METABOLIC EFFECTS OF CACHECTIN TUMOR-NECROSIS-FACTOR ARE MODIFIED BY SITE OF PRODUCTION - CACHECTIN TUMOR NECROSIS FACTOR-SECRETING TUMOR IN SKELETAL-MUSCLE INDUCES CHRONIC CACHEXIA, WHILE IMPLANTATION IN BRAIN INDUCES PREDOMINATELY ACUTE ANOREXIA

We have developed a murine model of wasting by injecting intracerebrally cells which continuously secrete h-cachectin/TNF (CHO-TNF) to: (a) determine the effects of cachectin/TNF produced inuously in the central nervous system (CNS), and (b) compare the metabolic effects of cachectin/TNF-secreting tumor in the brain to the cachexia caused by CHO-TNF tumor in the peripheral tissue (IM). Intracerebral CHO-TNF tumors produced increased serum h-cachectin/TNF levels with lethal hypophagia and weight loss (mean survival time of 11 d); these changes were not observed in association with nonsecretory control brain tumors. The metabolic consequences of intracerebral cachectin/TNF production were indistinguishable from acute, lethal starvation: whole-body lipid content was decreased significantly but protein was conserved. Although intramuscular cachectin/TNF-secreting tumors caused similar increases of serum h-cachectin/TNF levels, profound anorexia did not develop; wasting developed after a longer period of tumor burden (50 d) with classical signs of cachexia (i.e., anemia and depletion of both protein and lipid). These studies provide a reproducible animal model of site-specific cytokine production and suggest that, regardless of serum levels, cachectin/TNF produced locally in brain influences both the rate of development of wasting and its net metabolic effects.