Functional role of ADAMTS5 in adiposity and metabolic health.

Previous studies with gene-deficient mice (ADAMTS5-P) revealed that ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motifs, member 5) plays a functional role in adiposity and metabolic health. To confirm these observations, we have performed similar studies with an independently generated strain of ADAMTS5 deficient mice (ADAMTS5-J). Upon cold exposure as well as after high-fat diet feeding (diet-induced obesity or DIO model), these knockout (KO) mice developed less subcutaneous and gonadal white adipose tissue (WAT) as compared to their wild-type (WT) littermates (reduction was more pronounced in ADAMTS5-P mice).

Antioxidant Treatment Improves Cardiac Dysfunction in a Murine Model of Premature Aging.

Bmal1-(brain and muscle ARNT-like protein-1) deficient (Bmal1) mice prematurely age because of an increased reactive oxygen species (ROS) production. These mice also show a decline in cardiac function with age. We investigated whether an antioxidant treatment can ameliorate the declining cardiac function in prematurely aged Bmal1 mice.

ADAMTS5 deficiency protects against non-alcoholic steatohepatitis in obesity.

Background & Aims: Increased prevalence of obesity is paralleled by an increase in non-alcoholic steatohepatitis (NASH). We previously found that the expression of ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motifs; member 5) is enhanced in expanding adipose tissue. However, no information is available on a potential role in liver pathology.

CD36 deficiency blunts effects of diet on regulatory T cells in murine gonadal adipose tissue and mesenteric lymph nodes.

The effect of cluster of differentiation (CD)36 on regulatory T cells (Treg) was investigated in gonadal (GN) adipose tissues and mesenteric lymph nodes (MLN) of wild-type (WT) and CD36 deficient (CD36(-/-)) mice kept on standard fat (SFD, lean) or on high fat diet (HFD, obese). GN adipose tissue mass was smaller, but MLN size larger for obese CD36(-/-) versus obese WT mice. Overall, the reduction of Treg cells in GN adipose tissue and MLN after a HFD is much more prominent in WT than CD36(-/-) mice.

ADAMTS13 deficiency in mice does not affect adipose tissue development.

Background: BMI and ADAMTS13 levels are positively correlated in man. Development of obesity is associated with angiogenesis and inflammation, and increased ADAMTS13 synthesis in the liver.

Methods: Male wild-type (WT) and ADAMTS13 deficient (Adamts13-/-) mice were kept on normal chow (SFD) or high fat diet (HFD) for 15 weeks.

Gelatinase B (MMP-9) gene silencing does not affect murine preadipocyte differentiation.

Growth of adipose tissue involves differentiation of preadipocytes into mature lipid-containing adipocytes. The matrix metalloproteinases (MMPs) are known regulators of adipose tissue biology, and previous studies suggested a key role for gelatinase B (MMP-9) in adipogenesis. In the present study we have evaluated a potential functional role of MMP-9 by performing gene silencing in 3T3-F442A preadipocytes.

FGF receptor antagonism does not affect adipose tissue development in nutritionally induced obesity.

The fibroblast growth factor (FGF)-FGF receptor (FGFR) system plays a role in angiogenesis and maintenance of vascular integrity, but its potential role in adipose tissue related angiogenesis and development is still unknown. Administration of SSR, a low molecular weight inhibitor of multiple FGFRs, did not significantly affect body weight nor weight of subcutaneous or gonadal (GON) fat, as compared with pair-fed control mice. Adipocyte hypertrophy and reduced adipocyte density were only observed in GON adipose tissues of treated mice.

Effect of rosiglitazone on liver structure and function in genetically diabetic Akita mice.

Genetically diabetic Akita mice, kept on a high-fat and high-cholesterol diet, and treated with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone (10 mg/kg per day during 4 months), displayed rosiglitazone-induced side effects, similar to those observed in patients, including weight and fat gain and early signs of hypertrophic cardiomyopathy. As several cases of hepatotoxicity were reported in patients receiving rosiglitazone treatment, this study evaluated whether rosiglitazone also induced hepatotoxicity in these diabetic animals. Liver structure and function was analysed in wild-type and rosiglitazone-treated and untreated Akita mice, kept for 4 months on the high-fat and high-cholesterol diet.

Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance.

Oxidative phosphorylation in mitochondria is responsible for 90% of ATP synthesis in most cells. This essential housekeeping function is mediated by nuclear and mitochondrial genes encoding subunits of complex I to V of the respiratory chain. Although complex IV is the best studied of these complexes, the exact function of the striated muscle-specific subunit COX6A2 is still poorly understood.

Does rosiglitazone affect adiposity and cardiac function in genetic diabetic mice?

Rosiglitazone ((RS)-5-[4-(2-[methyl(pyridin-2-yl)amino]ethoxy)benzyl]thiazolidine-2,4-dione, RGZ)-induced adverse drug effects in diabetic patients were not adequately predicted by current preclinical rodent models. Therefore, we have used the Akita mouse with genetic predisposition to diabetes to unravel the underlying molecular mechanisms. The effect of RGZ on adipose tissue and on cardiac function was evaluated in diabetic Akita mice kept on a high fat-high cholesterol diet (HF-HCD) for 4 months.

Effect of weight loss on gelatinase levels in obese mice.

1. Gelatinases (matrix metalloproteinase (MMP)-2 and MMP-9) might play a role in the development and structural organization of adipose tissue. Obese mice were subjected to caloric restriction (from 82 to 27 kJ/day) for 6 weeks, in order to investigate the effect of drastic weight loss on gelatinase mRNA, protein and activity levels.

Impact of clock gene Bmal1 deficiency on nutritionally induced obesity in mice.

To evaluate the hypothesis that the clock gene Bmal1 (brain and muscle arnt like protein-1) plays a role in the development of obesity, 5-week-old male Bmal1-deficient (Bmal1(-/-)) mice and wild-type littermates (Bmal1(+/+)) were kept on a high-fat diet (HFD) for 15 weeks. Despite an initial accelerated weight gain of Bmal1(-/-) mice, body weight and subcutaneous (SC) and gonadal (GON) adipose tissue mass were comparable to Bmal1(+/+) mice at the end of the diet period. Noninvasive magnetic resonance imaging scanning revealed a modest increase in fat content in Bmal1(-/-) mice after 10 weeks of HFD, whereas at the start and the end of the HFD feeding no differences were observed between both genotypes.

Fumagillin reduces adipose tissue formation in murine models of nutritionally induced obesity.

The effect of fumagillin (a methionine aminopeptidase-type 2 (Met-AP2) inhibitor, with antiangiogenic properties) was investigated in murine models of diet-induced obesity. Eleven-week-old male C57Bl/6 mice (group 1) were given fumagillin by oral gavage at a dose of 1 mg/kg/day during 4 weeks while fed a high-fat diet (HFD) (20.1 kJ/g), and control mice (group 2) received solvent and were pair-fed.

Blood vessel density in de novo formed adipose tissue is decreased upon overexpression of TIMP-1.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in the development of obesity by contributing to adipogenesis, angiogenesis, and extracellular matrix degradation. We have evaluated a potential functional role of TIMP-1, which inhibits most MMPs, in in vivo adipogenesis. Therefore, human (h) TIMP-1 was overexpressed by injection in the tail vein of NUDE mice of an adenoviral vector 3 days before injection of 3T3-F442A preadipocytes in the back.

Evaluation of matrix metalloproteinases in atherosclerosis using a novel noninvasive imaging approach.

Objective: Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture.

Plasminogen activator inhibitor-1 impairs plasminogen activation-mediated vascular smooth muscle cell apoptosis.

The role of plasminogen activator inhibitor-1 (PAI-1) in vascular smooth muscle cell (VSMC) apoptosis mediated by plasminogen activation was studied with the use of aorticVSMC derived from mice with deficiency of PAI-1 (PAI-1 (-/-) ), tissue-type (t-PA (-/-) ) or urokinase-type (u-PA (-/-) ) plasminogen activator or from wildtype (WT) mice with corresponding genetic background. Plasminogen incubated with confluent VSMC was activated in a concentration-dependent and saturable manner for all four cell types, with maximal activation rates that were comparable for WT, u-PA (-/-) and t-PA (-/-) cells, but about two-fold higher for PAI-1 (-/-) cells. Plasminogen activation was impaired by addition of the lysine analogue 6-aminohexanoic acid, and by addition of t-PA and u-PA neutralizing antibodies, suggesting that it depends on binding to cell surface COOH-terminal lysine residues, and on plasminogen activator activity.

Generation of a stable activated thrombin activable fibrinolysis inhibitor variant.

Activated thrombin activable fibrinolysis inhibitor (TAFIa), generated upon activation of TAFI, exerts an antifibrinolytic effect. TAFIa is a thermolabile enzyme, inactivated through a conformational change. The objective of the current study was to generate a stable variant of human TAFIa.