Leptin and Cancer Anorexia Cachexia

Progressive wasting is common in many types of cancer and is one of the most important factors leading to death in cancer patients. Weight loss is a potent stimulus to food intake in normal humans and animals. The persistence of anorexia and the onset of cachexia in cancer patients, therefore, implies a failure of this adaptive feeding response [86]. Leptin, a member of the gp 130 family of cytokines, induces a strong T helper-1 lymphocyte response and is regarded as a proin-flammatory inducer [87]. Several data suggested a role of leptin in inflammatory diseases. Proinflammatory cytokines up-regulate leptin expression in white adipose tissue and increase plasma leptin levels in hamsters and mice [88]. However, in many common diseases associated with cachexia, such as chronic obstructive pulmonary disease and chronic inflammatory bowel disease, there is an inflammatory status caused by high proinflammatory cytokine levels, whereby leptin concentrations are decreased related to body fat mass. In patients with advanced non-small-cell lung cancer, serum leptin levels were lower than in controls and lower still in those who were cachectic who also showed an increase of proinflammatory cytokines and acute-phase reac-tants [32, 88]. In 29 advanced-stage patients with cancer at different sites, an inverse correlation was found between serum levels of leptin (low) and proinflammatory cytokines (high). Additionally there was an inverse correlation between the Eastern Cooperative Oncology Group performance status scale and serum levels of leptin. Regarding survival, patients with very high serum levels of proinflammatory cytokines and very low levels of leptin had very short survival [89-94].

In tumour-bearing rats, leptin concentrations decreased in plasma and adipose depots 4 days after the tumour cell injections. It has been suggested that leptin synthesis in visceral white adipose tissue of tumour-bearing rats might be modulated by tumour necrosis factor-alpha (TNF-a) or prostaglandin E2 produced by infiltrating macrophages present in the early stage of cachex-ia [31]. In tumour-bearing mice,leptin production is decreased while the hypothalamic leptin receptor and NPY expression are increased in response to fat depletion [95]. Overall, these findings suggest that peripheral adipocyte leptin synthesis is preserved in cancer patients and tumour animal models, and point to a central dysregulation of the physiological feedback loop.

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