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ROS, Thrifty-Inflammatory Tipping Points and the Endocannabinoid System
The endocannabinoid system (ECS) can be viewed as ‘thrifty’ and anti-inflammatory, sharing many characteristics with the FOXO group of transcription factors. As such it is likely that one of its functions is to counteract energy-utilising and oxidative stress-inducing processes. We propose that modern living can lead to an inflammatory/anti-inflammatory ECS arms race with the potential for tipping points when one process dominates over the other. Calorie restriction vs. excess. The “metabolic syndrome” is associated with increased activity of the innate immune system and reduced functional longevity (Pickup et al., 1997); it may also be viewed as compensatory mechanism to control weight (Fehm et al., 2006). Calorie restriction results in increased resistance to oxidative stress via increased activity of FOXO, and improved functional longevity (Morris, 2005). Evolutionarily, times of plenty were rare, which selected for high feed efficiency and resistance to oxidative stress. In parallel, a potent immune system co-evolved to maximise the chances to reproduce (Fernandez-Real & Ricart, 1999). A consequence of this co-evolution is an energy-store related increase in oxidative stress. Thus high feed efficiency may be equal to reduced oxidative stress and vice versa, as reactive oxygen species (ROS) are involved in signalling and proliferation (Menon & Goswami, 2007): ROS are critical in the ageing process. Thrifty tipping points. The ECS may be auto-protective, anti-inflammatory and energy saving (Pertwee, 2005). In contrast, leptin, which is both inflammatory and thermogenic, suppresses the ECS (Di Marzo et al., 2001) and is clearly anti-thrifty. It is likely that through a process of ‘opportunistic evolution’, the anorexic properties of inflammation have become important in preventing excessive weight gain. Hence, the anorexic nature of this system may be counter-regulated by an innately thrifty and protective ECS. As insulin resistance may be protective (Firdlyand & Philipson, 2006), and increased FOXO activity is associated with insulin resistance (Nakae et al., 2002), then continually high levels of leptin and insulin will induce chronic resistance. Thus, thrifty-inflammatory tipping points may occur between transitions from lean to optimal body-fat, from optimal body-fat to high body-fat, and from high body-fat to excessive pathological body-fat. Eating ourselves to death? As ROS is critical in cell growth and death, the overall function of the ECS may be to reduce ROS – as increased ROS signals growth and stress, except where it is used to remove unwanted cancer and immune cells. Hence, heightened ECS activity may be protective, which has implications for the development of treatments for obesity and type 2 diabetes: in some circumstances, suppressing appetite may increase long-term oxidative stress, as might increasing insulin output or sensitivity – all may suppress FOXO. Reducing oxidative stress may therefore be paramount to reduce the need for a protective thrifty response and maybe key in treating obesity and the metabolic syndrome.
Di Marzo et al. (2001) Nature 410, 822-825. |
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