FIGURE 3: Molecular and cellular processes linking chronic high-fat diet consumption with leptin resistance and obesity. The rise in circulating saturated fatty acids from chronic consumption of a high-fat diet leads to activation of TLR4 in hypothalamic microglia which then release pro-inflammatory cytokines such as TNF-α. This in turn leads to the release of the chemokine fractalkine from adjacent neurons which recruits circulating monocytes into the hypothalamus and which then differentiate into activated microglia. A vicious cycle is thus initiated which progressively worsens leptin resistance in hypothalamic neurons contributing to increased food intake and obesity. TLR4 – toll-like receptor 4, TNF-alpha – tumor necrosis factor alpha.