Carbohydrates to Prevent and Treat Obesity in a Murine Model of Diet-Induced Obesity.

Introduction: The biggest risk factor for obesity and its associated comorbidities is a Western diet. This Western diet induces adipose tissue (AT) inflammation, which causes an AT dysfunction. Since AT is a vital endocrine organ, its dysfunction damages other organs, thus inducing a state of chronic inflammation and causing various comorbidities.

Serum amyloid A3 deficiency impairs in vitro and in vivo adipocyte differentiation.

Obesity, caused by an excess adipose tissue, is one of the biggest health-threats of the 21 century. Adipose tissue expansion occurs through two processes: (i) hypertrophy, and (ii) hyperplasia, the formation of new adipocytes, also termed adipogenesis. Recently, serum amyloid A3 (Saa3) has been implicated in adipogenesis.

Does butein affect adipogenesis?

Butein is a plant flavonoid chalcone, with presumed anti-adipogenic properties. It was reported to impair preadipocyte differentiation, limit adipose tissue (AT) development and enhance white AT browning in rodents. In this study, we investigated the hypothesis that these effects of butein may occur via reduction of ADAMTS5 (A Disintegrin And Metalloproteinase with ThromboSpondin motifs 5) expression.

Advanced-age C57BL/6JRj mice do not develop obesity upon western-type diet exposure.

Obesity has become a global health-threat for every age group. It is well known that young mice (10-12 weeks of age) fed a western-type diet (WD) become obese and develop higher cholesterol levels and liver steatosis whereas insulin sensitivity is reduced. Less is known, however, about the effect of a WD on advanced-age mice.

Adiposity and metabolic health in mice deficient in intestinal alkaline phosphatase.

Intestinal alkaline phosphatase 3 (AKP3) is an enzyme that was reported to play a role in lipid metabolism and to prevent high fat diet-induced metabolic syndrome in mice. To investigate a potential functional role of AKP3 in diet-induced adiposity and metabolic health, we have kept male and female wild-type or AKP3 deficient mice on a high fat diet for 15 weeks to induce obesity and compared those with mice kept on standard fat diet. Body weight as well as adipose tissue mass were statistically significantly higher upon high fat diet feeding for mice of both genders and genotypes.

Role of ADAMTS13 in diet-induced liver steatosis.

Previous studies, predominantly based on increased or decreased plasma levels, have reported conflicting data on a potential functional role of ADAMTS13 in the pathogenesis of liver diseases, including non‑alcoholic steatohepatitis (NASH). The aim of the current study was to evaluate whether ADAMTS13 deficiency affects development of NASH. Therefore, male wild‑type (WT) and Adamts13 deficient (Adamts13‑/‑) mice were kept on a steatosis‑inducing diet devoid of methionine and choline (MCD) or a control diet (MCC) for 4 weeks.

ADAMTS13 deficiency promotes microthrombosis in a murine model of diet-induced liver steatosis.

ADAMTS13 cleaves ultralarge multimeric von Willebrand Factor (VWF), thereby preventing formation of platelet-rich microthrombi. ADAMTS13 is mainly produced by hepatic stellate cells, and numerous studies have suggested a functional role of ADAMTS13 in the pathogenesis of liver diseases. The aim of our study was to investigate a potential role of ADAMTS13 in formation of hepatic microthrombi and development of non-alcoholic steatohepatitis (NASH), and furthermore to evaluate whether plasmin can compensate for the absence of ADAMTS13 in removal of thrombi.

ADAMTS5 promotes murine adipogenesis and visceral adipose tissue expansion.

Enhanced expression of the aggrecanase ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motifs; member 5) has been observed in adipose tissue (AT) of obese rodents. Here, we have investigated the role of ADAMTS5 in adipogenesis, AT expansion and associated angiogenesis. In vitro differentiation of precursor cells into mature adipocytes was studied using murine embryonic fibroblasts (MEF) derived from wild-type (Adamts5(+/+)) and ADAMTS5 deficient (Adamts5(-/-)) mice, or 3T3-F442A preadipocytes with stable gene silencing of Adamts5.

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.

The Anti-Adipogenic Potential of COUP-TFII Is Mediated by Downregulation of the Notch Target Gene Hey1.

Background: Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) belongs to the steroid/thyroid hormone receptor superfamily and may contribute to the pathogenesis of obesity. It has not conclusively been established, however, whether its role is pro- or anti-adipogenic.

Methods And Results: Gene silencing of Coup-tfII in 3T3-F442A preadipocytes resulted in enhanced differentiation into mature adipocytes.

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.

Gelatinase A (MMP-2) promotes murine adipogenesis.

Background: Expansion of adipose tissue is dependent on adipogenesis, angiogenesis and extracellular matrix remodeling. A functional role in these processes was suggested for the gelatinase subfamily of the matrix metalloproteinases. Here, we have evaluated a potential role of gelatinase A (MMP-2) in adipogenesis.

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.

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.

From mice to men--mouse models in obesity research: what can we learn?

Obesity has become a world-wide epidemic and is associated with diseases such as diabetes, dyslipidaemia, cardiovascular disease and certain types of cancers. Understanding the adipose tissue developmental process, involving adipogenesis, angiogenesis and extracellular matrix remodelling, is therefore crucial to reveal the pathobiology of obesity. Experimental mouse models are extensively used to gain new insights into these processes and to evaluate the role of new key players, in particular proteolytic system components, in adipose tissue development and obesity.

Effect of vascular endothelial growth factor receptor 2 antagonism on adiposity in obese mice.

Development and maintenance of fat depots require angiogenesis, in which vascular endothelial growth factor (VEGF) and its receptors play a crucial role. We have evaluated the effect of blocking VEGF receptor 2 (VEGF-R2) with a MAB (DC101) on adipose tissue of mice with established obesity. Therefore, obese male wild-type C57B1/6 mice were treated with i.

MicroRNAs regulated by adiponectin as novel targets for controlling adipose tissue inflammation.

A low-grade proinflammatory state contributes to the metabolic syndrome (MS). Adiponectin (ApN), which is reduced in the MS, has emerged as a master regulator of inflammation/immunity. We wanted to identify whether microRNAs (miRNAs) may mediate the antiinflammatory action of ApN on adipose tissue (AT).

CD36 promotes adipocyte differentiation and adipogenesis.

Background: CD36 is a membrane glycoprotein, contributing to the pathogenesis of metabolic disorders, like obesity, which has become a major health concern worldwide.

Methods: A potential functional role of the scavenger receptor CD36 was investigated in in vitro adipocyte differentiation and in vivo adipogenesis.

Results: During differentiation of 3T3-F442A preadipocytes into mature adipocytes, expression of CD36 was upregulated and CD36 gene silencing resulted in impaired differentiation, as monitored by Oil Red O staining and expression of adipogenic markers.

Axl deficiency does not affect adipogenesis or adipose tissue development.

To evaluate a potential role of Axl, the high-affinity receptor of growth arrest-specific protein 6 (GAS6) in adiposity, murine embryonic fibroblasts (MEF) derived from mice with genetic deficiency of Axl (Axl(-/-)) or wild-type littermates (Axl(+/+)) were differentiated into mature adipocytes. In addition, Axl(-/-) and Axl(+/+) mice were kept on standard fat diet (SFD) or on high-fat diet (HFD) for 15 weeks. Deficiency of Axl in MEF did not affect differentiation, as shown by a similar uptake of Oil Red O and expression of the adipogenic markers aP2 and peroxisome proliferator activator receptor γ (PPARγ) at the end of the differentiation.

Maximal PAI-1 inhibition in vivo requires neutralizing antibodies that recognize and inhibit glycosylated PAI-1.

Plasminogen activator inhibitor-1 (PAI-1) regulates the activity of t-PA and u-PA and is an important inhibitor of the plasminogen activator system. Elevated PAI-1 levels have been implicated in the pathogenesis of several diseases. Prior to the evaluation of PAI-1 inhibitors in humans, there is a strong need to study the effect of PAI-1 inhibition in mouse models.

Association of vitronectin and plasminogen activator inhibitor-1 levels with the risk of metabolic syndrome and type 2 diabetes mellitus. Results from the D.E.S.I.R. prospective cohort.

It was the objective of this study to investigate the relation between vitronectin and plasminogen activator inhibitor (PAI)-1 plasma levels with nine-year incidences of the metabolic syndrome (MetS) and of type 2 diabetes mellitus (T2DM). Baseline plasma concentrations of vitronectin and PAI-1 were measured in 627 healthy participants from the prospective D.E.

Plasminogen activator inhibitor 1 is an intracellular inhibitor of furin proprotein convertase.

Proprotein convertases (PCs) are a family of serine proteases that are involved in the post-translational processing and activation of a wide range of regulatory proteins. The upstream role of PCs in the control of many physiological and pathological processes generates a growing interest in understanding their regulation. Here, we demonstrate that the serine protease inhibitor plasminogen activator inhibitor 1 (PAI-1) forms an SDS-stable complex with the PC furin, which leads to the inhibition of the intra-Golgi activity of furin.

Characterization of a panel of monoclonal antibodies toward mouse PAI-1 that exert a significant profibrinolytic effect in vivo.

Introduction: PAI-1 is the main physiological inhibitor of t-PA and u-PA. Elevated PAI-1 levels have been implicated in the pathogenesis of several thrombotic and non-thrombotic diseases. The effect of PAI-1 inhibition can be studied in mouse models, when appropriate immunological tools are available.

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.

Effect of tissue inhibitor of matrix metalloproteinases-1 on in vitro and in vivo adipocyte differentiation.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in 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 early stages of in vitro and in vivo adipogenesis. Overexpression of human TIMP-1 (hTIMP-1) in 3T3-F442A preadipocytes resulted in a somewhat slower differentiation into mature adipocytes, without affecting the total extent of differentiation.