TRANSPLANTABLE RAT GLUCAGONOMAS CAUSE ACUTE ONSET OF SEVERE ANOREXIA AND ADIPSIA DESPITE HIGHLY ELEVATED NPY MESSENGER-RNA LEVELS IN THE HYPOTHALAMIC ARCUATE NUCLEUS

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 co nsumption is comparable to untreated controls. Anorexia is followed by adipsia and weight loss, and progresses rapidly in severity, eventual ly resulting in reduction of food and water intake of 100 and 80%, res pectively. During the anorectic phase, the rats eventually become hypo glycemic and hypothermic. The tumor-associated anorexia shows no sex d ifference, and is not affected by bilateral abdominal vagotomy, indica ting 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 l eptin levels were reduced twofold in the anorectic phase. A highly sig nificant increase in hypothalamic (arcuate nucleus) NPY mRNA levels wa s found in anorectic rats compared with control animals. Since elevate d hypothalamic NPY is among the most potent stimulators of feeding and a characteristic of most animal models of hyperphagia, we conclude th at the MSL-G-AN glucagonoma releases circulating factor(s) that overri des the hypothalamic NPY-ergic system, thereby eliminating the orexige nic effect of NPY. We hypothesize a possible central role of proglucag on-derived peptides in the observed anorexia.