Transplantable rat glucagonomas cause acute onset of severe anorexia and adipsia despite highly elevated NPY mRNA levels in the hypothalamic arcuate nucleus.

Abstract

We have isolated a stable, transplantable, and small glucagonoma (MSL-G-AN) associated with abrupt onset of severe anorexia occurring 2-3 wk after subcutaneous transplantation. Before onset of anorexia, food consumption is comparable to untreated controls. Anorexia is followed by adipsia and weight loss, and progresses rapidly in severity, eventually resulting in reduction of food and water intake of 100 and 80%, respectively. During the anorectic phase, the rats eventually become hypoglycemic and hypothermic. The tumor-associated anorexia shows no sex difference, and is not affected by bilateral abdominal vagotomy, indicating a direct central effect. The adipose satiety factor leptin, known to suppress food intake by reducing hypothalamic neuropeptide Y (NPY) levels, was not found to be expressed by the tumor, and circulating leptin levels were reduced twofold in the anorectic phase. A highly significant increase in hypothalamic (arcuate nucleus) NPY mRNA levels was found in anorectic rats compared with control animals. Since elevated hypothalamic NPY is among the most potent stimulators of feeding and a characteristic of most animal models of hyperphagia, we conclude that the MSL-G-AN glucagonoma releases circulating factor(s) that overrides the hypothalamic NPY-ergic system, thereby eliminating the orexigenic effect of NPY. We hypothesize a possible central role of proglucagon-derived peptides in the observed anorexia.

Central Melanocortins and the Regulation of Weight During Acute and Chronic Disease

“…This has led, in turn, to the hypothesis that a decrease in the level of NPY expression is responsible for the cytokine-mediated anorexia seen in animal models of inflammation and chronic disease. However, the observations that there was no change -or even an increase in NPY mRNA and peptide expression in tumor-bearing rats, rats with dehydration-induced anorexia, and rats treated with LPS -indicates that downregulation of NPY expression is not a primary stimulus for anorexia in these models Jensen et al, 1998;Plata-Salaman et al, 1998;Watts et al, 1999). A decrease in the response to exogenous NPY in anorexic, tumor-bearing animals has been demonstrated but it is unclear if this represents an effect that is specific to NPY signaling or is a reflection of increased inhibitory tone exerted by another neurotransmitter system (Chance et al, 1996).…”

Anorexia in human and experimental animal models: physiological aspects related to neuropeptides

“…In contrast, Nara-ashizawa et al reported that CRH mRNA in the PVN was significantly up-regulated in cachectic tumorbearing mice [ Fig. 4 The hypothalamic feeding-regulating peptides in cisplatininduced anorexia J Physiol Sci mRNA in the hypothalamus was highly expressed in rats bearing glucagonoma [113]. However, Nakhate et al indicated that a cancerous condition might down-regulate CART in the hypothalamus in rats with N-methyl-N-nitrosourea-induced mammary tumors [119].…”

“…Nara-ashizawa et al reported that the gene expression of NPY was significantly increased in mice bearing human tumor cells (SEKI melanoma cells); however, the gene expressions of MCH and ORX were comparable compared to control mice [105]. The up-regulation of the gene expression of NPY has also been reported in rats bearing glucagonoma (MSL-G-AN) [113], tumor-bearing (methylcholanthrene-induced sarcoma) rats [114] and MAC16 (chronic adenocarcinoma)-bearing mice [115], whereas Plata-Salaman et al demonstrated that NPY mRNA expression was not different between pair-fed normal rats and prostate adenocarcinoma tumor cell-bearing rats [116]. Treatment with i.c.v.…”

Hypothalamic Neuropeptides and Appetite Response in Anorexia-Cachexia Animal

“…They also showed that there is no significant difference in MCH and orexin mRNA levels between the SEKI and control mice [41]. Jensen et al demonstrated that NPY mRNA levels in the Arc were markedly increased in anorexic rats bearing glucagonoma (MSL-G-AN) [42]. Chance et al demonstrated that NPY mRNA levels in the medial hypothalamus were significantly elevated in anorectic tumor-bearing (methylcholanthrene-induced sarcoma) rats, and that CRH mRNA in the medial hypothalamus tend to be reduced in anorectic tumor-bearing rats and paired-fed rats [43].…”