Inhalation of carbon monoxide is ineffective as a long-term therapy to reduce obesity in mice fed a high fat diet

Abstract

BackgroundPrevious studies have demonstrated that induction of heme oxygenase-1 results in weight loss in several rodent models of obesity. However, the specific role of the heme oxygenase-1 metabolite, carbon monoxide (CO), in this response has yet to be established. We recently reported that chronic treatment with CO releasing molecules results in prevention of weight gain in mice fed a high fat diet. In the present study, we sought to determine the effect of chronic CO inhalation on the development and reversal of high fat diet induced obesity.ResultsCO inhalation at both levels initially resulted in a prevention and reversal of body weight and fat mass over the first 10 weeks of treatment, however, this effect was not sustained. CO inhalation in the prevention groups also had an early effect to lower fasting blood glucose but this effect also was not sustained.ConclusionsOur results demonstrate that CO inhalation has a transient effect to prevent and reduce body weight which is not sustained chronically in mice fed a high fat diet. These results suggest that chronic CO inhalation therapy is not an effective treatment to induce long term weight loss.

The effects of chronic carbon monoxide treatment on diet-induced obesity and Rev-erb-alpha target gene expression in adipose tissue

“…Interestingly, the present results show no effect of approximately six weeks of daily CO inhalation (1 hour/day for 40 days) on body weight or insulin action in mice with established obesity. It is difficult to reconcile the differences between our findings and that of Hosick et al [8,9]. Since some of the beneficial effects of CO are mediated by an increase in reactive oxygen species [25], this response may be abrogated in mice with established weight stable obesity because of the already high levels of ROS [26].…”

“…Hosick et al demonstrated that carbon monoxide releasing molecules promote weight loss and improve insulin action [8]. Although 10 weeks of CO inhalation appears to reduce body weight, this effect is transient and completely absence at 35 weeks [9]. Interestingly, the present results show no effect of approximately six weeks of daily CO inhalation (1 hour/day for 40 days) on body weight or insulin action in mice with established obesity.…”

“…Since some of the beneficial effects of CO are mediated by an increase in reactive oxygen species [25], this response may be abrogated in mice with established weight stable obesity because of the already high levels of ROS [26]. Finally, the lack of a CO effect in the present study and that of Hosick et al [9] may be related to the delivery of the gas by inhalation rather than via CO releasing molecules [8], particularly since CO gas is primarily transported bound to hemoglobin and CO releasing molecules reach tissues independent of hemoglobin. However, we observed a significant increase in HO-1 expression in adipose tissue following the CO inhalation treatment indicating effective CO delivery to cells [8 17,20], although we did not directly measure tissue CO content or assess markers for CO action in other tissues.…”

“…Mice from the HFD-CO group were place in individual induction chambers where they received CO gas (250 ppm) for 60 min per day for 40 consecutive days [17,18]. This CO concentration is slightly higher than what has been show to increase carboxyhemoglobin levels [9]. Induction chamber CO levels were confirmed by a CO monitor.…”

“…CO has been shown to reduce inflammatory markers in both cultured cells and mice [7] and a novel CO releasing molecule can attenuate weight gain and preserve insulin sensitivity when mice are placed on a HFD [8]. However, whether or not CO alone can reverse already established obesity and insulin resistance is not established, although a recent study indicates that CO inhalation produces transient reduction in body fat of obese mice [9]. Further, the mechanism by which CO might promote weight loss and improve insulin sensitivity are not known.…”