Abstract

BACKGROUND

The KPC mouse model of pancreatic cancer is gaining use in research, but detailed understanding of ingestive behaviour changes in this and other cachexia models is limited.

METHODS

Male C57BL/6 J mice (7 weeks) were maintained under standard feed (PicoLab5L0D) and housing conditions (12:12 h; Light:Dark). Spontaneous feeding was observed in a Comprehensive Lab Animal Monitoring System: meal size, frequency, intermeal intervals and satiety ratio (i.e., time between meals divided by kcal energy in the preceding meal). Feeding was observed at baseline and over time after intraperitoneal injection syngeneic KPC pancreatic adenocarcinoma cells. Separate cohorts of mice were used to study homeostatic feeding responses at baseline and on Day 14 after KPC injection (KPC_14). These responses were fasting-evoked refeeding, ghrelin injection (1 mg/kg) and lights-out cue.

RESULTS

Spontaneous food intake declined by 50% by 14 days after tumour injection. At baseline, food intake was observed during 23 of 24 h daily; at KPC_14, hours without any food intake increased from 1 to 12 (p ≤ 0.0001). At KPC_14, intermeal intervals increased (light cycle: 60.5 ± 11.2 vs. 146.4 ± 19.6 min; p < 0.0001; dark cycle: 26.0 ± 3.8 vs. 42.0 ± 5.5 min; p = 0.0045), and the satiety ratio tripled (light cycle: 23.1 ± 5.9 vs. 69.4 ± 10.5 min/0.1 kcal; p < 0.0001; dark cycle: 11.3 ± 3.4 vs. 27.1 ± 5.0 min/0.1 kcal; p = 0.0028). By contrast, meal size and ingestion rate were unchanged. At KPC_14 mice showed reduced responses to homeostatic feeding cues. After 12-h starvation, refeeding intake during 4 h was 0.81 ± 0.3 g vs. 0.39 ± 0.19 g at KPC_14 (-52%, p = 0.02). Ghrelin response was also blunted 0.66 ± 0.19 g vs. 0.42 ± 0.27 g at KPC_14 (-36%, p = 0.005). Mice responded to lights-out with ~ 4 h of vigorous feeding, ingesting a total of 0.94 ± 0.2 g at baseline; this amount was reduced to 0.55 ± 0.3 g (-41%, p < 0.01) at KPC_14, predominantly due to a steep decline in feeding after the end of the first dark hour.

CONCLUSIONS

Mice with KPC show response to homeostatic feeding cues; however, these were of diminished amplitude and sustainability. Large increases in intermeal interval and satiety ratio were notable, with mice eating nothing at all for extended periods of time, consistent with enhanced satiety and/or a failure to generate signals sufficient to generate a new feeding event.

MeSH

Injections, Pancreatic Neoplasms, Disease Models, Animal, Eating, Neoplasms, Food, Appetite, Meals, Cachexia, Ghrelin, Sarcopenia, Cancer-Associated Cachexia