Obesity pharmacotherapy: current status.

Obesity is a medical condition in which excess body fat has accumulated to such an extent that it may have an adverse effect on health, leading to reduced life expectancy (Haslam and James, 2005). The lifestyle treatments directed at improving diet and physical activity are considered as first line treatment for obesity; however, if these fail, antiobesity medication is recommended. In the past years, numerous drugs have been approved for the treatment of obesity; however, currently, orlistat is the only food and drug administration (FDA) approved drug for long term management of obesity (Table 1). Lipolytic rate in white adipose tissue (WAT) has been positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression. It is a reasonable hypothesis that the difficulty in mobilizing lipids in adipocytes could contribute to increased adiposity and obesity, and thereby reducing the insulin sensitivity (Caminhotto et al., 2014). On the contrary, Girousse et al. (2013) has reported a new mechanism for the regulation of insulin sensitivity, who demonstrated that partial inhibition of lipolysis via reduced action of hormone sensitive lipase (HSL), either by genetic modification or by pharmacological inhibition, reshapes the fatty acid fluxes without increase of fat mass; improving glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis and leading to improved insulin sensitivity in mice. Orlistat is a well-known inhibitor of pancreatic lipase (PL) that is also reported to inhibit HSL; thus inhibiting the stimulated lipolysis (Clifford et al., 2000; Bustanji et al., 2010). It is reported that inhibition of HSL improves lipid profile while reduces plasma glucose (Claus et al., 2005). In this context, inhibition of lipolysis with orlistat provides a mechanism for the decrease plasma free fatty acids (FFA) and improvement in insulin sensitivity. Hence, the control of metabolic activity in WAT stands out as an important therapeutic intervention in the treatment of metabolic diseases (Caminhotto et al., 2014). Enç et al. (2009) reported that orlistat accelerates gastric emptying and attenuates gastric inhibitory peptide (GIP) release in healthy subjects; that play an important role in the modulation of lipid metabolism, obesity and insulin resistance. GIP, an insulinotropic hormone, is secreted from enteroendocrine upper gut K-cells postprandially. GIP similar to the incretin effect of glucagon-like peptide-1 (GLP-1), stimulates glucose-dependent insulin secretion. By acting on GIP receptors on adipocytes, GIP exhibits insulin mimetic properties such as elevation in glucose uptake, fatty acid synthesis, lipoprotein …