Regulation of food intake role of neuropeptides

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Leptin is a protein encoded by the gene LEP, and is a member of cytokine receptor family (Aleman et al. 2002). It is produced by adipocytes and acts on specific receptors in the hypothalamus (Brown et al. 2001). Leptin levels regulate a network of orexigenic and anorexigenic neuropeptides and are correlated with body fat mass (Brown et al. 2001). Neuropeptide Y (NPY) and ghrelin (an orexigenic signal from the gut to the brain, mostly expressed in neuroendocrine cells of the gastric fundus) (Pinkney and Williams 2002), are the most potent feeding stimuli. They are released with falling levels of leptin, in conjunction with other orexigenic peptides (orexin, endorphin dynorphine, and melanin-concentrating hormone (MCH)) (Inui 1999). Corticosteroids and medroxyprogesterone acetate (MPA) stimulate the release of NPY (Tisdale 2002). Conversely an increase in leptin generates the release of potent anorexigenic substances, such as neurotensin, melanocortin, colecistokinine, corticotropin-releasing factor (CRF), and cocaine and amphetamine-related transcript (CART) (Inui 1999).

The hypothalamus seems to be the area with highest density of receptors for cytokines. It has been suggested that they might mimic hypothalamic negative feedback signalling from leptin (Fearon and Moses 2002). However, some authors found no correlation between plasma levels of cytokines and leptin (Aleman et al. 2002). Moreover in non-malignant diseases leading to cachexia, such as COPD (Takabatake et al. 1999) and chronic heart failure (CHF) (Filippatos et al. 2000), leptin levels were found to be normal or decreased and did not correlate with cytokine levels. On the other hand, a recent report of 76 patients with newly diagnosed non-surgically treated non-small cell lung cancer (prior to treatment) demonstrated a direct relationship between leptin levels and body fat mass. However, these levels were inversely correlated with proinflammatory cytokines and acute phase proteins (Aleman et al. 2002).

Cachexia is not a direct consequence of a dysregulation of leptin production (Aleman et al. 2002; Brown et al. 2001; Mantovani et al. 2000). It is unlikely that weight loss in cancer arises primarily from a reduction in food intake. Proof of this is that nutritional support alone cannot reverse the process of wasting, body composition changes differ from those found in anorexia, and loss of muscle and adipose tissue often precede a decrease in food intake and can occur without anorexia (Inadera et al. 2002).

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