Cachexia is characterized by severe
weight loss, including adipose and muscle wasting, and occurs in a large percentage of
cancer patients.
Insulin resistance contributes to dysregulated metabolism in
cachexia and occurs prior to
weight loss in mice with colon-26
tumor-induced
cachexia. Therefore, we hypothesized that the
insulin sensitizer,
rosiglitazone, would attenuate the loss of adipose and muscle to result in improved outcomes for mice with late-stage
cachexia. Male CD2F1 mice were inoculated with colon-26
adenocarcinoma cells or vehicle. Treatments included vehicle,
rosiglitazone (10 mg/kg
body weight/day) or
rosiglitazone plus pair-feeding to food intake of vehicle-treated mice with
tumors.
Rosiglitazone delayed
weight loss onset by 2 d over the 16 d duration of this aggressive
tumor model. This finding was associated, in part, with increased food intake. In addition, adipose mass, adipocyte cross-sectional area and
inflammation were improved with
rosiglitazone. However, at the time of necropsy 16 d after
tumor inoculation
rosiglitazone had no effect on retention of muscle mass, strength or proteolysis in late-stage
cachexia. We did not measure stamina or endurance in this study. In early-stage
cachexia,
rosiglitazone normalized PDK4 and
PPAR-delta mRNA in quadriceps muscle and rescued the decrease in
insulin-stimulated
glucose disappearance in mice with
tumors.
Rosiglitazone may delay
weight loss onset by decreasing
tumor-induced markers of metabolic change in early-stage
cachexia. These changes predict for modest improvement in adipose, but no improvement in muscle strength in late-stage
cachexia.