ROLE OF LEPTIN, FTO AND VEGF GENES IN ADIPOGENESIS DERIVED ANGIOGENESIS

KAMAL, MEHWISH and Akhtar, Kamal and S, AALIYA and M, HALIM and A, EMILIA and K, Gotam (2014) ROLE OF LEPTIN, FTO AND VEGF GENES IN ADIPOGENESIS DERIVED ANGIOGENESIS. Bulletin of the Genetics Society of Malaysia, 20 (1). pp. 60-65. ISSN 1394-5750

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Abstract

Obesity is a disease caused by the accumulation of excess body fat mass which possesses adverse effects on health and leads to development of various diseases such as hypertension, cardiovascular diseases, type 2 diabetes and etc. (Ministry of Health Malaysia, 2004).Obesity is a severe issue facing most developed nations and many other emerging economies with the World Health Organization (WHO) estimating that there will be over 2 billion overweight and 700 million obese adults in the world by 2015 (WHO, 1997).Hence, obesity has raised alarming concerns internationally. In this new generation, the rate of obesity has tremendously been increasing due to poor lifestyle and eating habits such as high intake of high fat diet and junk foods. According to WHO, obesity has almost doubled since 1980 worldwide (WHO, 2000). Obesity is a result of interplay between genetic and environmental factors. The risk of obesity is determined not only by specific genotypes but also by certain gene-gene interactions Friedman, 2000). As per the Malaysia society of obesity in 2013, obesity disease is highlighted as the root cause of many other associated diseases (Roth et al., 2004).It has been reported that there were around three million obese Malaysians and the number is increasing tremendously and among them there were about five millions individuals who are suffering from type 2 or gestational diabetes ( Korner and Aronne, 2003).The most basic determinant of excess weight is due to the imbalance between calories consumed and calories burnt. There are several key hormones in the body that are involved and associated with obesity. Leptin and ghrelin for example are two crucial hormones which have been identified to contribute a major impact on overall body energy balance (Efthimia, 2013). Leptin is referred as a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss whereas ghrelin has a counteract role to leptin as it is a fast-acting hormone playing an important role in meal initiation (Fischer, 2009).Thus, a proper balance between these two hormones is crucial for overall body mass.Studies in the past have showed that possible abnormalities between leptin and ghrelin systems may contribute to the development of obesity which needs further investigation (Malik et al., 2008).Leptin among the best known hormone markers for obesity, exerts pleiotropic actions on several organ systems is a protein hormone which is involved in the regulation of energy intake and expenditure by the body. Leptin is an important cytokine which plays a role in the regulation of appetite, food intake and metabolism (Ingalls et al., 1950). The discovery of leptin, a product of the ob gene, in 1994 (Zhang et al., 1994) has raised hopes of many obese populations throughout the world for a probable solution to their fatness. Leptin is produced predominantly by adipose tissue and plays a pivotal role in the regulation of appetite and body weight (Ahima and Flier, 2000). Plasma leptin levels are significantly elevated in obese individuals, and leptin receptors are widely distributed in peripheral tissue including the cardiovascular system (Dubey and Hesong, 2006). The primary physiological role of leptin is to communicate to the central nervous system (CNS) the abundance of available energy stores and to avoid excess food intake and induce energy expenditure. The absence of leptin therefore leads to increased appetite and food intake that result in morbid obesity (Wallace et al., 2001). In the regulation of energy balance, leptin first crosses the blood brain barrier aided by its binding to the short form receptor, and then binds to the long form receptors in the hypothalamic nuclei. The net effect is a suppression of appetite and feeding, increased autonomic activity and thermogenesis (Margetic et al., 2002). Whilst the discovery of leptin has in a way provided a directional path to research in obesity, there is still a need G E N E T I K J A N 2 0 1 4 Page 61 of further studies that needs to be done to properly understand the role of leptin in obesity (Rahmouni and Haynes, 2004).Nevertheless, it has become evident from early on that leptin deficiency may not by itself totally explain obesity. The fact that it was not affecting the obese mice or rats themselves indicated that there was present an element of resistance in these animals. Previous studies have suggested that in addition to leptin deficiency in obesity, leptin resistance occurred due to failure to induce weight loss by leptin is hypothesized to occur at various levels in the leptin pathway (Sinha et al., 1996).Another study has showed how altered leptin signaling in obesity result and leads to obesity-related cardiovascular disease (Coleman and Herrmann, 1999) such as hyperleptinemia is a result due to disruption in leptin signaling pathway in the hypothalamus often results in obesity. Therefore, hyperleptinemia may be one potential mechanism linking obesity to atherosclerotic cardiovascular disease as depicted in figure 1. . Figure 1: Systemic leptin function. Chronic hyperleptinemia is a result due to central impairment of the leptin hormone while its sympathetic outflow is unchanged. (Source: Sept 14, 2007, The Journal of American Heart Association. http://circres.ahajournals.org/content/101/6/545) Since obesity disease has become as one of the most detrimental disease in the world, it is associated with several other diseases mentioned above, more research work has been done to investigate the role of different genes in associated with obesity such as VEGF and FTO genes. The Vascular endothelial growth factor (VEGF) gene is crucial in vascular genesis and angiogenesis (Carmeliet, 2005).During early stages of embryo development (embryogenesis), adipose tissue development are spatially and temporally linked with micro vessel growth. Thereby, adipogenesis and angiogenesis are tightly correlated during fat mass development. Endothelial cells isolated from different adipose tissues vary in their proliferative capacity, suggesting that adipocytes play both guidance and maintenance roles in vascular development (Dvorak, 2005).A recent study suggested that adipocytes and their accompanying endothelial cells might share a common progenitor that may differentiate into adipocytes or endothelial lineages depending on environmental cues (Ferrara and Kerbel, 2005).Human adipose tissue–derived stem cells can differentiate into endothelial cells and improve postnatal neovascularization. These findings raised an interesting and exciting possibility that targeting a common adipose progenitor is probably an effective approach for therapeutic intervention of obesity (Folkman, 2005).Adipose tissue has been long known to promote wound healing and to re-vascularise ischemic tissues including G E N E T I K J A N 2 0 1 4 Page 62 myocardium (Folkman, 2005).Previous research studies showed both at genetic and high calorie diet induced obesity involve a switch between angiogenic phenotype in adipose tissue to support adipogenesis (Silverman et al., 1998).Adipose tissue is a unique tissue in the body known for its plasticity of growth and regression throughout life. An extensive vasculature supports the adipose tissue, and a capillary network surrounds essentially every adipocyte as depicted in Fig. 2 (Brakenhielm et al., 2004). Like the growth of any other tissue, adipose tissue expansion during increased caloric intake requires angiogenesis in forming new blood vessels from pre-existing blood vessels. Research has showed that elevated level of leptin in obese individuals and excess body weight has demonstrated increase rate of breast cancer in postmenopausal women as leptin can overexpress mitogenic and angiogenic processes such as VEGF in peripheral organs. This leads to an interesting association of leptin in tumorigenesis and becoming an attractive target in breast cancer (Eva, 2007). Also previous study has shown that leptin, through activation of the endothelial Ob-R, generates and regulates a growth signal involving a tyrosine kinase-dependent intracellular pathway and promotes angiogenic processes. This leptin-mediated stimulation of angiogenesis is a key event associated in obesity, more studies involving angiogenesis agent such as VEGF offer exciting new therapeutic strategies for the prevention and treatment of obesity in the near future.

Item Type: Article
Subjects: Q Science > QP Physiology
Faculty / Institute: Faculty of Medicine
Depositing User: kamal A Akhtar
Date Deposited: 10 Mar 2015 00:20
Last Modified: 27 Apr 2015 04:19
URI: http://erep.unisza.edu.my/id/eprint/3080

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