Dependence of energy balance and hypothalamic neuropeptide gene expression on initial tumor load in mice

Animal models of cancer anorexia/cachexia are instrumental in investigating the underlying mechanisms. However, even among reports on the same cancer model, experimental procedures can vary, hindering the comparisons between studies.

To determine the impact of the number of implanted cancer cells on experimental outcomes, we directly compared tumor-bearing (TB) mice inoculated with Lewis-lung carcinoma at 1x10⁶ cells (TB_high) or 0.5x10⁶ cells (TB_low).

While both TB groups showed lower weight gain and adiposity than vehicle controls, TB_low mice displayed a larger reduction, possibly due to prolonged time to the endpoint. Body weight gain was highly correlated with food efficiency in all groups, while correlation with food intake was found only in TB_high group. Using these models, hypothalamic energy balance-related mRNA expression was examined, which found that Pomc and Hcrt were downregulated in TB_low mice, whereas Agrp was upregulated in TB_high mice. Npy and Pmch were unaltered. Expression of respective neuropeptide receptor mRNA, Mc3r, Mc4r, Hcrtr2, and Mchr1, were also not altered. Furthermore, hypothalamic expression of inflammatory genes Ccl2 and Il6 was tightly correlated with each other in all groups, while Ccl2 was negatively correlated with Hcrt and Pomc in TB_low mice, suggesting a role for CCL2 in regulating neuropeptide expression.

The metabolic profile and hypothalamic gene expression can vary with differential initial tumor load, suggesting that the relationship between systemic energy balance and cancer progression is complex and not strictly linear. This finding should be carefully considered in the design and interpretation of future animal experiments and clinical studies.