho Shimari ◽

Kana Maruyama-Fumoto ◽

Saki Iwata ◽

Kazumasa Shinozuka

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Vascular Dysfunction ◽

Compensatory Response ◽

Perivascular Adipose Tissue

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Endothelial and Perivascular Adipose Tissue Abnormalities in Obesity-Related Vascular Dysfunction

Journal of Cardiovascular Pharmacology ◽

10.1097/fjc.0000000000000469 ◽

2017 ◽

Vol 69 (6) ◽

pp. 360-368 ◽

Cited By ~ 17

Author(s):

Francesca Schinzari ◽

Manfredi Tesauro ◽

Carmine Cardillo

Keyword(s):

Adipose Tissue ◽

Vascular Dysfunction ◽

Perivascular Adipose Tissue ◽

Tissue Abnormalities

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Brown Fat Lipoatrophy and Increased Visceral Adiposity through a Concerted Adipocytokines Overexpression Induces Vascular Insulin Resistance and Dysfunction

Endocrinology ◽

10.1210/en.2011-1765 ◽

2012 ◽

Vol 153 (3) ◽

pp. 1242-1255 ◽

Cited By ~ 23

Author(s):

Almudena Gómez-Hernández ◽

Yolanda F. Otero ◽

Natalia de las Heras ◽

Óscar Escribano ◽

Victoria Cachofeiro ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Vascular Dysfunction ◽

Nuclear Factor Κb ◽

Brown Fat ◽

Visceral Adiposity ◽

Inflammatory Activity ◽

Nuclear Factor ◽

Antibody Treatment ◽

Tnf Α

In this study, we analyzed the role played by concerted expression of adipocytokines associated with brown fat lipoatrophy and increased visceral adiposity on triggering vascular insulin resistance and dysfunction in brown adipose tissue (BAT) insulin receptor knockout (BATIRKO) mice. In addition, we assessed whether vascular insulin resistance may aggravate vascular damage. The 52-wk-old, but not 33-wk-old, BATIRKO mice had a significant decrease of BAT mass associated with a significant increase of visceral white adipose tissue (WAT) mass, without changes in body weight. Brown fat lipoatrophy and increased visceral adiposity enhanced the concerted expression of adipocytokines (TNF-α, leptin, and plasminogen activator inhibitor 1) and nuclear factor-κB binding activity in BAT and visceral WAT, mainly in the gonadal depot, and aorta. Although those mice showed insulin sensitivity in the liver and skeletal muscle, insulin signaling in WAT (gonadal depot) and aorta was markedly impaired. Treatment with anti-TNF-α antibody impaired the inflammatory activity in visceral adipose tissue, attenuated insulin resistance in WAT and aorta and induced glucose tolerance. Finally, 52-wk-old BATIRKO mice showed vascular dysfunction, macrophage infiltration, oxidative stress, and a significant increase of gene markers of endothelial activation and inflammation, the latter effect being totally reverted by anti-TNF-α antibody treatment. Our results suggest that brown fat lipoatrophy and increased visceral adiposity through the concerted overexpression of cytoadipokines induces nuclear factor-κB-mediated inflammatory signaling, vascular insulin resistance, and vascular dysfunction. Inhibition of inflammatory activity by anti-TNF-α antibody treatment attenuates vascular insulin resistance and impairs gene expression of vascular dysfunction markers.

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