On the Possible Role of Inflammation in Obesity and Type 2 Diabetes in Schizophrenia

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It is well known that genetic and environmental factors interact to favor weight gain, changes which disrupt metabolism. The body fat stores are normally maintained within a narrow range by energy homeostasis. This process is controlled by the brain regions, such as hypothalamus, that control appetite and energy balance in addition to peripheral signaling systems that monitor energy stores. Glucose, free fatty acids, insulin and leptin are examples of the signaling molecules that activate the hypothalamus thereby controlling the metabolic rate and the desire to eat. Obesity does not simply arise from the passive accumulation of excess body weight but is an active adaptation to the elevation of body fat. Clearly, the genetic background of the individual contributes to the variation in the response to elevated body fat which helps to explain why some individuals are protected against weight gain while the majority is not despite the fact that they live in the same environment and eat the same food.

When energy intake exceeds expenditure, the resultant state of nutrient excess triggers responses in vascular endothelial cells, hepatocytes, myocytes, adipocytes, monocytes and macrophages resulting in metabolic dysfunction [34]. The cellular responses to the nutrient excess include the production of reactive oxygen species (ROS) that are generated by the mitochondrial oxidation of glucose and fatty acids. The resulting oxidative stress frequently results in cellular damage and triggers the inflammatory response [35]. Long-chain fatty acids and co-enzyme Q derivatives that are usually metabolized by the mitochondria also accumulate under these conditions and reflect a decrease in mitochondrial oxidative function. The final result of these changes is an activation of the C-jun N-terminal kinase and kappa-B pathways that promote inflammation. Thus inflammation appears to be a common end point of obesity.

The link between obesity and diabetes occurs as a result of a reduction in insulin function, thereby reducing the uptake of glucose into the target tissues. It is established that phosphotidylinositol-3-hydroxykinase, the inositol receptor substrate pathway, is particularly sensitive to inactivation by inflammatory mediators [36, 37]. Thus, with continuing nutrient excess tissues become insulin insensitive thereby leading to an extension of insulin resistance to most tissues as the inflammatory state progresses.

In addition to regulating nutrient utilization in peripheral tissues, the insulin receptor signaling system has been implicated in the actions of insulin and lepin on neuronal function. From experimental studies, it would appear that even short-term exposure to a palatable, energy-rich diet impairs the responsiveness of the hypothalamus to the effects of insulin and leptin [38]. This reduces the feedback regulatory mechanism whereby the brain normally reduces food intake in response to the increase in peripheral fat stores.

From the foregoing, it can be seen how inflammation participates in the link between obesity and type-2 diabetes. The 'beta-cell exhaustion hypothesis' of diabetes postulates that diabetes results when pancreatic beta cells fail to produce sufficient insulin due to insulin resistance thereby initiating type-2 diabetes [39].

Obesity is also linked to cardiovascular disease, both conditions occurring frequently in patients with schizophrenia. This is due to the impact of nutrient excess on the vascular endothelial cells. A major function of these cells is to activate nitric oxide synthase to produce the potent, but short-lived, vasodilator nitric oxide. The insulin receptor system-phosphoinositol-3-kinase pathway is a major factor in the control of nitric oxide synthesis in most tissues so that nutrient excess that reduces the activity of this pathway rapidly leads to a reduction in nitric oxide synthesis. Thus, the decrease in nitric oxide, combined with the accumulation of fat in the coronary circulation as a consequence of increased fat synthesis, provides a link between cardiovascular disease, diabetes obesity and inflammation [40].

While it is unlikely that the inhibition of the insulin-sensitive pathway by inflammatory mediators is the only factor of importance, it does emphasize the value of the integrative approach to studying metabolic disease and how such an approach may contribute to the physical ill health associated with major psychiatric disorders such as schizophrenia.

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