Evidence has suggested that chronic inflammation is a potential mechanism whereby obesity leads to a variety of metabolic diseases. Chronic inflammation involves prolonged crosstalk between parenchymal and stromal cells in response to tissue stress, thereby leading to organ malfunction and tissue remodeling. For instance, obese adipose tissue is characterized by adipocyte hypertrophy, followed by increases in angiogenesis and macrophage infiltration and enhanced fibrosis, which is known as “adipose tissue remodeling” (J. Leukoc. Biol. 88: 33-39, 2010). During the paracrine interaction between adipocytes and macrophages, saturated fatty acids, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced lipolysis, may serve as an endogenous ligand for TLR4 complex, a major pathogen sensor, thus establishing a vicious cycle that aggravates and prolongs inflammatory responses (Arterioscler. Thromb. Vasc. Biol. 25: 2062-2068, 2005; Arterioscler. Thromb. Vasc. Biol. 27: 84-91, 2007). On the other hand, non-alcoholic steatohepatitis (NASH) is considered a hepatic phenotype of the metabolic syndrome. We have recently demonstrated that mice deficient in melanocortin-4 receptor (MC4R), a hypothalamic key regulator of food intake and energy expenditure, provide a novel mouse model of NASH with which to investigate the sequence of events that comprise diet-induced hepatic steatosis, liver fibrosis, and hepatocellular carcinoma (Am. J. Pathol. 179: 2454-2463, 2011 ). Our data suggest that obesity-induced adipose tissue inflammation causes increased adipocyte lipolysis, thus contributing to ectopic fat accumulation and enhanced fibrosis in the liver. It is likely that during the progress of the metabolic syndrome, inflammatory responses, once induced within obese adipose tissue, expands to multiple remote organs through complex organ networks involving both endocrine and neural mechanisms.