The MCH system has been extensively studied for its roles in regulating energy homeostasis (Pissios et al. 2006
). These data have suggested that the MCH system may be involved in many situations where energy homeostasis is perturbed. We chose to study the MCH system’s potential role in diet-induced thermogenesis induced by increased dietary fat consumption. This stimulus has been shown to affect the hypothalamic pathway which maintains homeostasis. In this report, we use MCH1R KO mice to show that the MCH system is involved in maintaining homeostasis when animals are exposed to increased fat consumption.
We show that the MCH system is involved in the adaptation to high-fat diet provided acutely. When they were fed with normal chow, MCH1R KO mice showed hyperphagia as previously described, possibly secondary to their increased metabolism and activity (Marsh et al. 2002
). In young and lean animals, transition from low- to high-fat diet leads to a marked hyperphagia due to the novelty and palatability of the high-fat diet. This transition is then followed by a reduced food intake to account for the higher energy content of the diet. MCH1R KO mice, however, did not exhibit hyperphagia but instead an immediate reduction in food intake. This suggests that MCH1R KO mice do not show a tendency to prefer high-fat diet. Most notably, the feed efficiency of MCH1R KO mice during the 72 h of HF diet was significantly lower than that of WT mice which suggests that the MCH system might regulate metabolic responses upon exposure to high-fat diet. This led us to monitor the acute metabolic changes of these mice upon high-fat diet consumption by monitoring their RER and VO2
When exposed to high calorific food in mice, VO2
increases due to increase in locomotor activity. Both WT and MCH1R KO mice have been shown to exhibit an increase in locomotor activity upon transition to a MHF diet (Zhou et al. 2005
), but the effect on VO2
was not reported. Our results show no significant difference in the VO2
of MCH1R KO mice upon exposure to high-fat diet. This is surprising especially since mice lacking ppMCH exhibit a higher VO2
and a higher locomotor activity after 24 h of high-fat diet than WT mice (Kokkotou et al. 2005
). It may, however, be explained at least in part by our RER results. RER values represent the energy fuel that animals use. High RER indicates increased utilization of carbohydrates for energy consumption whereas low RER indicates increased utilization of fatty acids. Therefore, high RER values in animals lead to increased risk of weight gain. Transition to HF diet usually decreases RER values to increase fat oxidation so that animals do not gain weight. Our study shows that RER values of WT mice increased significantly during the first 24-h HF diet before decreasing during the 24–72 h of HF diet, as expected. On the other hand, the RER values of MCH1R KO mice subjected to the same paradigm are high on LF diet and gradually decrease when put on HF diet. They do not show the burst in increase in the first 24 h of HF diet as do the WT mice. This suggests that the MCH1R KO mice can increase fat oxidation more efficiently. This might also have contributed to the resistance to weight gain in MCH1R KO mice upon HF diet. This finding suggests that the MCH system can modulate fat/carbohydrate oxidation, especially when animals are acutely exposed to HF diet. This is in agreement with the studies that have reported that MCH1R antagonists induce significant weight loss than a pair-fed group (Huang et al. 2005
; Ito et al. 2010
). Ito et al. reported that chronic MCH1R antagonist treatments into DIO mice slightly increased fatty acid oxidation and reduced serum-free fatty acid level, but not triglyceride level (Ito et al. 2010
). These findings suggest that MCH1R signaling modulates fatty acid oxidation when animals are exposed to HF diet. Also, it has been reported that MCH1R KO mice have slightly lower triglyceride level than WT mice (77
10 mg/dl for WT vs. 69
6 mg/dl for MCH1R KO; Marsh et al. 2002
). We therefore predict that the reduced body weight gains of MCH1R KO mice upon HF diet might be accompanied by lower triglyceride/free fatty acid levels. Together, these data point at the MCH system as being involved in the adaptation of the organism to excess caloric consumption.
In summary, our experiments show that the endogenous MCH system has an important role in regulating energy homeostasis upon high-fat diet consumption. It, however, remains to be described how the MCH system regulates these processes.