While adipose tissue is a central site of inflammation in obesity, the resultant metabolic sequelae are systemic. What are the mechanisms by which inflammation within adipose tissue influences other organ systems? One such mechanism is the intimate anatomic association between VAT and the liver. Increased VAT leads to increased delivery of free fatty acids, inflammatory adipocytokines to the liver via the portal venous system, phenomena that are directly implicated in the pathogenesis of hepatic steatosis and steatohepatitis. As a result, alterations in inflammatory cytokine expression and lymphocyte function similar to those observed in adipose tissue are also present in the liver. Hepatic inflammation in turn influences metabolism and disease pathogenesis in other organ systems. For example, mice genetically engineered to over-express NFκB in the liver exhibit insulin resistance not only locally within hepatic tissue, but in skeletal muscle as well, suggesting in vivo communication between these tissues through humoral mediators. The liver is, therefore, an important secondary anatomic site of inflammation in obesity.
Adipocytokines may influence other organ systems via hormonal effects. Many of the same mediators which are increased in adipose tissue in obesity are also increased in serum, suggesting an adipose tissue source. Despite well-established hormonal effects of adipokines with respect to satiety, however, whether similar hormonal mechanisms are active with respect to immune and inflammatory function is uncertain, as are hormonal effects for classic adipose tissue-derived cytokines. For example, while exogenous TNF-αhas well-described widespread systemic effects, a paucity of data support the hypothesis that adipose tissue is a primary source of systemic, bioactive TNF-α in vivo. TNF-α levels are lower in venous than arterial blood from SAT, and adipose tissue expresses high levels of soluble TNFR, which may sequester TNF-α within tissues. Current data, therefore, do not convincingly establish a hormonal effect of adipose-tissue-derived TNF-α. More compelling evidence exists for a hormonal role for IL-6; up to one third of circulating IL-6 is thought to be derived from adipose tissue, but distinguishing between hormonal and paracrine effects in vivo has proven difficult. Specific hormonal activities of adipocytokines are therefore as of yet not well-established but are certainly plausible.
Finally, excess lipid itself contributes to systemic inflammation in obesity. Increased dietary fat intake is thought to overwhelm adipocyte storage abilities, leading to increased circulating free fatty acids and subsequent ectopic lipid deposition in virtually all tissues, with widespread physiologic consequences. Lipids are cytotoxic to most cells: lipid deposition in pancreatic islets has been implicated in the pathogenesis of diabetes, while lipid deposition within endothelial cells contributes to hypertension, in part by inducing resistance to the vasodilatory effects of insulin. Lipid accumulation in hepatocytes defines steatosis and is a causal agent in the progression of steatosis to steathohepatitis, while in skeletal muscle, ectopic lipid deposition has been associated with peripheral insulin resistance. Indirect evidence of the role of adipose tissue as a protective buffer against the systemic effects of lipids is provided by observations in humans and animals with lipodystrophy, in whom adipose tissue is absent and associated with widespread ectopic lipid deposition and severe insulin resistance, which in mice is reversed by transplantation of healthy adipose tissue. The mechanisms of lipid cytotoxicity are not fully understood, but free fatty acids uncouple oxidative phosphorylation and increase mitochondrial production of reactive oxygen species, as well as induce stress responses in endoplasmic reticulum. In addition to these cytotoxic effects, lipids also play an important role in direct activation of the innate immune system via Toll-like receptor (TLR) signaling. TLRs play an important role in regulating innate immune responses to both infectious and sterile inflammatory stimuli, and free fatty acids are important ligands for TLR-2 and TLR-4. TLRs therefore represent a direct molecular link between hyperlipidemia, a central clinical feature of obesity, and activation of the innate immune system. TLR-2 and TLR-4 are expressed in a wide range of cells, including macrophages and adipocytes, and upon binding free fatty acids, activate NFκB, upregulate inflammatory cytokine expression and induce insulin resistance. TLRs play a role in other co-morbidities of obesity as well; human TLR gene polymorphisms are associated with decreased susceptibility to atherosclerosis, diabetes, and cancer, while over-expression of TLR-4 in vascular endothelial cells exacerbates and under-expression attenuates atherosclerosis. TLR signaling has also been implicated in steatohepatitis; a TLR-4 agonist exacerbates and TLR-2 deficiency ameliorates steatohepatitis in mice. These examples stress the importance of TLR signaling in mediating the effects of excess lipid on obesity-related inflammation and disease pathogenesis (10