The acquisition of obesity: insights from cellular and genetic research

Wabitsch, Martin

doi:10.1017/s0029665100000367

Cited by 27 publications

(21 citation statements)

References 31 publications

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“…32 Thus, we investigated if TNP-470 treatment could prevent obesity in mice fed a high-fat diet (45 kcal% fat in food). Unlike in ob/ob mice, TNP-470 had little influence on food intake in these wt mice ( Figure 5A).…”

Section: Antiobesity Effect In High-fat Diet-fed Wt Micementioning

confidence: 99%

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

Bråkenhielm

Cao²,

Gao³

et al. 2004

Circulation Research

289

238

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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...

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Section: Antiobesity Effect In High-fat Diet-fed Wt Micementioning

confidence: 99%

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

Bråkenhielm

Cao²,

Gao³

et al. 2004

Circulation Research

289

238

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“…While this involves shrinkage of adipocytes, there is now considerable evidence that apoptosis is also involved in the turnover of adipocytes. 48,49 The subject of adipocyte apoptosis has been reviewed previously in this journal and we will not cover it in more detail here. 50 …”

Section: Adipocyte Differentiationmentioning

confidence: 99%

Integrative physiology of human adipose tissue

et al. 2003

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Adipose tissue is now recognised as a highly active metabolic and endocrine organ. Great strides have been made in uncovering the multiple functions of the adipocyte in cellular and molecular detail, but it is essential to remember that adipose tissue normally operates as a structured whole. Its functions are regulated by multiple external influences such as autonomic nervous system activity, the rate of blood flow and the delivery of a complex mix of substrates and hormones in the plasma. Attempting to understand how all these factors converge and regulate adipose tissue function is a prime example of integrative physiology. Adipose tissue metabolism is extremely dynamic, and the supply of and removal of substrates in the blood is acutely regulated according to the nutritional state. Adipose tissue possesses the ability to a very large extent to modulate its own metabolic activities, including differentiation of new adipocytes and production of blood vessels as necessary to accommodate increasing fat stores. At the same time, adipocytes signal to other tissues to regulate their energy metabolism in accordance with the body's nutritional state. Ultimately adipocyte fat stores have to match the body's overall surplus or deficit of energy. This implies the existence of one (or more) signal(s) to the adipose tissue that reflects the body's energy status, and points once again to the need for an integrative view of adipose tissue function.

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“…Endostatin is a well-documented angiogenesis inhibitor. Despite these intriguing studies, the mechanistic role of endostatin in adipogenesis and dietary-induced obesity, which is the most common form of human obesity (15), remains to be elucidated.…”

mentioning

confidence: 99%

Endostatin Prevents Dietary-Induced Obesity by Inhibiting Adipogenesis and Angiogenesis

Wang

Chen

et al. 2015

Diabetes

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Endostatin is a well-known angiogenesis inhibitor. Although angiogenesis has been considered as a potential therapeutic target of obesity, the inhibitory effect of endostatin on adipogenesis and dietary-induced obesity has never been demonstrated. Adipogenesis plays a critical role in controlling adipocyte cell number, body weight, and metabolic profile in a homeostatic state. Here we reveal that endostatin inhibits adipogenesis and dietary-induced obesity. The antiadipogenic mechanism of endostatin lies in its interaction with Sam68 RNA-binding protein in the nuclei of preadipocytes. This interaction competitively impairs the binding of Sam68 to intron 5 of mammalian target of rapamycin (mTOR), causing an error in mTOR transcript. This consequently decreases the expression of mTOR, results in decreased activities of the mTOR complex 1 pathway, and leads to defects in adipogenesis. Moreover, our findings demonstrate that the antiangiogenic function of endostatin also contributes to its obesity-inhibitory activity. Through the combined functions on adipogenesis and angiogenesis, endostatin prevents dietary-induced obesity and its related metabolic disorders, including insulin resistance, glucose intolerance, and hepatic steatosis. Thus, our findings reveal that endostatin has a potential application for antiobesity therapy and the prevention of obesity-related metabolic syndromes.

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The acquisition of obesity: insights from cellular and genetic research

Cited by 27 publications

References 31 publications

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

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

Integrative physiology of human adipose tissue

Endostatin Prevents Dietary-Induced Obesity by Inhibiting Adipogenesis and Angiogenesis

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