, 2003, Xu et al., 2003 and Shu et al.,

2012). This macrophage proliferation, coupled with increased TLR4 and other pattern recognition receptors on adipocytes, leads to an increase in the pro-inflammatory cytokine profile (Hotamisligil et al., 1993, Hotamisligil et al., 1995, Uysal et Daporinad al., 1997 and Shu et al., 2012). Increased pro-inflammatory cytokines, adipokines, and fatty acids then have downstream effects on liver and muscle, which contribute to systemic insulin resistance (Shu et al., 2012). Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)α activate serine kinases that directly and indirectly phosphorylate insulin receptor substrate (IRS) 1 and 2, resulting in a reduced ability of insulin to stimulate phosphatidylinositol-3 kinase (PI-3K)-dependent pathways that normally result in glucose uptake and metabolism (Hirabara et al., 2012). Feeding-related pathways in the hypothalamus are also disrupted by inflammation, with insulin and leptin less able to suppress hunger and feeding, further contributing to the maintenance of a high fat diet and thus obesity Trametinib (Thaler and Schwartz, 2010). Obesity- and high fat diet-associated systemic inflammation was identified some time ago, with early reports suggesting obese humans and high fat diet-fed rodents

have elevated circulating pro-inflammatory cytokines compared with controls, and macrophage infiltration into the WAT (Pickup and Crook, 1998, Weisberg et al., 2003 and Wellen and Hotamisligil, 2003). The suggestion that obesity can also result in central inflammation, however, Anacetrapib is a relatively recent one. In 2005, de Souza and colleagues showed high fat diet elevates the expression of pro-inflammatory cytokines and activation of the pro-inflammatory

transcription factor nuclear factor κB (NFκB) in the hypothalamus (De Souza et al., 2005). Several other investigations followed, suggesting high fat diet can cause hypothalamic inflammation and that this inflammation can interrupt normal feeding- and metabolism- related signaling. Thus, high fat feeding leads to infiltration and activation of microglia (the brain’s resident macrophages) in the hypothalamus, activation of inflammatory signaling, and increases in local inflammatory mediators such as cytokines (Fig. 1) (De Souza et al., 2005, Zhang et al., 2008, Milanski et al., 2009, Posey et al., 2009 and Thaler et al., 2012). Importantly, this central inflammation can actually contribute to leptin and insulin resistance, favoring weight gain and maintaining an elevated body weight (De Souza et al., 2005 and Posey et al., 2009). As with systemic increases in pro-inflammatory cytokines, increases in TNFα, IL-6 etc.