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...
Abstract-Atherosclerosis is a complex disease, bearing many of the characteristics of a chronic inflammatory process.Both cellular and humoral immune responses may be involved in the disease development. Oxidized low-density lipoprotein (oxLDL) is suggested to be an autoantigen in atherosclerosis. A protective effect against atherosclerosis has been demonstrated in animals immunized with oxLDL. Such a protection is associated with elevation of T cell-dependent IgG antibodies against oxLDL. In addition, it has been shown that immunization with Freund adjuvant alone also confers protection against development of atherosclerosis. We therefore hypothesized that CD4ϩ T cells are critical in the development of atherosclerosis and that they are involved in protective immune reactions after immunization. The development of atherosclerosis was studied in apolipoprotein E knockout (apoE KO) mice and CD4/apoE double knockout (dKO) mice that were immunized with either oxLDL in Freund adjuvant or adjuvant alone, or left untreated. Our results show that (1) the absence of CD4ϩ cells in apoE KO mice leads to reduced atherosclerosis, indicating that CD4ϩ cells constitute a major proatherogenic cell population, and (2)
Human GH (hGH) has been shown to stimulate hepatic low density lipoprotein (LDL) receptor expression in man in vivo. To further characterize this effect in vitro, we determined the expression of LDL receptors in cultured human hepatoma (HepG2) cells exposed to hGH. After incubation with hGH, stimulation of LDL receptors appeared at a concentration of 0.25 nM hGH. The presence of hGH receptors on HepG2 cells could be demonstrated by immunocytochemistry using a hGH receptor-specific monoclonal antibody. Binding studies, using 125I-labeled hGH, revealed high affinity binding with the appropriate somatogenic specificity. The LDL receptor induction was specific for hGH, as both bovine GH and recombinant human PRL were without effect. The LDL receptor stimulation occurred in parallel with increased levels of LDL receptor messenger RNA. Inclusion of dexamethasone and thyroid hormone in the incubation medium enhanced the LDL receptor stimulation by hGH. Although incubation with insulin-like growth factor-I (IGF-I) stimulated LDL receptor expression, the hGH-induced stimulation was unaltered after preincubation of cells with a monoclonal mouse anti-IGF-I antibody, suggesting that the release of IGF-I is not involved in LDL receptor stimulation by hGH. We conclude that hGH specifically induces the LDL receptor in cultured HepG2 cells at both the protein and the messenger RNA level, and that the induction is independent of IGF-I release.
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