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2004, Number 2

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Rev Endocrinol Nutr 2004; 12 (2)

Pharmacogenomics of the obesity: Adjusting the secondary glucometabolic alterations to an excess of fat

Bastarrachea RA, Tejero E, Cai G, Comuzzie AG

Language: Spanish
References: 45
Page: 80-81
PDF size: 117.24 Kb.


ABSTRACT

Obesity is currently presented as a feedback complex neurohormonal model system controlled by the hypothalamus where the appetite centers are located. These centers receive afferent inputs about the status of the body fat reserves, mainly through leptin, the best known and the most studied adipose tissue hormone. The integration of this information elicit efferent signals related to the regulation of food intake and energy balance, and hormonal messages that modulate the accumulation of fat, leading to three strategies to develop antiobesity drugs: inhibitors of food intake, inhibitors of absorption and thermogenic drugs. Although leptin, its receptor and the hypothalamic neuropeptides are definitively implicated in the pathophysiology of obesity, at a genetic and a molecular level the reason some individuals accumulate more fat beyond what is healthy for them remains an enigma. This review intends to present a new approach for obesity drug discovery through pharmacogenomics and the emerging knowledge of key pathogenic mechanisms such as the role of lipotoxicity as a cause of glucometabolic insulin resistance, leading to a host of new molecular drug targets such as AMP-activated protein kinase (AMPK) activators, acetyl-CoA carboxilase (ACC) inhibitors, recombinant adiponectin derivatives, fatty acid synthase (FAS) inhibitors, protein tyrosine phosphatase 1B inhibitors, glucagon-like peptide (GLP-1) agonists, dipeptidylpeptidase (DPP)-IV inhibitors, glucokinase activators and liver-selective glucocorticoid receptor antagonists among others. Several compounds have already been validated through genetic engineering in animal models.


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