Shifting the phenotype; reducing the need for insulin The ability of PPAR γ to improve glucose dispersal is well described, and is now being described for PPAR δ [ 70] and PPAR α (although there have been some conflicting results) [ 71, 72]. One of the main ways they do this is to channel fatty acids to where they are needed; this prevents the build up of excessive intramyocellular lipid, which is thought to be one of the major causes of insulin resistance in obesity [ 73]. In addition, it is also becoming clear that an increase in ROS can also cause insulin resistance [ 74]. This would support the observation that increasing free fatty acid (FFA) concentrations can induce NFkB activity (and ROS) [ 75], and in the liver, this may partly explain hepatic insulin resistance [ 76]. However, it has been long known that ROS is involved in insulin (and that of other growth factors) signalling, possibly through NADPH oxidase (Nox) production of H 2O 2 (reviewed by Goldstein, Mahadev 2005) [ 77]. This would imply that not only is control of intracellular redox vital, but that excessive insulin signalling, (apart from suppressing FOXO), may also contribute to increased cellular oxidative stress. It has been proposed for some time that 'thrifty' genes would have given our ancestors a survival edge in harder times by enabling rapid storage of fat, but in times of plenty, may have resulted in increased levels of diabetes [ 78]; key to this insulin resistance may be the role of lipids. In contrast, in times of plenty selective pressure may have resulted in 'unthrifty' genes, which would be associated with insulin sensitivity. For instance, the PPAR γ ala allele, which is diabetes protective and probably arose between 32,000 to 58,000 years ago [ 79]. Thus, both insulin resistance and sensitivity can be potential survival traits – so what is the role of the PPARs in determining this balance? Keeping FOXO active: PPARs modulate insulin 'drive' The facility of a rapid food-induced insulin response and the ability to store food efficiently after starvation, while retaining a degree of insulin resistance post-prandially, may be example of a "thrifty adaptation" to spare glucose for the CNS and provide energy for muscle during times of hardship – both for movement and thermogenesis [ 80]. Certainly, muscle insulin resistance combined with adipose insulin sensitivity may comprise a 'fat catch-up' paradigm by ensuring fatty acid channelling to adipose tissue and decreased muscle thermogenesis [ 81]. In addition, the recent discovery of a hormone associated with longevity called 'klotho' that can induce insulin resistance and upregulate FOXO [ 82] is therefore significant, as is supports the observation that the right degree of insulin resistance may aid long-term survival. For instance, if normal human subjects are starved for 48 hours, they become insulin resistance, which is thought to be a natural response to maintain glucose levels and is related to decreased glucose dispersal by down-regulation of muscle PDC [ 83]. This insulin resistance is probably related to increased intramyocellular fat, as during starvation, FFA levels rise [ 84]. Similarly, 60 hour starvation of patients with T2D or obesity can result in increased insulin resistance, but only in those who were relatively insulin sensitive to begin with; in some highly insulin resistant patients, starvation improved sensitivity [ 85]. Indeed, it has been observed for many years that crash dieting can actually induce severe insulin resistance and T2D is some obese patients [ 86]. FOXO, which is one of the most important transcription factors in improving functional longevity during fasting, is negatively regulated by insulin [ 9]. 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 insulin-mediated downregulation of FOXO. This process is also 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 also suppress insulin release [ 87, 88]. Interestingly, saturated fat is far more insulinotropic than unsaturated fat [ 89], which might suggest that PPARs are more effective at reducing insulin production in response to unsaturated fats. This is in keeping with the susceptibility of unsaturated fats to oxidative damage. In contrast, saturated fat is less effective than unsaturated fat at stimulating the incretin, glucagon-like peptide-1 (GLP-1), from the gut [ 90]. The biological activities of GLP-1 include stimulation of glucose-dependent insulin secretion and insulin biosynthesis, inhibition of glucagon secretion and gastric emptying, and inhibition of food intake. This may suggest an evolved bias towards unsaturated dietary fat intake from the gut, but an internal system to react to nascent saturated fat produced from glucose (or fructose): i.e. we are far more able to tolerate ingestion of unsaturated fat, compared to saturated fat – but the system is designed to recognise and deal with de novo saturated fat generated from carbohydrate. Human data suggest that rosiglitazone can activate desaturases, so reducing levels of saturated fat in the system [ 91], which would further indicate that reduction of excess saturated fat is a biological imperative. We propose that at it simplest, muscle insulin sensitivity may result in increased thermogenesis through futile cycling and thus, would be associated with an 'unthrifty' genotype. Key in either the thrifty, or unthrifty genotypes (as indicated by the PPAR ala/pro mutation), would be the role of the PPARs: increased adipose PPAR γ activity would result in better fat storage (adipose insulin sensitivity), whereas an improved ability to burn fat in muscle (PPAR α/δ) might be associated with better muscle insulin sensitivity and less efficient feed efficiency (but a better tolerance to cold). Hence, by modulating tissue-specific fatty acid metabolism and storage, PPARs are able to maximise FOXO activity and thus optimise resistance to oxidative stress by reducing the need for insulin. One obvious exception to this is the mutually suppressive effects of PPAR γ and FOXO in adipose tissue [ 22]; increased PPAR γ activity would act to store fatty acids, while still maintaining an anti-inflammatory effect (reduce oxidative stress) by suppression of NFkB. Certainly, basal NFκB activity increases during adipocyte differentiation [ 92]. This would suggest a possible adipose-inflammatory paradigm, whereby increased NFkB activity could conceivably suppress both FOXO and PPAR γ, resulting in 'inflammatory' lipolysis. During starvation, FOXO would be expected to suppress both NFkB and PPAR γ and result in 'starvation' lipolysis. However, in obesity, this natural suppression of inflammation is lost due to the high adipose-related inflammatory signal, which suppresses both PPAR γ and FOXO: this could lead to the metabolic syndrome. The metabolic syndrome; PPARs keep the acute phase response in check It has been suggested that in addition to the 'thrifty' genotype, another adaptation may also be needed to develop the metabolic syndrome, and that is a 'high cytokine responder' genotype, with an improved ability to resist injury (i.e. a stronger inflammatory response) [ 93]. It has been known for many years that injury can result in profound insulin resistance and is associated with the APR, which is a systemic inflammatory injury response to protect the host (being both haemostatic and anti-microbial) characterised by the hepatic production of acute phase proteins (e.g. c-reactive peptide, CRP) and glucose, increased cytokine production and turnover of protein, glycerol free and fatty acids, and has been called the 'hypermetabolic response' [ 94, 95]. This 'hypermetabolic' (catabolic) state can be mimicked by injection of the stress hormones cortisol, glucagon and ephedrine in human volunteers [ 96]. However, this 'hypermetabolic' state is usually associated with increased thermogenesis (pyrexia) and is anorexic, and probably involves inflammatory-mediated modulation of appetite systems, such as the melanocortin pathway [ 97]; this is clearly not the case in the metabolic syndrome. Interestingly, leptin is known to mediate the effects of lipopolysaccharide (LPS) induced anorexia and fever [ 98], but central leptin (and insulin) resistance is a common finding in obesity and could be related to leptin itself via effects on phosphatidylinositol 3-kinase (PI3K) and phosphodiesterase 3B (PDE3B) activities and reduction in cyclic AMP (cAMP) [ 99] and/or the pro-inflammatory effects of a high fat diet [ 100]. This might also represent a another thrifty adaptation to ensure a high state of 'inflammatory readiness', but conservation of energy stores. It was suggested by Pickup and colleagues in 1997 that 'syndrome X' (now called the metabolic syndrome) was in fact a disease caused by the chronic activation of the innate immune system and contributed to the hypertriglyceridaemia, low HDL cholesterol, hypertension, glucose intolerance, insulin resistance and accelerated atherosclerosis of NIDDM [ 101]. This hypothesis for the development of T2D (and the metabolic syndrome) was further supported by data from the Athersclerosis Risk in Communities study (ARIC) [ 102]. Importantly, the APR and inflammation can result in increased insulin output, which can in turn suppress the APR – so providing a possible negative feedback mechanism [ 103]. Interestingly, IL-6, a potent inflammatory cytokine-inducer of the APR produced by adipose tissue, is significantly associated with insulin resistance and insulin levels in men: this relationship may further indicate a 'thrifty' adaptation, which both enhances resistance to infection and ability to store energy [ 104]. Mutations in the IL-6 gene are associated with increased risk of diabetes [ 105]. The APR response has now been shown to down-regulate PPAR activity in most tissues, including adipocytes [ 106] – which is to be expected, as PPARs are generally anti-inflammatory and improve insulin sensitivity. Indeed, they have been described as negative acute phase proteins [ 107]. At the site of injury (due to hypoxia), HIF-1 (and NFkB) may suppress PPAR activity directly. Away from the site of injury, pro-inflammatory mediators such as angiotensin II can mediate many of the effects of the APR via activation of NFkB and thereby also inhibit PPAR activity [ 108, 109]. We suggest that at some point in the clinical evolution of the metabolic syndrome and T2D a 'tipping point' is reached, resulting in an inflammatory-driven downregulation of PPARs (figure 3). All of this would strongly indicate that the metabolic syndrome is an exaggerated thrifty response, characterised by insulin resistance, which not only induces a propensity to store fat, but results in a fat-mass related activation of the APR (and resistance to its normal suppression by insulin). However, unlike the well described hypermetabolic injury response, appetite is maintained and thermogenesis suppressed (see below for possible explanation). | Figure 3A modern imbalance: an out of control 'thrifty' response. Proposal as to what happens when an ancient hunter-gatherer genotype meets a modern lifestyle. Thrifty response and expanding adipose tissue eventually leads to an over-whelming inflammatory signal. (more ...) |
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