The metabolic syndrome: common origins of a multifactorial disorder

Transcription

1 Review Endorinology and Metabolism Unit, DOHaD Division, Institute of developmental Sienes, Southampton General Hospital, Southampton, UK Correspondene to: Professor C D Byrne, Endorinology and Metabolism Unit, DOHaD Division, Institute of developmental Sienes, Southampton General Hospital, Southampton SO16 6YD, UK; dtb@soton.a.uk Reeived 25 February 2009 Aepted 28 June 2009 The metaboli syndrome: ommon origins of a multifatorial disorder K D Brue, C D Byrne ABSTRACT The metaboli syndrome (MetS) represents a ombination of ardiometaboli risk determinants inluding obesity (entral adiposity), insulin resistane, gluose intolerane, dyslipidaemia, non-aloholi fatty liver disease and hypertension. MetS is rapidly inreasing in prevalene worldwide as a onsequene of the ontinued obesity epidemi, and as a result will have a onsiderable impat on the global inidene of ardiovasular disease and type 2 diabetes. Currently, there is debate onerning whether the risk of ardiovasular disease is greater in patients diagnosed with MetS than that of the sum of the individual risk fators. At present, no unifying origin that an explain the pathogenesis of MetS has been identified and therefore no unique pharmaologial treatment is available. This review summarises and ritially evaluates the urrent linial and sientifi evidene supporting the existene of MetS as a multifatorial endorine disease, for whih maternal nutrition may be a ommon pathogeni mehanism. In addition, we suggest that etopi fat aumulation (suh as viseral and hepati fat aumulation) and the proinflammatory state are entral to the development of the MetS. In 1988, Reaven postulated that insulin resistane (IR) was the ause of gluose intolerane, hyperinsulinaemia, inreased very-low-density lipoprotein (VLDL), dereased high-density lipoprotein (HDL) and hypertension. 1 Twenty years later, the insulin resistane syndrome has graduated to beome the metaboli syndrome (MetS). MetS is thought to represent a ombination of ardiovasular risk determinants, inluding obesity (espeially entral adiposity), gluose intolerane and IR, dyslipidaemia (inluding hypertriglyeridaemia, inreased free fatty aids (FFAs) and dereased HDL-holesterol) and hypertension, and more reently has also been assoiated with linial manifestations suh as polyysti ovarian syndrome (PCOS), atheroslerosis, proinflammatory state, oxidative stress and non-aloholi fatty liver disease (NAFLD). As a multiomponent ondition, MetS imparts an approximate doubling of risk for atherosleroti ardiovasular disease. 2 However, it is urrently unertain whih omponent of the syndrome onfigures this risk. In fat, there is urrently a ontroversial debate surrounding the identity of MetS and its pedagogi utility and diagnosti apaity. 3 4 A ritiism of MetS is its lak of weighting for the individual syndrome omponents, and onsequently whether the syndrome as a whole ounts more than the sum of its parts remains unlear. 3 In addition, the proponents of MetS are often ritiised for their failure to identify a unifying pathogeni mehanism 5 or single geneti ause, whih in turn has prevented the formulation of a unique treatment. 6 It is likely that a seemingly simple mehanism has not been identified beause MetS has a highly omplex aetiology inluding inherited genes, intrauterine environment, abnormal patterns of fat aumulation and physial inativity. 7 In this review, we will summarise and ritially evaluate the urrent linial and sientifi evidene that supports the existene of MetS as a multifatorial endorine disease and not a luster of oinidental features. We will disuss the omplex aetiology, pathogenesis and linial outomes of the syndrome and in doing so highlight its usefulness as a diagnosti tool. Finally, we will desribe how many of the MetS omponents may share a ommon origin and how inreased risk suseptibility may result from inappropriate maternal nutrition and developmental priming, therefore highlighting a ommon underlying pathophysiologial proess. 8 DEFINITION OF MetS There have been several definitions of MetS, but the most ommonly used riteria for definition at present are from the World Health Organization (WHO), 9 the European group for the study of Insulin Resistane (EGIR), 10 the National Cholesterol Eduation Programme Adult Treatment Panel III (NCEP ATP III) 11 and the International Diabetes Federation (IDF)(2005). 12 Table 1 presents the diagnosti features of eah definition. Although eah definition possesses ommon features, there are several parameters that differ. For example, the WHO and EGIR lassifiations require the measurement of IR, whih is determined by an oral gluose tolerane test and hyperinsulinaemi euglyaemi lamp. As this method is labour intensive, it is primarily used in a researh environment. 13 In ontrast, the ATPIII definitions were developed to be appliable in the outpatient lini and therefore have remained a bakbone for subsequent lassifiations suh as the IDF diagnosti riterion. 13 It is plausible that alternative definitions have ontributed to variations within the literature and questions surrounding the pedagogi apaity of the MetS. Nonetheless, the strength of assoiations between IR and abdominal obesity as a main ontributing fore driving the onset of MetS is potentially unifying the field. The fat the abdominal obesity is the only mandatory diagnosti riterion in the IDF lassifiation learly emphasises this. Postgrad Med J: first published as /pgmj on 5 November Downloaded from on 15 September 2018 by guest. 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2 Table 1 Features of the World Health Organization (WHO), European Group for the Study of Insulin Resistane (EGIR), National Cholesterol Eduation Program (NCEP) Expert Panel on Detetion, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP-III) and International Diabetes Federation (IDF) definitions of metaboli syndrome Central obesity WHO (WHO onsultation, 1999). Impaired gluose tolerane or diabetes and/or insulin resistane and two other fators WHR >0.9 (men), 0.85 (women) and/ or BMI.30 kg/m 2 EGIR (Balkau and Charles, ). Presene of fasting hyperinsulinaemia (the highest 25%) and two other fators Waist >94 m (men), >80 m (women) CORRELATION OF THE INCREASE IN MetS PREVALENCE WITH INCREASING OBESITY PREVALENCE When Reaven originally developed the insulin resistane syndrome onept, he did not inlude any marker of obesity in his desription. Many years later, it is lear that in most ases obesity, partiularly viseral (or entral) obesity, is important for the development of many of the other MetS omponents and downstream manifestations. In the USA, the prevalene of MetS is driven by the growing obesity epidemi, whih is ourring throughout Western soiety and is partiularly notable in south-eastern USA. 14 In fat, MetS has reahed epidemi proportions aross the whole of the USA and, in unison, so has the expression of obesity, gluose intolerane, type 2 diabetes, vasular inflammation and a prothromboti phenotype. 6 It has been reported that the inidene of MetS inreases with the severity of obesity and has been observed in 50% of obese adolesents. 15 Type 2 diabetes is five to six times more ommon in obese people (body mass index (BMI).30 kg/m 2 ) than in those of normal weight. 16 Even within diverse populations exposed to different environmental fators, inreasing BMI is positively assoiated with prevalene of both impaired gluose tolerane and type 2 diabetes In turn, this inreasing BMI also orrelates with other MetS omponents, inluding inreasing total holesterol, low-density lipoprotein (LDL)-holesterol and triaylglyerols (TAGS) and dereasing HDL-holesterol and hypertension. VISCERAL OBESITY IS A MECHANISTIC LINK BETWEEN THE MetS COMPONENTS In response to these observations, it an be feasibly argued that the most ommon ontributor to the rise in MetS is exessive body fat aumulation. 21 However, more speifially, one of the most important ausal omponents of MetS is the aumulation of etopi fat. This often results in a pathophysiologial ondition that has reently been termed adiposopathy, and is defined as pathogeni adipose tissue that is promoted by a ATP-III (NCEP Expert Panel on Detetion, 2001). Three or more of the following fators (TAGs and HDL ounted separately) Waist >102 m (men),.88 m (women) IDF. Central obesity and two other fators ( Waist.94 m (European men),.90 m (Asian men),.80 m (women) Blood pressure (mm Hg) >140/90 >140/90 or treated for hypertension.130/85 or treated for hypertension >130 SBP or >85 DBP or treated for hypertension Dyslipidaemia (mmol/l) Dysglyaemia (mmol/l) Insulin resistane TAGs >1.7, HDL,0.9 (men),,1.0 (women) Fasting gluose >6.1 and/or 2 h post-hallenge gluose >7.8 on diabetes Gluose uptake during hyperinsulinaemi euglyaemi lamp in lowest quartile for population Other fators WHO (WHO onsultation, 1999). Impaired gluose tolerane or diabetes and/or insulin resistane and two other fators) TAGs >2.0 or HDL-holesterol,1.0 or treated for dyslipidaemia Fasting plasma gluose.6.1, but non-diabeti Presene of fasting hyperinsulinaemia (ie, among the highest 25% of the non-diabeti population) EGIR (Balkau and Charles, ). Presene of fasting hyperinsulinaemia (the highest 25%) and two other fators TAGs >1.7, HDL-holesterol:,1.0 (men),,1.3 (women) Fasting plasma gluose >6.1 Not appliable Miroalbuminuria (urinary albumin exretion rate.20 mg/min or albumin/reatinine ratio.30 mg/g) TAGs >1.7, HDL-holesterol,,1.04 (men),,1.29 (women) Fasting gluose >5.6 or previous diagnosis of impaired gluose tolerane or diabetes Not appliable BMI, body mass index; DBP, diastoli blood pressure; HDL, high-density lipoprotein; SBP, systoli blood pressure; TAG, triaylglyerol; WHR, waist/hip ratio. None Review positive energy balane and sedentary lifestyle in genetially and environmentally suseptible patients Adiposopathy is thought to be linially manifest through a ombination of adipoyte hypertrophy, adipose tissue growth, etopi fat distribution and, espeially, viseral adipose tissue aumulation, all of whih may ause adverse immune and metaboli disturbane 24 and may ontribute to the development of MetS. There are a number of epidemiologial studies to support the notion of adiposopathy and, in partiular, to support a oherene between viseral obesity and the prevalene of inreased MetS leading to inreased CVD Waist/hip ratio, whih is used as a marker of viseral obesity, orrelates positively with fasting plasma gluose and is onsequently a risk fator for the development of type 2 diabetes, 21 whih is independent of, and additive to, BMI. 27 Another marker of entral obesity inreased waist irumferene has also been shown to signifiantly inrease the risk of CVD, through a positive effet on systoli and diastoli blood pressure inrease. 28 Although the assoiation between viseral fat and MetS is strong, the mehanism is not fully eluidated. FAT AND INFLAMMATION The most hallenging aspet to unifying the MetS omponents is understanding and identifying ommon ellular mehanisms that provide a pathophysiologial link between eah metaboli abnormality and the development of disease. 13 It has been hypothesised that viseral fat may be at the entre of an underlying mehanism, primarily through its release of substanes that are ausal to metaboli abnormalities. A study of extremely obese subjets (mean (SD) BMI 54.7 (12.6) kg/m 2 ) showed that mean plasma interleukin (IL)-6 onentrations were signifiantly raised in the portal vein and orrelated diretly with C-reative protein (CRP), suggesting that viseral fat provides a mehanisti ausal link to systemi inflammation. 29 In fat, CRP has been shown to strengthen the relationship between MetS and oronary heart disease events. 30 Postgrad Med J: first published as /pgmj on 5 November Downloaded from on 15 September 2018 by guest. Proteted by opyright. Postgrad Med J 2009;85: doi: /pgmj

3 Review Atheroslerosis is also hypothesised to have a proinflammatory pathogenesis and results from a ombination of the innate and adaptive immune system effetors pathways. 31 Etopi fat aumulation may diretly affet these pathways via the release of immune fators. In addition, dietary fat intake per se may also diretly influene inflammatory pathways. Reent studies have shown that high dietary fat intake is assoiated with oxidative stress and ativation of the proinflammatory transription fator nulear fator kappa-beta (NFkB). 32 In ontrast, a diet rih in fruit and fibre has no inflammation-induing apaity ompared with a high-fat diet even if it has the same alorie ontent. 33 ROLE OF ADIPOCYTOKINES IN MetS In support of the role of etopi fat as entral to the pathogenesis of MetS, there are several lines of evidene to suggest that etopi fat may be involved in the genesis of IR. Adipose tissue is now regarded as an endorine organ sereting a number of hormones and bioative substanes termed adipoytokines (adipokines). The best haraterised of these adipokines are leptin, adiponetin, tumour nerosis fator alpha (TNFa) and IL Several other adipokines, inluding visfatin, plasminogen ativator inhibitor-1, angiotensin, resistin and gluoortioids, have been identified. 37 Speifially, it is thought that elevated prodution of the proinflammatory adipokines due to expanded viseral adiposity (and inreased marophage infiltration) ontributes to the development of IR, type 2 diabetes and inreased risk of CVD. 37 However, there is a omplex interplay between these moleules and the pathogeni mehanisms leading to IR. For example, obesity-indued TNFa may ontribute to IR by stimulating the release of other proinflammatory ytokines into the irulation. In addition, both resistin and visfatin, although initially assoiated with the development of IR, have now been shown to have opposing expression in different models of obesity. For a detailed review of the role of adipokines in IR, see Adipose tissue and adipokines in health and disease. 38 Whereas the irulating onentrations of the proinflammatory ytokines are raised in obese people, 39 adiponetin, whih is exlusively sereted by adipose tissue, appears to be redued. 37 Although the preise physiologial role of adiponetin is not fully eluidated, it is onsidered to be a marker of insulin sensitivity, and plasma onentrations of adiponetin orrelate negatively with IR. In mie, administration of adiponetin has been shown to improve insulin sensitivity via a derease in hepati gluose output and inreased fatty aid oxidation in musle Conversely, patients with type 2 diabetes have lower plasma onentrations of adiponetin than BMI-mathed ontrol subjets. 48 Similarly, hypertensive patients also have low onentrations of adiponetin. 49 Adiponetin exists in three moleular-mass forms in the irulation. However, the speifi biologial ation of these different moleular forms and how they reat with the adiponetin reeptors remain to be larified. It is paradoxial that obese subjets have low adiponetin onentrations ompared with lean people, as they have more fat and therefore should produe greater amounts of adipokines. In fat, adiponetin appears to be under the ontrol of adipokineinitiated signalling pathways. For example, adiponetin expression and seretion in adipoytes has been shown to be redued by TNFa. 50 It is possible that a hange in fat distribution and quantity may deregulate otherwise ruially balaned adipokine onentrations, whih may play a key role in the development of a proinflammatory state and inreased CVD and IR. IR AND MetS IR is the most linially aepted ausal omponent of MetS. It is lassially defined as an impaired gluose response to insulin in key insulin-sensitive tissues, suh as adipose tissue, liver and skeletal musle, and more reently ardiovasular tissue. 51 IR is assoiated with CVD, and meta-analyses have shown an independent positive assoiation between fasting plasma insulin onentrations and the risk of CVD mortality. 35 Although the preise mehanisms leading to IR in eah tissue type have not yet been fully determined, potential pathways leading to IR have been attributed to either pre-reeptor or post-reeptor defets. 34 For example, impaired ellular signalling events that our post-reeptor, within the target tissue, result in impaired gluose transport and a ompensatory inrease in insulin to overome the defet. 34 Although any imbalane in the insulin signalling pathway may lead to metaboli disturbane, the most studied is the phosphatidylinositide-3-kinase and protein kinase B (Akt) pathway. Upon insulin binding, the insulin reeptors rapidly ativate (via phosphorylation) several intraellular protein asades, suh as insulin reeptor substrate 1, whih reruits and ativates phosphatidylinositide-3-kinase. Ativation of this pathway is ruial in all insulin-sensitive tissue, inluding ardiovasular tissue, and therefore disruption may result in IR and hyperinsulinaemia. 34 This IR may have a diret adverse effet on dietary nutrient exhange (eg, gluose) in key tissues suh as skeletal musle, ontributing to other omponents of MetS suh as hyperglyaemia. 52 VISCERAL OBESITY AND FFAs Inreased onentrations of viseral fat may be also ontribute to an IR state, beause, by its nature, it is more resistant to the metaboli effets of insulin than subutaneous fat. 6 Instead, it is more responsive to lipolyti hormones, gluoortioids and ateholamines The most dramati abnormality in the FFA metabolism of viseral fat is the failure to suppress FFA onentrations through adipose tissue lipolysis normally in response to hyperinsulinaemia. 55 This results in an inreased CVD risk profile, with impaired endothelial dysfuntion, vasular smooth musle ell proliferation, and alteration of irulating LDL-holesterol and HDL-holesterol. 56 This onstantly inreased release of FFA into the portal system also provides inreased substrate for hepati prodution of TAGs, 53 a situation that is likely to ontribute to the development of nonaloholi fatty liver and IR. In addition, FFAs themselves ontribute to IR. The intraellular aumulation of FFAs in nonadipose tissues in high quantities may indue the overprodution of damaging metabolites and strutural abnormalities and ultimately indue nerosis and systemi inflammation, whih again is assoiated with the development of CVD. NAFLD: A NOVEL COMPONENT OF MetS The liver is an organ that is vulnerable to etopi fat aumulation. Currently, the inidene of NAFLD mirrors the prevalene of obesity and MetS, and NAFLD is now one of the most ommon auses of hroni liver disease worldwide Approximately 33% of the Amerian adult population have NAFLD. 59 Reent estimates of prevalene in the USA are 20 30% for hepati steatosis and 3.5 5% for non-aloholi steatohepatitis, and up to 80% of people with type 2 diabetes may have some form of NAFLD. 59 Notably, NAFLD is not a single disease entity, but desribes a spetrum of liver onditions. The disorder ranges from simple fatty liver (steatosis) to more severe steatosis oupled with marked Postgrad Med J: first published as /pgmj on 5 November Downloaded from on 15 September 2018 by guest. Proteted by opyright. 616 Postgrad Med J 2009;85: doi: /pgmj

4 Main messages The metaboli syndrome (MetS) represents a ombination of ardiometaboli risk determinants inluding obesity (entral adiposity), insulin resistane, gluose intolerane, dyslipidaemia, non-aloholi fatty liver disease and hypertension. MetS is rapidly inreasing in prevalene worldwide as a onsequene of the ontinued obesity epidemi. There is debate about the pedagogi apaity and usefulness of MetS as a diagnosti tool. The main reason for this entres around the apparent lak of a unifying pathogeni mehanism and the variability in the diagnosti riteria. The International Diabetes Federation riteria puts emphasis on entral obesity and may be the most linially aessible method to date. One of the most important ausal omponents of MetS is the aumulation of etopi fat, seen as inreased viseral adiposity. Etopi fat ourring in the visera may be at the entre of an underlying mehanism, primarily through a pararine effet to derease tissue insulin sensitivity in key tissues suh as liver. In addition, the release of substanes suh as adipokines from etopi fat may at to promote a proinflammatory state, derease insulin sensitivity and, in turn, adversely modify ardiovasular risk fators. The liver is partiularly suseptible to etopi fat aumulation, and non-aloholi fatty liver disease (NAFLD) is now onsidered to be the hepati manifestation of MetS. NAFLD may progress in suseptible people with inreasing steatohepatitis and progressive liver fibrosis. NAFLD may be developmentally primed through exposure of the developing offspring in utero to inappropriate maternal nutrition during pregnany. Therefore, we suggest that this developmental origin may provide a unifying mehanism to explain MetS suseptibility and the broad spetrum of the MetS phenotype extending from dysglyaemia to inreased blood pressure, dyslipidaemia, entral obesity and NAFLD. inflammation termed non-aloholi steatohepatitis (NASH), whih an progress to fibrosis, and subsequently to liver irrhosis (15 17%), liver failure (3%) and hepatoellular arinoma. 61 Interestingly, all omponents of MetS orrelate with liver fat, as determined by 1 H-magneti resonane spetrosopy, and, although these measures inrease with obesity, they remain signifiant even when adjusted for BMI. 62 Therefore it is not surprising that NAFLD is onsidered the hepati manifestation of MetS In support of this, reent epidemiologial studies have shown that severe NAFLD is linked to an inreased risk of CVD, independent of underlying ardiometaboli risk fators. 66 These studies suggest that NAFLD may be atively involved in the pathogenesis of CVD, potentially through the inreased release of pro-atherogeni fators from the liver (CRP, fibrinogen, plasminogen ativator inhibitor-1 and other inflammatory ytokines). Alternatively, NAFLD is involved in whole-body IR and dyslipidaemia. For example, one signifiant hepati steatosis ours, the liver beomes insulin-resistant and overprodues both gluose and VLDL, whih in turn leads to hyperglyaemia, hypertriglyeridaemia and low HDL onentrations. 67 However, whether IR preedes etopi fat deposition or whether fat aumulation is a onsequene of IR remains an unanswered question. Current researh questions Review Do the metaboli syndrome (MetS) riteria require further review to appraise the thresholds for eah of the five simple features of the syndrome, as used in the International Diabetes Federation and Adult Treatment Panel III riteria? Should the simple easily measurable individual features of MetS be onsidered as part of a ontinuum of inreasing risk for type 2 diabetes, ardiovasular disease and non-aloholi fatty liver disease? Should the term dysglyaemia replae the term type 2 diabetes to (a) aknowledge the evidene that inreasing gluose onentrations inrease the risk of mirovasular ompliations, (b) move away from the notion that type 2 diabetes reflets a single disease entity, and () allow the treatment of gluose onentrations to be onsidered as the management of a ontinuously distributed risk fator within a population? What are the preise pathogeni mehanisms linking etopi fat aumulation to the other MetS omponents? What makes an individual more suseptible to etopi fat distribution? What are the mehanisms underlying the developmental priming of the MetS omponents? As previously desribed, etopi fat is an important soure of inflammatory fators, ytokines and adipokines. It is possible that adipose tissue inflammation plays a role in the pathogenesis of NAFLD. Indeed, analysis of adipose tissue from subjets with severe liver steatosis has suggested that inflamed adipose tissue haraterises people with a high liver fat ontent In mie, the overexpression of an inflammatory marker in adipose tissue (CCL2/MCP1) is thought to lead to marophage infiltration and hepati steatosis. 70 However, it is also possible that hepati inflammation may preede that of other insulinsensitive tissues, as the hepati ativation of NFkB via overexpression of IkB kinase b an indue IR in the liver and musle in addition to an inrease in signs of systemi inflammation (IL-6). 71 This study also reported that the same situation arises in response to a high-fat diet. In response to these findings, we an draw similarities between hepati fat and more traditional sites of proinflammatory, adiposopathi etopi fat, predominantly influened by a high-fat diet. Therefore, liver with a more severe form of NAFLD (NASH) may play an even larger role in the whole-body inflammatory state, beause the liver itself is in an advaned state of inflammation. It is also possible to hypothesise that, in some people, liver fat per se may at as the adiposopathi etopi fat (potentially independent of viseral fat) ontributing to the development of MetS. DEVELOPMENTAL ORIGINS OF NAFLD NAFLD learly plays an important role in the development of MetS omponents and the inflammatory state. But how does hepati lipid aumulate to abnormal onentrations in the first plae is the primary and ruial question. Several events may result in a fatty liver, partiularly in the ontext of IR. These inlude inreased FFA delivery due to inreased lipolysis from both viseral and subutaneous adipose tissue, and or inreased intake of dietary fat, oupled with dereased oxidation and inreased de novo hepati lipogenesis. 72 Analysis of hepati TAG ontent has shown that fatty aids ontributing to TAG Postgrad Med J: first published as /pgmj on 5 November Downloaded from on 15 September 2018 by guest. Proteted by opyright. Postgrad Med J 2009;85: doi: /pgmj

5 Review aumulation were derived from a plasma supply of FFAs (59%), de novo hepati lipogenesis (26%) and the diet (15%). 73 These data may seem ounter-intuitive, as fatty liver largely appears to be a onsequene of diet-indued obesity. However, we have reently tested in mie the hypothesis that exposure to a maternal high-fat diet during pregnany an predispose the offspring to develop a progressive fatty liver phenotype in adulthood. 74 We have shown that this appears to our through two distint mehanisms. The prenatal high-fat exposure upregulates the gene expression of key enzymes involved in hepati de novo lipogenesis and TAG synthesis. We hypothesise that this inreased supply of lipids from the prenatal high-fat diet developmentally primes the offspring s metaboli pathways to ope with exogenous lipids. Upon seondary exposure to a diet high in fat in postnatal life, these primed metaboli pathways readily aumulate fat within the liver, resulting in etopi fat storage and a NASH-like phenotype. We observe this phenomenon at a developmental time point equivalent to early adulthood, before the onset of IR, but after the onset of obesity. 75 This timeline suggests that, in our animal model, etopi fat aumulation may preede NASH, whih in turn may preede IR. Another mehanism that leads to developmentally primed NAFLD is mitohondrial dysfuntion. Mitohondrial dysfuntion has been previously desribed in animal models and in people with NASH Our data show that offspring of dams that were exposed to a high-fat diet have redued mitohondrial eletron transport hain (ETC) enzyme omplex ativity, whih persists until adulthood. The ETC is responsible for oxidative phosphorylation and is intimately linked to the itri aid yle and b-oxidation, therefore its impairments must further redue the offspring s hepati apaity to deal with superfluous dietary fats, thus ontributing to hepati lipid aumulation. In addition, a derease in ETC ativity may lead to imbalaned membrane potential, whih prolongs the half-life of eletron arriers and Figure 1 Shemati diagram of the metaboli syndrome (MetS) with suggested mehanisms linking the MetS omponents. The maternal environment an developmentally prime the metaboli apaity of key tissues, and this, ombined with the geneti ode, establishes the individual s suseptibility to developing MetS. The expression of the final adult MetS phenotype is dependent on the relative influenes of the severity of the developmental priming, geneti ode variation and environmental fators throughout life. We also suggest that etopi fat aumulation per se (as ours in non-aloholi fatty liver disease (NAFLD) in addition to viseral fat aumulation) and the proinflammatory state are key to the development of MetS. CVD, ardiovasular disease. inreases the generation of reative oxygen speies. 82 This effet would initiate lipid peroxidation and ativate NFkB inflammatory pathways and exaerbate the existing inflammatory state. Mitohondrial dysfuntion has also been impliated in several other studies investigating the developmental programming of MetS. For example, reent findings have shown that dietindued obesity leads to mitohondrial impairment. 83 In addition, studies using a transgenerational animal model of IR have shown that mitohondrial dysfuntion (observed as a redution in mitohondrial DNA) is developmentally programmed in response to maternal nutrition. 84 In simple invertebrate model systems, it has been established that very early stresses during the initial stages of development ause persistent hanges to mitohondrial ativity, 85 thus establishing a preedent for programming mitohondria. Mitohondria are entral to lipid homoeostasis, are maternally inherited, at as a vetor for dietary-indued stress, and produe hanges that persist into adulthood; olletively, this implies that mitohondrial dysfuntion may be a key ommon mehanism ontributing to inreased suseptibility to MetS. A COMMON DEVELOPMENTAL ORIGIN FOR MetS A andidate underlying mehanism that ould unify the apparently disparate omponents of MetS, and whih follows a similar soioeonomi trend, is maternal obesity or the maternal diet during pregnany. Reent estimates in the USA are that about one-third of women are obese when they reah hild-bearing age. 86 This presents a major health burden, as maternal obesity at oneption alters gestational metabolism and affets plaental, embryoni and fetal growth and development. 87 In addition, a wealth of evidene is aumulating to suggest that an inappropriate maternal diet an influene the suseptibility of the offspring to develop omponents of MetS in adult life. Originally, muh of the early fous of this researh was on retrospetive linial studies in whih early life measurements have been undertaken in people who have been studied in adulthood. These studies detailed the relationship between low birth weight and subsequent adult CVD and led Barker and olleagues to hypothesise that adverse environmental fators in early life ause disruption of normal growth and development, whih beame known as the developmental origins of health and disease hypothesis (DOHaD). Reent experimental studies in animals support the DOHaD hypothesis and its role in the development of other omponents of MetS in addition to CVD. Speifially, it has been shown Key referenes Alberti KG, Zimmet P, Shaw J. The metaboli syndrome: a new worldwide definition. Lanet 2005;366: Fontana L, Eagon JC, Trujillo ME, et al. Viseral fat adipokine seretion is assoiated with systemi inflammation in obese humans. Diabetes 2007;56: Bays H, Rodbard HW, Shorr AB, et al. Adiposopathy: treating pathogeni adipose tissue to redue ardiovasular disease risk. Curr Treat Options Cardiovas Med 2007;9: Marhesini G, Brizi M, Bianhi G, et al. Nonaloholi fatty liver disease: a feature of the metaboli syndrome. Diabetes 2001;50: Taylor PD, Poston L. Developmental programming of obesity in mammals. Exp Physiol 2007;92: Postgrad Med J: first published as /pgmj on 5 November Downloaded from on 15 September 2018 by guest. Proteted by opyright. 618 Postgrad Med J 2009;85: doi: /pgmj

6 that maternal undernutrition during ritial periods an prime adipose tissue deposition to give rise to later obesity, espeially when hallenged postnatally with a hypernutritional diet. 95 There is also evidene to suggest that it may have a detrimental effet on gluose homoeostasis. For example, manipulation of the fetal energy supply (low protein) has been shown to modify the proess of islet ell expansion, leading to small b-ell mass at birth, whih beomes even more pronouned when the proteinrestrited diet is maintained until weaning. 96 Experimental findings from models of overnutrition are more limited and are beginning to ome into the field. Preliminary studies have shown that overfeeding during the preweaning period permanently inreases adipoyte hypertrophy. 97 Inreased body weight and a twofold inrease in the viseral fat depot weight in adult offspring of fat-fed dams (24% fat by weight; lard) has also been reported. 84 In addition, our studies have shown that high-fat-indued developmental priming of body fat aumulation is exaerbated when dietary hallenge ontinues in the post-weaning phase. 75 This onept is illustrated in fig 1. Colletively, these data suggest that maternal diet may be a ommon origin and support the notion that early development may prime inreased suseptibility to the multifatorial disorder that is MetS in later life (fig 1). SUMMARY MetS is a highly omplex multifatorial endorine disorder, whih shares not one, but several ommon underlying mehanisms (fig 1), whih inlude etopi fat aumulation, impaired insulin sensitivity and inreased systemi inflammation. We suggest that etopi fat aumulation per se (as ours in NAFLD in addition to viseral fat aumulation) and the proinflammatory state are key to the development of MetS. The pathophysiologial effets that result as linial disease are diverse (eg, type 2 diabetes, NAFLD, PCOS, CVD), and their phenotypi presentation depends on the relative extent to whih eah of the person s ues, either developmental and geneti or environment, influene the metaboli apaity of key tissues ontributing to the onset of MetS in later life. Regardless of its variable presentation, and the ongoing debate on the validity of dihotomous thresholds on ontinuous variables, the MetS is a simple diagnosti tool. It has important use for the liniian and an emphasise the need to provide lifestyle advie to the patient. Moreover, identifiation of individual MetS features that are below the threshold for individual pharmaologial treatment indiates the need to estimate ardiovasular risk, and highlights the need for speifi treatment suh as statins to derease ardiovasular risk. The reent JUPITER trial has shown that statin treatment dereases the inidene of major ardiovasular events in people with normal LDLholesterol onentration and a marker of inflammation (inreased CRP onentrations) 98 that is often present in MetS. However, in the follow-up period, an inrease in physiian-reported inident diabetes was observed. Although there was no differene in median fasting plasma gluose in the rosuvastatin and plaebo arms of the study, there was a 0.1% inrease in HbA1 in the rosuvastatin arm of the study versus the plaebo. Although the ardiovasular benefits of statin treatment most likely outweigh the marginal adverse effets on gluose metabolism in these patients, the data suggest the need for routine monitoring of gluose onentrations in statintreated patients with MetS. We suggest that identifiation of MetS in suseptible people may prompt the early diagnosis of other previously undeteted MetS omponents suh as NAFLD and PCOS, ultimately to the benefit of the patient. MULTIPLE CHOICE QUESTIONS (TRUE (T) OR FALSE (F); ANSWERS AFTER THE REFERENCES) 1. Simple ATPIII and IDF riteria for identifying metaboli syndrome utilise the following measurements: A. age B. sex C. smoking status D. plasma triaylglyerols E. blood pressure 2. Metaboli syndrome is assoiated with inreased risk of: A. type 1 diabetes B. type 2 diabetes C. ishaemi heart disease D. erebrovasular disease E. foot ulers 3. Metaboli syndrome is assoiated with inreased fat in the following sites: A. liver B. abdomen C. hips D. bone E. lungs 4. Etopi fat is assoiated with: A. anti-inflammatory state B. proinflammatory state C. release of anti-inflammatory ytokines D. release of proinflammatory ytokines E. release of proinflammatory adipoytokines Review 5. A predisposition to the development is thought to be due to: A. exposure to a balaned diet during development B. exposure to a poor diet during development C. geneti fators D. lifestyle fators E. all of the above Aknowledgements: We thank Luinda England for help with the manusript. We also aknowledge the BBSRC (grant ode BB/DOD/163311) for supporting the researh undertaken by our group that is ited in this review. Funding: BBSRC. Competing interests: None. Provenane and peer review: Commissioned; externally peer reviewed. REFERENCES 1. Reaven GM. Banting leture Role of insulin resistane in human disease. Diabetes 1988;37: Grundy SM. Metaboli syndrome: therapeuti onsiderations. Handb Exp Pharmaol 2005;(170): Ferrannini E. Metaboli syndrome: a solution in searh of a problem. 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