Angiogenesis Inhibitor, TNP-470, Prevents Diet-Induced and Genetic Obesity in Mice

Abstract

Abstract-Adipose tissue growth has been proposed to involve recruitment of new blood vessels. Here, we test the hypothesis that delivery of an angiogenesis inhibitor in mice may prevent diet-induced obesity, the most common type of obesity in humans. We show that systemic administration of a selective angiogenesis inhibitor, TNP-470 (AGM-1470), prevents obesity in high caloric diet-fed wt mice as well as in genetically leptin-deficient ob/ob mice. Inhibition of obesity in mice by TNP-470 involves a reduction of vascularity in the adipose tissue. This therapeutic strategy appears to selectively affect the growth of adipose tissue as measured by the ratio between total fat and lean body mass. Interestingly, the treatment with TNP-470 results in decreased serum levels of low-density lipoprotein cholesterol. Furthermore, insulin levels are reduced, which indicates increased insulin sensitivity, suggesting that angiogenesis inhibitors may prevent the development of type II diabetes. Our findings suggest that similarly to growth and organogenesis in other tissues, adipose tissue growth is dependent on angiogenesis. Our observations may have conceptual implications for the prevention of obesity and related disorders. O besity has become a worldwide major public health problem. Approximately 30% of the population in the US is estimated to be obese. 1 The obese population has an increased risk for diabetes, dyslipidemia, cardiovascular disease, cancer, and sleep-breathing disorders. [2][3][4][5] The causes of increased human obesity are directly linked to a high dietary fat intake and to reduced physical exercise. In fact, obesity resulting from inappropriate food-intake is the most common cause of human obesity, although genetic factors may also play a role. 4,6 The inappropriate growth of adipose tissue by increasing both the number and size of adipocytes leads to obesity. Several hormones and cytokines, such as leptin and neuropeptide Y, have been found to be critical components controlling adipogenesis in the body. 7,8 Inactivating mutations of either leptin (ob/ob) or its functional receptors (db/db) result in genetic obesity in mice and humans. 2,8 Leptin have been shown to stimulate angiogenesis. 9 -11 These findings suggest that the targets of adipogenesis regulatory hormones are located both in the central nervous system and in peripheral tissues. Tissue growth and organ regeneration are angiogenesis-dependent. 12 Several studies show that adipogenesis and angiogenesis are tightly correlated during fat mass deposit. [13][14][15][16] We hypothesized that adipogenesis is concomitantly accompanied by new blood vessel growth, and thus suppression of angiogenesis would prevent adipogenesis and obesity independent of the obesity cause. To test this hypothesis, we chose a well-characterized angiogenesis inhibitor, TNP-470 (AGM-1470), to treat high-fat diet-fed C57Bl/6 wt and ob/ob mice. TNP-470 is a synthetic analog of fumagillin, which selectively inhibits endothelial cell growth and angiogenesis. 17 The angiost...

The anti-angiogenic herbal composition Ob-X inhibits adipose tissue growth in obese mice

“…This is supported by reports that treatment with angiogenesis inhibitors resulted in weight reduction and adipose tissue loss, showing that adipose tissue mass is sensitive to angiogenesis inhibitors and can be regulated by its vasculature. [6][7][8] Extensive changes in ECM remodeling have also been shown to occur during adipose tissue growth. Two types of proteolytic systems, the plasminogen/plasmin (fibrolytic) and matrix metalloproteinase (MMP) systems, have been implicated in tissue remodeling, via degradation of ECM and basement membrane components, or activation of adipocyte growth factors.…”

Preventing diet-induced obesity in mice by adipose tissue transformation and angiogenesis using targeted nanoparticles

“…A few other studies demonstrated that methionine aminopeptidase inhibitors, fumagillin and beloranib, could induce sustained weight reduction by reducing the production of new fatty acids in the liver and reducing the pathological angiogenesis in adipose tissue (24,25). Other groups have also demonstrated that angiogenesis inhibitors such as TNP-470, angiostatin, and endostatin exhibited antiobesity effects by inhibiting blood vessel growth in preclinical models (3,5). However, this line of inquiry has been challenged by the fact that energy expenditure requires active angiogenesis (6).…”

“…Recent evidence reveals that adipose tissue development is associated with microvessel growth and requires vascular remodeling (4). In addition, the modulation of blood vasculature can directly affect adipose tissue metabolism (3,5,6). The crosstalk among many types of cells including adipocytes, endothelial cells (ECs), and stromal cells is mediated by multiple angiogenic factors that play pivotal roles in cooperatively modulating adipogenesis (2).…”

“…Few therapeutic agents are available for treating obesity in the clinic due to the complex interplay of genetic, environmental, and cultural factors (9). Previous studies have shown that modulations against vascular development in adipose tissues could alter tissue metabolism and inhibit the development of obesity in mice as well as monkeys (3,5,10). However, treating obesity with antiangiogenesis therapy has been hindered by the fact that energy expenditure in certain types of adipose tissue is critically dependent on angiogenesis (6), and an approach to differentially deliver an antiangiogenic agent to the adipose tissue has remained largely elusive.…”

Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis

“…Immunomhistochemical staining was performed according to previously published methods [39][40][41] . Paraffin-embedded tumour issue sections (5 mm) were double-stained with anti-endomucin (1:400; eBioscience, 14-5851-85) and anti-aSMA (1:200; DAKO, M0851) antibodies, followed by staining with a mixture of secondary antibodies comprised of Alexa Fluor 555-labelled goat anti-rat (1:400; Molecular Probes) and Alexa Fluor 488-labelled donkey anti-mouse (1:400; Molecular Probes).…”