In summary, we postulate that as transcriptional factors, PPARs have evolved to improve functional longevity by integrating lipid storage and burning with both reduction of insulin levels and suppression/resolution of inflammation and thus reduction of ROS and oxidative stress (figure ). This critical role is summarised by the 'transcriptional triad' (figure ). Key in this is the ability of PPARs to overcome the 'hypoxia-lipid conundrum', so preventing hypoxia-driven lipid damage and excessive activation of the APR: insulin resistance is induced by increased ROS, inflammatory mediators and deposition of intramyocellular lipids – all things normally suppressed by the PPARs. By reducing the need for insulin, they can optimise FOXO, which upregulates many genes involved in resistance to oxidative stress. Although PPARs have been mostly shown to decrease oxidative stress, there are reports of PPAR γ ligands increasing ROS – especially in cancer cells, which leads to apoptosis and is associated with mitochondrial dysfunction [110
]. Given the reliance of many cancer cells on glycolysis (the 'Warburg' effect) and the fact that cancer invokes many inflammatory pathways [113
], this could be viewed as another mechanism to ensure functional longevity.
A possible function for the PPARs. A summary proposing the overall function of the PPARs (peroxisomal-proliferating activated receptors).
The key to understanding the PPARs is their role as lipid sensors in transcriptional control during starvation, feeding and inflammation: fat is essential for long-term survival. During fasting/starvation, muscle insulin resistance is clearly a thrifty response and is associated with fat deposition, and enables glucose sparing, while in the liver, it encourages gluconeogenesis: at its simplest fatty acids and glycerol flow out of adipose tissue to supply energy. During fasting, many tissues start to burn fats – a process that requires PPAR α and δ. In contrast, during feeding, it is necessary to store and/or replenish energy – either as glycogen, or as lipid in adipose tissue: a degree of muscle insulin resistance, and adipose tissue insulin sensitivity, will channel lipid to the correct store. Key in this is PPAR γ. However, this balance is determined by muscle mass: more muscle means higher glucose dispersal, but muscle is also metabolically active and an important site of thermogenesis, and therefore, energy loss – which, we suggest, may be partly determined by mass action and futile cycling (the muscle 'metabolite door' is more open due to insulin sensitivity). Certainly, PPAR δ (and probably α) are important the utilisation of lipid energy muscle. During injury/inflammation, energy is required for the immune system, so insulin resistance is increased and lipids flow out of adipose tissue – which is not to dissimilar to the fasting response. However, unlike the fasting response, the insulin resistance is likely to be largely cytokine induced, plus, it is usually associated with pyrexia (increased futile cycling & thermogenesis) and anorexia – it is a hypermetabolic response. Furthermore, unlike fasting, inflammation is associated with increased oxidative stress. It is also associated with suppression of PPAR activity – however, PPARs would act as negative regulators to modulate the response and improve insulin action.
The transcriptional adaptive response to fasting involves upregulation of FOXO, PGC-1α and PPAR α – all of which enhance resistance to oxidative stress and the ability to burn fat, while ensuring glucose sparing. Thus, insulin resistance is essential for survival, but too much can result in a feed-forward "feed-inflammatory" response: the 'thrifty' response out of control – as it also suppresses the hypothalamic satiety effects of insulin and leptin. At the transcriptional level, FOXO activity appears to be orexigenic in the hypothalamus [114
] – insulin (and inflammatory mediators) would suppress its activity. Hence, PPARs, by suppressing oxidative stress and improving insulin action, can prevent this from happening.
The out of control 'thrifty' response: new lifestyle, old genes – a modern PPAR imbalance
It is now well accepted that "modern epidemics" such as obesity, the metabolic syndrome, and type 2 diabetes reflect that the modern human is simply "drowning in a sea of saturated fats". It is generally thought that this is due to a ancient genotype being exposed to a modern environment. Thus, if we accept that we are simply "Stone Agers in the fast lane" [115
], we need to rebalance our systems, either artificially or naturally, to protect us against the ravages of modern living and to slow the aging process. For instance, evidence suggests that dietary manipulation to increase the polyunsaturated/saturated fat ratio can be advantageous [116
], and the benefits of physical activity are well known, including the ability to delay and prevent type 2 diabetes [119
]. One might argue, however, that sections of the population exhibiting the "thrifty genotype" may be especially at risk and need to dramatically change their diet and lifestyle in order to optimize their functional longevity. In many respects, the long-lived calorie-restriction phenotype is the complete opposite of the shorter-lived metabolic syndrome phenotype. Evidence suggests that our ancestors did not often live much beyond the age of 40, so an ability to store fat quickly, which accentuated the potency of the innate immune – was never really a problem in the long term: it is probably an example of 'antagonistic pleiotropy', which gave a survival advantage while young, ensuring reproductive success.
Modulation of PPARs appears to occur in the APR, which occurs as part of an injury-related response. During this reaction to injury, it may be necessary to downregulate PPARs, as they have many effects that are counterproductive to tissue healing (e.g., they reduce insulin, resistance, suppress expression of inflammatory cytokines and are anti-proliferative). Many of the pathways that are thought to achieve this downregulation are involved in allowing the metabolism of fats. Significantly, many of the signs and symptoms of the APR are shared by the metabolic syndrome. Therefore, it is not untoward to speculate that the downregulation of PPARs may well be at the root of the metabolic syndrome. The cause of this downregulation may well be the modern lifestyle, leading to an out of control 'thrifty response'. Modulating PPARs may be one way to help prevent this. In this respect, it may be possible to "rebalance" our systems through changes in diet, lifestyle, and, possibly, therapeutic intervention (figure ) – the PPARs may therefore play a very important role in 'metabolic balance'. The benefits of PPAR activation/modulation are clear from trials where PPARs have been activated by pharmacological and natural ligands [120
]. However, the increased mortality of some patients with compromised cardiac function in trials with the newer dual PPAR agonists does suggest that modulation of PPAR function needs to be handled carefully in some populations [122
], as enhancing their activity may counter-act an ancient injury survival system.
Restoring metabolic balance. Lifestyle changes and therapeutic interventions in redressing the imbalance leading to restoration of metabolic and inflammatory balance. Sustained weight loss critical for optimum results.