Abstract
The peroxisomal proliferating-activated receptors (PPARs) are lipid-sensing transcription factors that have a role in embryonic development, but are primarily known for modulating energy metabolism, lipid storage, and transport, as well as inflammation and wound healing. Currently, there is no consensus as to the overall combined function of PPARs and why they evolved. We hypothesize that the PPARs had to evolve to integrate lipid storage and burning with the ability to reduce oxidative stress, as energy storage is essential for survival and resistance to injury/infection, but the latter increases oxidative stress and may reduce median survival (functional longevity). In a sense, PPARs may be an evolutionary solution to something we call the 'hypoxia-lipid' conundrum, where the ability to store and burn fat is essential for survival, but is a 'double-edged sword', as fats are potentially highly toxic. Ways in which PPARs may reduce oxidative stress involve modulation of mitochondrial uncoupling protein (UCP) expression (thus reducing reactive oxygen species, ROS), optimising forkhead box class O factor (FOXO) activity (by improving whole body insulin sensitivity) and suppressing NFkB (at the transcriptional level). In light of this, we therefore postulate that inflammation-induced PPAR downregulation engenders many of the signs and symptoms of the metabolic syndrome, which shares many features with the acute phase response (APR) and is the opposite of the phenotype associated with calorie restriction and high FOXO activity. In genetically susceptible individuals (displaying the naturally mildly insulin resistant 'thrifty genotype'), suboptimal PPAR activity may follow an exaggerated but natural adipose tissue-related inflammatory signal induced by excessive calories and reduced physical activity, which normally couples energy storage with the ability to mount an immune response. This is further worsened when pancreatic decompensation occurs, resulting in gluco-oxidative stress and lipotoxicity, increased inflammatory insulin resistance and oxidative stress. Reactivating PPARs may restore a metabolic balance and help to adapt the phenotype to a modern lifestyle.
Highlights
Peroxisomal proliferating-activated receptors (PPARs) were discovered in 1990 with the cloning of a murine orphan receptor that was activated by peroxisomal proliferating compounds, their name [1]
They probably arose during metazoan evolution and at least three isoforms have been identified, α, γ and δ, each encoded by a different gene [2]
We suggest that the phenotype associated with calorie restriction is the opposite of that seen with the metabolic syndrome and the balance between the two may be determined, to a large degree, by PPAR activity
Summary
Peroxisomal proliferating-activated receptors (PPARs) were discovered in 1990 with the cloning of a murine orphan receptor that was activated by peroxisomal proliferating compounds (such as the fibrates), their name [1]. We suggest that a critical function of the PPARs is to reduce insulin "drive" (via appropriate tissue insulin sensitisation) and thereby increase functional longevity by preventing the insulinmediated downregulation of FOXO This process is http://www.nuclear-receptor.com/content/5/1/1 extended directly to insulin production, as PPARs are involved in controlling glucose-stimulated insulin release, a process that is modulated by fatty acids and may involve UCPs: increased PPAR α activity is associated with down regulation of insulin production during fasting, while PPAR γ islet over-expression can suppress insulin release [87,88]. This critical role is summarised by the 'transcriptional triad' (figure 1) 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. 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
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