The effect of caloric restriction to stimulate food intake and reduce energy expenditure promotes the eventual recovery of lost weight. These adaptive responses are thought to be mediated by the combination of reduced plasma leptin and increased glucocorticoid levels that, in turn, increase signaling by hypothalamic neuropeptide Y (NPY, which stimulates food intake (FI) and reduces energy expenditure), while decreasing signaling by peptides that promote weight loss, such as melanocortins and corticotrophin releasing hormone (CRH). In models of wasting illness such as tumor anorexia, however, lost weight is not regained, suggesting that this adaptive response is impaired. To test this hypothesis, we studied male Long-Evans rats after subcutaneous implantation of a Leydig cell tumor. As compared to controls fed ad libitum (C; n=10), mean daily FI of tumor-bearing (T; n=10) rats was reduced by 29.6% (p<0.0001) 23d after tumor implantation, and resulted in failure to gain weight relative to C (1.6±1.4 vs 24±1g; p<0.05). Plasma leptin levels were reduced by 65%, while corticosterone levels were increased 10-fold in T compared to C rats (p<0.05 for both). Hypothalamic NPY mRNA levels measured by in situ hybridization were elevated in T rats (by 42%; p<0.05), while proopiomelanocortin (POMC, the melanocortin precursor) and CRH mRNA levels were reduced by 80% and 33%, respectively (p<0.05 for both). Despite identical FI in a second control group that was pair-fed to the intake of T rats (n=10), more weight was gained in this group (9.3±1.8g; p<0.05), suggesting that energy expenditure was increased in T rats. In summary, Leydig cell tumors cause sustained anorexia and increased energy expenditure despite appropriate changes in plasma leptin and corticosterone levels, and in hypothalamic NPY, POMC, and CRH gene expression. We conclude that disordered energy homeostasis in this model involves mechanisms other than, and potentially downstream of, known hormonal and hypothalamic mediators of the response to caloric restriction.
|Original language||English (US)|
|Journal||Investigative Ophthalmology and Visual Science|
|State||Published - Feb 15 1996|
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