Environmental Enrichment Potentiates Glucose-Induced Anorexia in Mice

Abstract The hypothalamus controls food intake and metabolism by integrating nutrient and hormonal signals from peripheral tissues. Both central and peripheral administration of glucose leads to a reduction in food intake in rodents. Similarly, administration of the adipocyte hormone leptin or the gastrointestinal hormone xenin reduces food intake. In contrast, impairments in hypothalamic signaling of these factors cause hyperphagia and obesity in rodents and humans. Environmental factors affect behavior including feeding behavior and energy metabolism in rodents and humans. Studies have found that environmental enrichment (EE), in which mice interact with complex sensory and motor stimulation, led to a significant reduction in adiposity and resistance to diet-induced obesity in mice. This effect is independent of energy expenditure and is associated with enhanced hypothalamic signaling, but the exact mechanism is unknown. We hypothesized that EE potentiates the feeding suppressing effects of anorectic signals. To address this hypothesis, 4-week-old male C57BL/6 mice were group housed (5/cage) under standard laboratory conditions or EE conditions with free access to regular rodent chow and feeding response to glucose, leptin and xenin was examined. EE cages were supplemented with a house, running wheels, igloos, wood logs, maze and nesting materials. Four weeks after initiating EE protocol, mice were fasted for 8 h and received an intraperitoneal injection of glucose (2 mg/g b.w.) or saline just before the onset of the dark phase. Treatment assignments were reversed for the second injection so that each animal received both treatments with a washout period of 1 week. Mice were given food immediately after the injection and food intake was measured for 4 h after the injection at 0.5–1 h intervals. The same design was repeated using leptin (2.5 μg/g b.w.) and xenin (15 or 50 μg/g b.w.). Glucose injection caused a significant reduction of food intake in both control and EE mice. However, anorexic effect of glucose was more significant in EE group compared to the control group (main effect of treatment: P = 0.0016 for control and P < 0.0001 for EE, two-way ANOVA). Significant reductions in food intake were observed between 0.5 and 2.5 h after glucose injection in EE mice, while no significant reduction was observed thereafter. Moreover, three-way ANOVA showed a significant interaction between housing condition and treatment (P = 0.0086). In contrast, although both leptin and xenin caused a significant reduction in food intake, there was no significant interaction between housing condition and treatment. These data suggest that environmental enrichment enhances the anorectic action of glucose without altering feeding response to leptin and xenin. It is speculated that enhanced hypothalamic glucose sensing may mediate beneficial effects of environmental enrichment on metabolism.