Role of Leptin in Inflammation and Its Possible Connection to Obesity in Schizophrenia

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In most obese patients, obesity is associated with chronic low-grade inflammation of white adipose tissue. This results from the chronic activation of the innate immune system that subsequently leads to insulin resistance, impaired glucose tolerance and diabetes [41]. In obesity, the white adipose tissue is characterized by the increased synthesis and secretion of a range of inflammatory mediators such as tumor necrosis factor (TNF) and IL-6. In addition, the adipose tissue is infiltrated by macrophages that act as a major source of pro-inflammatory cytokines when activated. Conversely, weight loss leads to a reduction in the gene expression of the pro-inflammatory cytokines [42]. However, the adipocytes and macrophages are responsible for the increase not only of the pro-inflammatory cytokines but also for leptin and resistin. The increase in leptin exerts a strong negative feedback on insulin sensitivity thereby enhancing insulin resistance [43]. This situation is compounded by the impact of the glucocorticoids on the regulation of leptin; hypercortisolemia, a common feature of schizophrenia and other major psychiatric disorders, stimulates the release of leptin and thereby further enhances insulin resistance [44].

As has been mentioned previously, premature death due to cardiovascular disease is a common occurrence in both schizophrenia and depression. IL-6 is increased in both schizophrenia and major depression and is known to induce hepatic C-reactive protein that has been implicated in cardiovascular disease [45]. In addition to such changes, obesity is associated with a decrease in circulating adiponectin. Adiponectin is a cardioprotective agent that reduces the inflammatory action of pro-inflammatory cytokines such as TNF on the arterial walls and thereby protects against atherosclerosis [46].Thus a reduction in the availability of adiponectin in obesity indirectly contributes to an increase in vulnerability to cardiovascular disease. Figure 2 summarizes the link between impaired immunity, cardiovascular disease and obesity in schizophrenic patients.

Irrespective of the cause, epidemiological evidence suggests that obesity increases the risk of autoimmune disease and such immune related diseases as asthma. It has been speculated that this arises due to the decrease in immunological tolerance associated with the increase in the pro-inflammatory cytokines and leptin, and the decrease in adiponectin [47]. It has been demonstrated that both IL-6 and leptin downregulate the regulatory T cells thereby reducing antigen surveillance. Thus, obesity, through the induction of chronic low-grade inflammation and decreased immu-nological tolerance to antigens, increases the activity of the Th-2 humoral pathway thereby increasing the risk of allergies and immune-related disorders. Such changes are a common feature of schizophrenia.

Thus, in patients with schizophrenia a vicious cycle is created due to the inflammatory changes. These changes not only impact on the brain to contribute to the psychopathology of the disorder but are also responsible for the decline in physical health that characterizes such patients.

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