During prolonged starvation, the organism gradually converts its metabolism from that depend- ent on glucose and amino acids to one dependent on lipids and their breakdown products-ketone bodies. This change results in a decrease in oxygen consumption and a sparing of protein breakdown (cf. McAndrew, 1986). In patients with cancer cachexia, these metabolic adaptations normally seen during starvation do not occur. As noted earlier, there is a recycling of lactate (Figure 17.4) as well as pyruvate and an increase in the use of acetoacetate (ketone body) by neoplastic tissue (cf. McAndrew, 1986).
Alterations in fat metabolism in the entire tumor-bearing organism have been seen both in experimental animals and in patients. These alterations include increases in circulating triglycer- ides, free fatty acids (FFA), and glycerol (Noguchi et al., 1988; Legaspi et al., 1987). Body fat constitutes 90% of energy reserves in the adult organism, and loss of whole-body fat is a consis- tent feature of cancer cachexia (cf. Tisdale, 1997). While normal individuals suppress lipid mo- bilization after administration of glucose, this process is impaired in patients with neoplastic disease, in whom the oxidation of fatty acids continues throughout the stage of progression. The hypertriglyceridemia seen in animals bearing neoplasms may also be due in part to the fact that lipoprotein lipase expression and activity in both fat and muscle decline from the normal level, possibly owing to some humoral factor produced by or as a result of the neoplastic growth (Noguchi et al., 1991). The effect of neoplastic growth on adipose tissue extends even to apopto- sis of adipocytes in most of the cancer-bearing patients studied (Prins et al., 1994). It has been speculated that the liver exhibits a demand for the utilization of free fatty acid to supply the energy for increased gluconeogenesis in cancer patients (Levin and Gevers, 1981). In this vein, the feeding of a diet in which up to 80% of the calories was supplied as medium-chain triglycer- ides resulted in a reduction in weight loss as well as in the percentage contribution of the neo- plasm to the final body weight (Tisdale et al., 1987). Furthermore, this regimen restored the nitrogen balance to that seen in non-tumor-bearing controls (Beck and Tisdale, 1989b). More recently, Pariza et al. (1999) have demonstrated that conjugated isomers of the fatty acid linoleic acid have effects in experimental animals that may inhibit carcinogenesis at each of the major stages. In relation to this discussion, dietary conjugated linoleic acid (CLA) was found to protect against cachexia induced in mice by the administration of tumor necrosis factor. The suggested mechanism for this effect is an alteration or inhibition of the signal transduction pathway in- duced by this cytokine (Pariza et al., 1999). In concert with the increases in triglycerides, there is an elevation in the low-density lipoproteins in the plasma. It is these lipoproteins that are synthe- sized in the liver and carry triglycerides to peripheral tissues and to a great extent to the neo- plasm (Clark and Crain, 1986). Thus, the lack of glucose inhibition of fat mobilization from the fat depots, the continued oxidation of fatty acids, and the absence of increased dietary fat intake lead to a depletion of fat stores with concomitant increase in metabolic rate from fatty acid oxi- dation required for gluconeogenesis. Maintenance of the Cori cycle combines with alterations in fat metabolism to contribute to a net loss of body weight in the cancer-bearing patient.