Obesity-Initiated Metabolic Syndrome and the Kidney: A Recipe for Chronic Kidney Disease?
Susan P. Bagby
Division of Nephrology & Hypertension, Department of Medicine; OHSU Heart Research Center; Department of Physiology & Pharmacology; Oregon Health & Science University, Portland, Oregon
Correspondence to Dr. Susan P. Bagby, Departments of Medicine and Physiology/Pharmacology, Division of Nephrology & Hypertension, Oregon Health & Sciences University, 3314 SW US Veterans Hospital Road (PP262), Portland, OE 97239-2940. Phone: 503-494-8490; Fax: 503-494-5330; E-mail: bagbys{at}ohsu.edu
Metabolic syndrome, originally described in 1988 as "syndromeX" by Reaven et al. (1), has evolved in our collective thinkingfrom a vague association of common chronic disease states toa formally defined cluster of clinical traits with adverse impacton cardiovascular risk (2). The cause is incompletely understoodbut represents a complex interaction among genetic, environmental,and metabolic factors, clearly including diet (3,4) and levelof physical activity (4,5). These abnormalities are mediatedby—and interconnected by—complex pathways that affectenergy homeostasis at cellular, organ, and whole-body levels.This review focuses on obesity-initiated metabolic syndrome,first to provide a pathogenetic overview of extrarenal metabolicderangements; second to consider predisposing conditions shapedby genetic or environmental factors, including growth constraintsin utero; and finally to consider the impact of metabolic syndromeon the kidney in its prediabetic phase. The pathogenesis ofhypertension in the context of metabolic syndrome is consideredseparately in this series. Similarly, central nervous systempathways that contribute to disordered energy homeostasis isaddressed in detail by others. The mechanisms of irreversiblerenal injury from hypertension and overt diabetes are well documentedand are beyond the scope of this review; nonetheless, they loomlarge in the long-term renal future of the patient with metabolicsyndrome. The current worldwide epidemic of obesity-initiatedmetabolic syndrome, with its potential for renal damage, mandatesour commitment to early renal protection in the obese and tovigorous prevention of obesity in both pediatric and adult populations.
The Adult Treatment Panel III (ATPIII) of the National CholesterolEducation Program (NCEP) (2) defines metabolic syndrome clinicallyas any three of the following five traits (Table 1): abdominalobesity, impaired fasting glucose (reflecting insulin resistance),hypertension, hypertriglyceridemia, and low HDL cholesterol.In addition, the NCEP ATPIII recognizes prothrombotic and proinflammatorystates as characteristic of metabolic syndrome (2). Importantly,as subsequent paragraphs detail, these simple clinical criteriafor diagnosis belie the emerging complexity of the underlyingmetabolic derangements (6). Thus, insulin resistance is viewedas the essential common denominator of metabolic syndrome, regardlessof cause. Abdominal obesity, now identified solely by waistcircumference criteria (Table 1), is the single most commoncause of insulin resistance, and key mechanisms that mediatethis pathway are becoming clear (6). Hypertension [defined inthis high-risk context as 130/85 (2)] and the typical patternof atherogenic dyslipidemia—hypertriglyceridemia, lowHDL cholesterol, and increase in small dense LDL particles (2)—arealso likely downstream consequences of insulin resistance withidentifiable contributions from specific organs. Clinical criteriaalso do not emphasize the role of disordered skeletal musclemetabolism in this syndrome or highlight for the clinician thetherapeutic power of regular exercise to offset insulin resistance.Finally, concepts now evolving from research advances suggestthat the current clinical definition identifies individualsat a relatively advanced stage, well beyond onset of irreversibleorgan/tissue injury. Consequently, one immediate research challengeis to define, in the temporal evolution of metabolic syndrome,where interventions can both reverse metabolic derangementsand prevent the tissue damage that conveys long-term risk.
On the basis of the Third National Health and Nutrition ExaminationSurvey (NHANES III; 1988 to 1994), the prevalence of metabolicsyndrome in the U.S. population 20 yr of age is 23.7% (7), risingto >40% in those 60 yr of age and in those from specificgeographic regions (e.g., south Texas) (8). This compares witha 30.5% prevalence of obesity (body mass index [BMI] 30) anda 64.5% prevalence of overweight (BMI 25) in the NHANES IIIU.S. population sample, reflecting marked increases of 7 to10%, respectively, in the previous decade (9). Among non-U.S.populations, prevalence ranges from 49.4% of 1625 hypertensiveindividuals in Spain (10), 19.8% in Greece (11), and 17.8% inolder Italians (12). The last cohort exhibited a stepwise increasein insulin resistance severity (by Homeostasis Model Assessment)with increasing numbers of metabolic syndrome features (12).Importantly, overt metabolic syndrome is not limited to adults(13). Cruz et al. (14) examined 126 overweight Hispanic childrenwho were aged 8 to 13 and had a family history of type 2 diabetes;62% exhibited abdominal obesity, and 30% met criteria for metabolicsyndrome. As in adults, obesity in the pediatric populationis increasing, with Hispanic and non-Hispanic black adolescentsat greatest risk (15).
The 2002 NCEP ATPIII panel rated metabolic syndrome equivalentto cigarette smoking in magnitude of risk for premature coronaryheart disease (2). In epidemiologic studies, metabolic syndromeincreases risk of developing overt diabetes (16), cardiovasculardisease (17,18), and cardiovascular mortality (17). In a prospectiveFinnish cohort, both NCEP ATPIII and World Health Organizationcriteria for defining metabolic syndrome predicted a five- toninefold increase in risk of new diabetes over 4 yr (16). Lakkaet al. (17), in a cohort of 1209 disease-free Finnish men whowere aged 42 to 60 yr and followed for >11 yr, found thatthe presence of metabolic syndrome conferred a three- to fourfoldincreased risk for death from coronary heart disease. UsingNHANES III data, Ninomiya et al. (7) described an approximatelytwofold increase in myocardial infarction and stroke risk inthe presence of metabolic syndrome.
Pathogenesis of Obesity-Initiated Metabolic Syndrome
The NCEP panel identifies the root causes of metabolic syndromeas overweight/obesity, physical inactivity, and genetic factors(2). Unraveling underlying mechanisms has been complicated bythe unique multiorgan complexity of this trait cluster. Fundamentally,the metabolic syndrome reflects disordered energy homeostasis.Just as evolution prepared us well for surviving hypotensionbut poorly for combating hypertension, it has apparently equippedus for surviving the fast but not the feast. Unger (19,20) describedmetabolic syndrome as "a failure of the system of intracellularlipid homeostasis which prevents lipotoxicity in organs of overnourishedindividuals," a system that normally acts "by confining thelipid overload to cells specifically designed to store largequantities of surplus calories, the white adipocytes." Centralto the breakdown of this system are (1) exogenous fuel overload,(2) ectopic accumulation of lipid in nonadipose cells (21),and (3) insulin resistance (3,16).
To summarize concepts to be detailed below, the evolution ofmetabolic syndrome seems to proceed not as a linear sequenceof events but along a matrix of interconnected pathways thatmediate interactions among multiple organs and also link theseorgans as a functional unit to regulate total-body energy homeostasis(Figure 1). Each organ/cell type is typically both a targetand an effector within this matrix. Furthermore, disturbancewithin this matrix of pathways can be initiated by stimuli actingat any one of multiple sites in the matrix (e.g., in adipocytes,in hepatocytes, in skeletal myocytes), each independently capableof disturbing whole-body fuel homeostasis. However, initiationof metabolic syndrome by obesity, in keeping with the now-recognizedrole of adipose tissue as an endocrine organ, is characterizedby powerful systemic stimuli that together impair energy homeostasisin multiple organs simultaneously, leaving no room for protectivecompensation. This multiplicity of pathways and targets likelyexplains the efficacy of obesity as the major generator of metabolicsyndrome.
Figure 1. Pathogenesis of obesity-initiated metabolic syndrome. Increased abdominal fat mass yields high circulating free fatty acids (FFA), which drives increased cellular FFA uptake. Reduced release of adiponectin from expanding abdominal white adipose tissue (WAT) reduces mitochondrial FA uptake/oxidation in multiple tissues. Despite increased release of leptin from WAT, which normally also enhances FA oxidation, tissue resistance to leptin further promotes cytosolic FA build-up. As a result, excess intracellular FA and its metabolites (fatty acyl CoA, diacylglyceride) accumulate, causing insulin resistance (see pathway, Figure 2). Organ-specific consequences include increased hepatic gluconeogenesis and reduced skeletal muscle glucose uptake; the latter raises plasma glucose content and stimulates pancreatic insulin release, and hyperinsulinemia ensues. The newly available glucose plus high insulin now comes back full circle to stimulate further WAT lipogenesis. Increasing fat cell size induces release of chemotactic molecules (e.g., monocyte chemoattractant protein-1) with macrophage infiltration plus TNF- and IL-6 generation. These cytokines generate an inflammatory reaction and enhance adipocyte insulin resistance in WAT.
Figure 2. Intracellular pathways of insulin resistance. Accumulation of FA and its metabolites (fatty acyl CoA and diacylglycerol) induce protein kinase C isoforms, leading to serine/threonine phosphorylation of insulin receptor substrate-1 (IRS-1) on serine 302. This renders the IRS-1 resistant to tyrosine phosphorylation by the activated insulin receptor. As a result, downstream effects of insulin receptor activation—Akt activation and translocation of the glucose transporter Glut 4 to the plasma membrane—is reduced. Glucose uptake is thereby diminished, secondarily decreasing both glucose-derived glycogen synthesis and glucose-dependent lipogenesis. Activation of the JNK pathway by elevated cytoplasmic FA may provide an additional pathway for induction of insulin resistance. Adapted from reference 52.
Generation of Obesity-Associated Metabolic Syndrome: Reversible Derangements of the Metabolic Matrix
Obesity-initiated metabolic syndrome is consistently associatedwith specific metabolic abnormalities: high circulating freefatty acids (FFA) (22); increased intracellular lipid contentof not only white adipose tissue (WAT) but also hepatocytes,skeletal myocytes, pancreatic cells, cardiomyocytes, gastrointestinalenterocytes, and vascular endothelial cells (23,24); insulinresistance in (at least) the same list of tissues; and reducedfunctional activity of two insulin-sensitizing adipokines thatpromote tissue fuel oxidation, adiponectin (25–27), andleptin (27). As abdominal fat expands, adiponectin is progressivelyreduced (25) while leptin levels are progressively elevated(28), the latter reflecting tissue leptin resistance (20,29).Although not yet included in formal clinical definitions, additionalfeatures are increasingly considered integral to obesity-initiatedmetabolic syndrome: macrocytic infiltration of WAT (30,31),increase in local and circulating inflammatory markers [C-reactiveprotein (32), TNF- (33), plasminogen activator inhibitor-1 (34,35),and IL-6 (36)] and hyperhomocysteinemia (37). How do we integratethese diverse elements into a coherent process that permitsrational clinical interventions? New data suggest that excessvisceral fat mass alone is sufficient to generate all elementsof the metabolic syndrome.
Role of Abdominal Obesity
Most studies support the view that the metabolic syndrome thatnow confronts U.S. physicians in epidemic proportions is largelyinitiated by abdominal obesity. The four most crucial elementsthat link abdominal obesity to other features of the metabolicsyndrome seem to be elevated FFA, reduction in circulating insulin-sensitizingadiponectin, peripheral-tissue resistance to the insulin-sensitizingactions of leptin, and enhanced macrophage infiltration in fattissue with release of proinflammatory cytokines (Figure 1).Abdominal fat is unique in its metabolic features as comparedwith peripheral fat depots, exhibiting larger adipocytes thatcontain more triglyceride (TG) and exhibit greater insulin resistancethan smaller adipocytes. Adipocyte resistance to the lipogeniceffect of insulin yields higher basal rates of lipolysis withincreased release of FFA into the portal venous system. Thisdirect access to the liver (see below) may also contribute tothe unique impact of visceral fat on energy homeostasis. Abdominalfat may also secrete less leptin than subcutaneous fat. ThusCnop et al. (28), comparing lean-insulin resistant, lean insulin-sensitive,and obese insulin-resistant adults, found that leptin levelscorrelated with increasing subcutaneous—but not visceral—fatmass, proposing yet another metabolic distinction between thesetwo compartments. Abdominal fat mass expansion is also coupledwith reciprocally reduced release of adiponectin, a multifunctionalcollagen-like molecule with potent capacity to stimulate fueloxidation in peripheral tissues (25). Abdominal fat additionallyexpresses higher levels of renin-angiotensin system components:increased angiotensinogen and increased angiotensin II (AngII) AT1 receptors (38). Finally, epidemiologic studies confirmthe unique significance of abdominal fat mass in predictingmicroalbuminuria, diabetes, and overall cardiovascular risk(39). It was this compelling evidence for a unique role of centralor visceral obesity—in contradistinction to subcutaneousobesity—that prompted the NCEP ATPIII decision to specifyabdominal obesity in the clinical definition of metabolic syndrome.
These phenomena originating in abdominal adipose tissue generatethe clinical picture that we recognize as metabolic syndrome.The roles of FFA excess and adiponectin deficiency are reviewedbelow in the context of their actions in individual organs;the role of leptin is addressed subsequently to compare andintegrate prevailing views of how insulin resistance evolves.
Under conditions of normal energy homeostasis, the liver servesas a short-term energy reservoir, taking up absorbed dietaryglucose and FFA, synthesizing/storing glycogen, synthesizing/storingTG, and packaging TG into VLDL. During fasting, the liver mustsustain a continuous supply of plasma glucose, acutely by glycogenolysisand later in the fasting period by gluconeogenesis. SecretedVLDL provides ongoing TG and ultimately FA fuel to skeletalmuscle, heart, and other peripheral tissues via lipoproteinlipase activity in the vascular space.
Effect of Excess FFA on Liver
Intracellular FFA content is a function of substrate deliveryfrom the plasma and FFA utilization (efflux into mitochondriafor oxidation or cytosolic synthesis of intracellular lipids).With abdominal obesity, the increased FFA released into theportal vein from excess visceral fat lipolysis have direct accessto the liver. Because cellular FA uptake is substrate dependent,increased hepatocyte FFA uptake ensues (23). Elevated cytoplasmicFA content leads to hepatic insulin resistance. This processinvolves competition of FA and glucose for access to mitochondrialoxidative metabolism. The molecular mechanism was recently describedby Shulman et al. (40,41) (Figure 2), wherein elevated intracellularfatty acyl CoA activates protein kinase C (PKC), causing phosphorylationof serine-302 of insulin receptor substrate-1 (IRS-1). Thisrenders IRS-1 unavailable for tyrosine phosphorylation by theactivated insulin receptor and reduces all downstream actionsof insulin. As a result, the fasting state is simulated andhepatocyte enzymatic machinery is shifted to favor enhancedhepatic gluconeogenesis at the expense of glycogen synthesis.The consequent increase in liver-derived glucose in plasma leadsto hyperinsulinemia, a hallmark of metabolic syndrome in itsearliest stage and a marker of insulin resistance.
The capacity of the insulin-resistant liver to impair secondarilysystemic energy homeostasis is illustrated by transgenic studiesintroducing an insulin-resistant form of the rate-limiting enzymeof liver gluconeogenesis: phosphoenolpyruvate carboxykinase(42). Creating isolated hepatic insulin resistance led to systemichyperglycemia, hyperinsulinemia, and a moderate increase infat mass (42). The last reflects WAT utilization of surpluscirculating glucose for insulin-induced lipogenesis. In effect,this represents a redistribution of fuel away from the liverto adipose fat stores. These findings emphasize the potentialfor activating the abnormal metabolic matrix simply by inducinghepatic insulin resistance and also illustrate the dual roleof the liver as target and effector in metabolic syndrome derangements.In dogs that were fed an isocaloric moderate-fat diet, strikingvisceral obesity was associated with marked reduction in theability of insulin to suppress hepatic gluconeogenesis, evenbefore any reduction in insulin-stimulated glucose uptake appeared;investigators concluded that hepatic insulin resistance playsa dominant role in the pathophysiologic cascade initiated byabdominal obesity (43).
FFA overload also provides substrate for increased hepatic TGsynthesis and for TG-rich VLDL assembly and secretion. Althoughdetails are beyond the scope of this review, the peripheralmetabolism of these VLDL generate a small, dense form of highlyatherogenic LDL [reviewed by Avramoglu et al. (44)] along withan increase in plasma TG. In addition, increased hepatic lipaseactivity in the insulin-resistant state reduces levels of protectiveHDL-2 cholesterol (45), which is essential to the transportof cholesterol from tissues back to the liver. Thus, hepaticinsulin resistance, high plasma TG, and low plasma HDL are pathogeneticallylinked manifestations of altered lipid regulation in metabolicsyndrome.
Effect of Adiponectin Deficiency on Liver
In addition to the effects of elevated FFA load, the energy-relatedfunctions of the liver are profoundly affected by the reducedcirculating levels of the adipokine adiponectin. The actionsof this multifunctional protein are organ specific and uniformlyinsulin sensitizing. Adiponectin normally promotes insulin sensitivityin liver in part by enhancing FA oxidation (46); this reducesaccumulation of cytoplasmic FA, thereby reducing intracellularFA levels and enhancing insulin action via IRS-1 availabilityto the insulin receptor. Second, like insulin, adiponectin normallysuppresses hepatic gluconeogenic enzymes and induces glycogeneticenzymes. Increase in 5'-AMP-activated kinase mediates theseeffects of adiponectin (46,47). Conversely, deficiency of adiponectinin states of abdominal obesity directly contributes to insulinresistance by further enhancing accumulation of intracellularFA and FA metabolites and by stimulating hepatic glucose output.The impact of insulin-sensitizing adipokines is apparent fromtransgenic mouse models that completely lack fat (and thus bothadiponectin and leptin) (48). Animals are insulin resistant;the provision of physiologic levels of both adiponectin andleptin fully restores normal energy homeostasis, whereas eitheralone is only partially effective (48). These studies underscorethe regulatory role of fat-derived adipokines and lend logicto the seeming paradox that either too little or too much adiposetissue can lead to insulin resistance (21).
Increased circulating FFA also have an impact on skeletal muscleenergy homeostasis. Skeletal muscle is normally a major siteof glucose and FA uptake, accounting for the bulk of total-bodyglucose utilization and deriving 60% of resting energy fromFA. As in the hepatocyte, increase in intramyocellular FA inskeletal muscle has been shown to impair insulin receptor signalingby PKC-dependent serine phosphorylation of IRS-1; this leadsto reduced IRS-1 availability for tyrosine phosphorylation,reducing Glut 4 translocation to the myocyte plasma membranewith consequent reduction in glucose uptake (6). Secondarily,glucose-driven lipogenesis and glycogen synthesis in skeletalmyocytes are also reduced. Accordingly, elevated circulatingFFA contribute to insulin resistance in both liver and skeletalmuscle.
As in the hepatocyte, reduced adiponectin secretion secondaryto increased visceral fat mass augments insulin resistance inskeletal muscle, also in part via reducing FA oxidation rate,further increasing intramyocellular FA content and impairinginsulin action (48). Using magnetic resonance spectroscopy ininsulin-resistant offspring of patients with type 2 diabetes,Petersen et al. (49) found evidence of a 30% reduction in mitochondrialoxidative phosphorylation together with impaired muscle FA oxidationand an 80% increase in intramyocellular lipid content. Overtdiabetes has also been associated with impaired muscle oxidativecapacity (50,51). Finally, the insulin resistance of aging isassociated with impaired mitochondrial FA oxidative capacityin skeletal muscle (52).
Impaired energy production is a particularly important consequenceof insulin resistance in skeletal muscle. Diabetic and prediabeticpatients have impaired maximal exercise capacity, reduced maximaloxygen consumption, and slower oxygen uptake at initiation oflow-level exercise, potentially contributing to the fatigueand reduced physical activity typical of obesity/insulin resistance(53). Exercise stimulates skeletal muscle oxidative enzymesand activates mitochondrial biogenesis (54). Inactivity wouldbe predicted to reduce basal metabolic rate both by reducingmuscle mass and by augmenting defective muscle energy production.The practical physical consequences of these skeletal musclemetabolic abnormalities have not yet been widely studied inmetabolic syndrome but are likely to reinforce the vicious cycleof ongoing weight gain and sedentary lifestyle.
The pancreas is the ultimate arbiter of insulin availability,determining the point at which overt diabetes will occur. Earlyin the course of metabolic syndrome, hepatic gluconeogenesisstimulates the pancreas to hypersecrete insulin, yielding normoglycemichyperinsulinemia. Increased FFA uptake by pancreatic cells alsoincreases glucose-induced insulin secretion and modifies expressionof peroxisome proliferator–activated receptor- (PPAR-),glucokinase, and Glut 2 transporter (23). In the spontaneouslyobese captive rhesus monkey, hyperinsulinemia is sustained andprogressively increases, eventually falling as overt hyperglycemiaappears (55). Once hyperglycemia ensues, insulin-secreting cells become targets of glucotoxicity: reduction in insulin-stimulatedinsulin secretion, late increase in mitochondrial free-radicalproduction, and lipid overload–induced apoptosis (lipotoxicity;see also below) with progressive loss of cell mass (56–58).Adverse effects of hyperinsulinemia per se on organ structureand function in the prehyperglycemic phase of metabolic syndromeare not well defined but are relevant to establishing optimumtiming of intervention. It is worthy of emphasis that lifestyleinterventions that reduce hyperglycemia can markedly decreaseprogression to overt diabetes (59).
Available evidence indicates that the insulin-receptor signalingpathway mediating glucose uptake in vascular endothelium requiresstimulation of endothelial nitric oxide (NO) synthase and NOproduction (60), a potent vasodilatory and antithrombotic stimulus.Comparable endothelial responses—enhanced NO productionwith vasodilation—are induced by adiponectin (61). Theseactions mediate a hemodynamic component of energy distribution,enhancing tissue blood flow to optimize nutrient delivery. Wheninsulin resistance ensues, insulin-induced NO production isconcomitantly impaired, representing one of several mechanismslinking abdominal obesity/insulin resistance and hypertension.Implications of endothelial dysfunction for hypertension inmetabolic syndrome are addressed in detail by Dr. Sowers elsewherein this issue.
In addition to FFA excess and adiponectin deficiency, functionalleptin deficiency in peripheral tissues is believed to playa significant role in the evolution of obesity-initiated insulinresistance. Leptin is secreted in proportion to body fat massand, under normal circumstances, signals via central nervoussystem receptors to attenuate appetite and to enhance sympatheticoutflow, the latter stimulating energy utilization and thermogenesis.Increase in fat-derived plasma leptin seen with abdominal obesitystates is paradoxically coupled with poorly understood leptinresistance to central appetite-suppressing and to peripheralinsulin-sensitizing effects of leptin (see below), thus a functionalleptin deficiency. Central pathways of adipocytokines are addressedseparately in this series. Unger and colleagues (62) proposed,on the basis of compelling experimental evidence, that peripheral-tissueleptin resistance is a crucial factor leading to insulin resistancein metabolic syndrome (19). They contended that leptin’smajor role in normal energy homeostasis is not prevention ofobesity, as originally conceived, but rather protection of nonadipocytesagainst the cytotoxicity of intracellular lipid overload duringperiods of nutrient excess (21,24). Leptin potently activatescellular fuel consumption by stimulating FA oxidation, reducinglipogenesis, enhancing glucose entry and metabolism, and dramaticallyshrinking fat stores in adipose tissue (63) as well as in muscleand liver cells (24). Accumulation of cytoplasmic FA thus couldreflect functional leptin deficiency acting via impaired mitochondrialoxidative capacity and concomitantly enhanced lipogenesis. Theensuing insulin resistance could be viewed as a compensatorycytoprotective response to prevent further accumulation of intracellularlipid, i.e., reduced glucose entry attenuates glucose-derivedlipogenesis (21). The mechanisms of peripheral resistance tothe fuel-burning actions of leptin are not yet known. In reality,excess FFA in the circulation, leptin resistance, and adiponectindeficiency are likely acting in concert to generate intracellularFA excess, although their precise sequence and relative importanceremain to be determined. The biochemical pathways involved inthese intracellular processes have been reviewed in detail byUnger (19,21), Petersen and Shulman (64), and Shulman (6). Thecrucial participation of PPAR-, -, and - in mediating tissue-specificactions of adiponectin and leptin—and their alterationsin metabolic syndrome—are addressed separately in thisseries.
Although excess abdominal fat serves to initiate dysfunctionalenergy homeostasis in multiple other organs, it eventually becomesalso a target tissue. It is first a target of excess glucosein the vascular space. Increased glucose availability from liver-basedgluconeogenesis and from muscle-based reduction in glucose uptake,together with pancreas-dependent hyperinsulinemia, promote lipogenesisin WAT (42) (Figure 1). This poses the disturbing possibilitythat abdominal obesity creates a self-perpetuating cycle.
Excess cortisol activity is known to shift fat from peripheral(gluteal and subcutaneous) to central visceral depots and tomimic many aspects of metabolic syndrome. It thus is not surprisingthat glucocorticoid excess has been suspected in the cause ofmetabolic syndrome. Recently, increased activity (65) and atwofold increased expression of 11 hydroxy steroid dehydrogenase1 (11HSD1) in adipose tissue of nondiabetic centrally obesewomen (66) were reported. This enzyme acts predominantly toconvert inactive cortisone to the active cortisol form, thusgenerating glucocorticoid at a tissue level. Expression levelsof 11HSD1 were directly proportional to waist circumferenceand insulin resistance (66). Supporting the relevance of locallygenerated glucocorticoid in WAT, transgenic mice overexpressing11HSD1 in adipocytes faithfully reproduced the metabolic syndrome(67,68), whereas deficient mice were metabolically resistantto high-fat feeding (69). Once again, a change confined to fattissue induces systemic metabolic dysregulation.
Expanding WAT also becomes the primary target of an inflammatoryprocess. Recent studies in mice and human adipose tissue elegantlydocumented this process and implicated the role of macrophageinfiltration and macrophage-derived inflammatory mediators inobesity and metabolic syndrome (30,31). Weisberg et al. (31)demonstrated that increasing body mass and increasing fat-cellvolume (i.e., fat content) each correlates linearly with bonemarrow–derived macrophage infiltration in WAT and linearlywith increased expression of macrophage-linked proinflammatorygenes (Figure 3). Xu et al. (30) similarly found that upregulatedgenes in WAT of obese mouse models were primarily inflammatorygenes linked to macrophage infiltration/activation; furthermore,in diet-induced obesity, this inflammatory process within WATpreceded insulin resistance. TNF- and IL-6 have been shown toinduce insulin resistance in vitro and to contribute to insulinresistance in mouse models of obesity (36,70). This in situinflammatory reaction within WAT therefore may induce/augmentinsulin resistance in the adipocytes per se, coming full circlein generation of multiorgan energy dysregulation.
Figure 3. Macrocyte infiltration in WAT correlates linearly with body mass index and adipocyte size/fat content (31). In human subcutaneous adipose tissues obtained from individuals with widely ranging body mass index (BMI), density of macrophage infiltration (measured by PCR quantification of CD68 mRNA, a specific macrophage marker) correlated linearly with BMI (a) and with average adipocyte cross-sectional area, an index of cell fat content (b). Squares and diamonds represent female and male subjects, respectively. (c and d) Representative photomicrographs of adipose tissue biopsies from obese (BMI 50.8 kg/m2; c) and lean (BMI 25.7 kg/m2; d) female subjects show the larger adipocyte area in obesity; arrows indicate F4/80+/bone marrow–derived macrophages. In studies in agouti (Ay) and obese (Lepob) mice and in humans, adipose tissue macrophages accounted for virtually all of adipose TNF-, inducible nitric oxide synthase, and IL-6 expression (31), cytokines implicated in locally enhancing insulin resistance in WAT (Reproduced by permission from Weisberg SP, et al., J Clin Invest 112: 1796-1808, 2003).
Predisposition to Obesity-Initiated Metabolic Syndrome
A number of factors influence risk for development of obesity-initiatedmetabolic syndrome. The increasing risk with age (4,71) parallelsthe declining muscle mass and muscle oxidative capacity of aging(52). Hormonal changes with aging are also involved: the compensatoryincrease in T3-mediated thermogenesis induced by dietary fatin young rats is lost with aging (72). Lifestyle factors aresimilarly influential. In cohorts followed prospectively, regularphysical activity and adherence to the Mediterranean diet significantlyreduced risk (10). In the Framingham Offspring Cohort, dietswith low glycemic index and high whole-grain attributes alsodecreased risk of developing metabolic syndrome (3). In additionto demographic and lifestyle modulators, recent interest hasfocused on two mechanisms of predisposition operative earlyin life: environmental "programming" by adverse events operativeduring early growth and development and genetic factors. Bothcan permanently modify postnatal organ functional capacity,permanently alter gene expression patterns and homeostatic setpoints,and also exhibit maternal transmission across generations (73,74);as a result, the distinction between classic genetic inheritanceand environmentally programmed effects can no longer rely solelyon maternal phenotype.
Asymmetric Intrauterine Growth Restriction Produces the "Thrifty Phenotype"
Epidemiologic studies over the past 15 yr have uncovered a consistentrelationship between low birth weight and increased risk fordeveloping adult metabolic syndrome (75), a phenomenon now knownas developmental "programming." For example, in the HertfordshireStudy, prevalence of metabolic syndrome according to birth weightfell stepwise from 30% of subjects who were 5.5 lb to 6% ofthose who were 9.5 lb (76). A key feature that conveys riskin programming is not low birth weight per se but rather a formof asymmetric growth restriction wherein weight is disproportionatelyimpaired relative to height, and sizes of kidney, liver, pancreas,and skeletal muscle are disproportionately reduced relativeto heart and brain (77,78). When asymmetrically growth-restrictedinfants encounter nutrient abundance postnatally, there is spontaneous"compensatory" or "catch-up" growth such that body weight increaseis accelerated and crosses percentiles during childhood (79,80).In a rat model of global maternal calorie restriction, offspringthat were weaned to normal diets postnatally were permanentlyhyperphagic, hyperinsulinemic, and hyperleptinemic; exhibitedcatch-up growth; and developed increase in central fat massand hypertension as adults; all features were exaggerated bya highly palatable "cafeteria" diet (81). Human epidemiologicstudies based on large longitudinal databases from diverse countriesnow demonstrate that rapid compensatory growth in childhoodis a significant enhancer of adult cardiovascular disease riskin offspring with intrauterine growth restriction (IUGR), specificallyincluding central obesity (76,82,83), diabetes (84–86),hypertension (87,88), and coronary disease (79,80). Specificpatterns of postnatal growth after IUGR influence the magnitudeof risk for specific elements of the metabolic syndrome. Thus,in a South African cohort, low-birth-weight children who wereexposed to nutrient abundance and catch-up growth exhibitedincreased propensity for fat more than lean mass depositionand increased risk of obesity and insulin resistance by age7 as compared with those who did not undergo catch-up growth(89). In a Finnish cohort that contained extensive longitudinalgrowth data in childhood, the subset of individuals who subsequentlydeveloped hypertension as adults exhibited a distinct patternof childhood growth: low birth weight followed by an exaggeratedgrowth rate in weight greater than height to attain increasedBMI levels by 12 yr (88) (Figure 4). When the population wassubdivided, children who were destined to develop only hypertensionexhibited exaggerated growth to attain average-for-age BMI byage 7, which remained constant thereafter; children who weredestined to develop both hypertension and diabetes as adultsexhibited a similar pattern between birth and age 7 but differedby continuing rapid growth between 7 and 15 yr of age to reachexcess BMI (87). Thus, early growth restriction in an asymmetricpattern leads to "programmed" increase in appetite, excess foodintake when available, exaggerated childhood "catch-up" growthwith a propensity for accruing fat more than lean body mass,and preferential deposition of abdominal more than peripheralfat (89,90). Hales (91) termed this constellation of traitsthe "thrifty phenotype."
Figure 4. Pattern of infant and childhood growth in children who developed hypertension as adults. Growth rates are expressed as SD units (z scores) from the overall population average (set at zero). The 1404 of 8760 children who subsequently required antihypertensive medications as adults exhibited low birth weight and low birth BMI but exaggerated growth in weight and BMI between 5 and 12 yr of age. (Reproduced by permission from Barker DJ, et al., J Hypertens 20: 1951-1956, 2002).
Asymmetric IUGR Permanently Impairs Organ Structure and Maximal Functional Capacity
Another consequence of IUGR that predisposes to metabolic syndromederives from unique developmental patterns of kidney, pancreas,and muscle in utero and their impact postnatally when structurallyimpaired at critical windows of development. Because each organdevelops its respective functional units before birth, no additionalunits can form postnatally; maximal organ capacity thus is fixedat birth. Fetal undernutrition, depending on the developmentalperiod of exposure, can lead to permanently reduced nephronnumber (78,92–95), permanently reduced pancreatic insulin-secreting cells (96–98), and permanently reduced skeletal musclefiber number (99,100) and mitochondrial mass (101). Followingthe original hypothesis of Brenner and Chertow (92), Erikssonet al. (88) proposed for kidney—and others for pancreas(98)—that postnatal increase in body size beyond the birthweight percentile will impose metabolic and excretory demandsthat exceed organ capacities. These structurally based functionallimits in key organs after IUGR would be expected to predisposeto metabolic syndrome derangements at multiple sites simultaneously.In the face of abundant nutrients, the thrifty phenotype generatesbody size excess relative to organ capacity, deposits excessabdominal fat, and promotes abdominal obesity. Reduced pancreaticinsulin secretory mass/capacity may hasten transition from hyperinsulinemiato overt diabetes. Lower muscle mass—which persists inadults who experienced IUGR (102)—could promote obesityvia low basal metabolic rate and biologically based inactivity;the reduced skeletal muscle oxidative capacity and smaller mitochondriadescribed in offspring with IUGR (101) could increase susceptibilityto insulin resistance by favoring accumulation of intramyocellularFFA. From the renal perspective, Lackland et al. (103), comparing1230 young ESRD subjects (70% caused by diabetes or hypertension)with 2460 matched control subjects in South Carolina, showedthat low birth weight increased relative risk of early-onsetESRD.
Studies in a Microswine Model of IUGR: Reduced Nephron Number, Intrarenal Ang II Excess, and Hypertension in Adult Offspring
Our investigative group has pursued the hypothesis that exaggeratedpostnatal increase in body mass in the face of developmentallyfixed nephron deficit would favor nephron adaptations of hypertrophyand hyperfiltration and increase in glomerular capillary pressureindependent of obesity. That is, two independent consequencesof IUGR—nephron deficit and thrifty-phenotype traits—interactto create imbalance between metabolic/excretory load and renalexcretory capacity (Figure 5). To test this, we developed amicroswine model of IUGR using maternal protein restrictionduring the window of nephrogenesis (in swine, the last one thirdor gestation plus first 2 wk postnatally). Offspring of low-proteinsows, as compared with control offspring, exhibit a typicalasymmetric pattern of growth restriction, have evidence of 30%reduction in nephron number, undergo 100% catch-up growth ofbody and organ sizes, and develop hypertension as young adults(6 mo) (104). In adults, renal weight and function are normal,but glomerular volume is increased, compatible with nephronhypertrophy and hyperfiltration. Woods et al. (94) reportedsimilar findings in rat offspring of protein-restricted dams.We further proposed that this mismatch of excretory load toexcretory capacity would induce compensatory nephron hyperfiltrationvia activation of the renin/Ang II system. In examining plasmacomponents of renin/Ang II activity (105), we find no differencesamong low-protein versus normal-protein offspring for Ang II,plasma renin activity, or renin substrate concentration. Incontrast, intrarenal Ang II levels are elevated in hypertensiveadult low-protein offspring (106). This pattern of normal renin/AngII status in plasma but activated status intrarenally is reminiscentof that observed in the diabetic kidney (107). In our 6-mo-oldyoung-adult offspring of maternal protein restriction, glomerulomegalyand intrarenal Ang II excess are present in the absence of proteinuria(106). To distinguish between body mass excess and developmentalprogramming of the renin/Ang II system as causes of these changes,we are currently examining whether prevention of catch-up growthby early postnatal caloric restriction modifies the renal adaptations,intrarenal Ang II, and hypertension.
Figure 5. Proposed interaction between thrifty phenotype behaviors and fixed reduction in nephron number after intrauterine growth restriction. Fetal nutrient deprivation of any cause encompassing the last half of pregnancy typically impairs renal development and reduces nephron number. No new nephrons form after birth in humans. Nutrient deprivation also "programs" the fetus to utilize energy more efficiently, optimizing survival. Postnatally, the offspring exhibit hyperphagia on the basis of ad libitum food intake, increased efficiency in utilization of calories, and metabolic changes that reduce maximum capacity for energy consumption (reduced muscle mass, smaller mitochondria). If food is available in the environment, then hyperphagia drives caloric intake to yield rapid compensatory growth in weight more than height, crossing centiles to achieve typically normal BMI. Even in the absence of overt obesity, this now-normal body mass is relatively excessive for the fixed reduction in nephron number. In a microswine model, catch-up growth is associated with intrarenal angiotensin II excess and hypertension in young adults. This may be analogous to the increased risk of hypertension and proteinuria when obesity precedes unilateral nephrectomy.
Developmental Programming of Postnatal Gene Expression
A third way in which IUGR may predispose to metabolic syndromeis fetal programming of gene expression that then persists toimpair postnatal homeostatic functions. In the IUGR that resultsfrom severe maternal diabetes (in contrast to asymmetric macrosomiaof milder maternal diabetes) (108), offspring exhibit reducedinsulin secretion and low insulin receptor density in utero;this persists postnatally to generate insulin resistance anddiabetes. Another important example of permanently altered geneexpression has been described for the hypothalamic-pituitary-adrenalaxis in rats (73). Maternal nutrient restriction has been associatedwith decrease in placental 11OHSD2, which normally functionsto inactivate maternal cortisol and keep fetal cortisol levelsat less than one tenth of maternal levels. Fetal exposure toexcess glucocorticoid permanently reduces adult hippocampalglucocorticoid receptor mRNA and increases adult corticosteronelevels, suggesting a programmed reduction in postnatal sensitivityto cortisol feedback (109).
Programming Can Occur after Birth and Can Be Transmitted to Offspring
Nutritional programming of postnatal homeostasis during periodsof developmental plasticity is not confined to the fetal period.Srinivasan et al. (110) showed metabolic programming in neonatalrats in response to high-carbohydrate versus normal high-fatmilk formula during postnatal days 4 to 24. Adaptations in thehigh-carbohydrate pups included life-long hyperinsulinemia,increased number and size of pancreatic islets, and adult-onsetobesity (110). It is especially noteworthy that the high-carbohydrate-fedfemale rats transmit this phenotype to their progeny (110),much as diabetic mothers transmit risk of diabetes to offspringvia the intrauterine environment (108). Similarly, female IUGRoffspring deliver low birth weight babies (73), another exampleof a transgenerational effect that may confound interpretationof studies in which transmission of maternal traits has beenviewed as "genetic." This transgenerational reach of fetal programming(111,112) is not currently understood but potentially relatesto factors such as developmentally impaired vascularizationof the uterus and/or nutritional effects on a female infant’sdeveloping ova.
In addition to age, demographic factors, and developmental programming,germline transmission of predisposing factors clearly contributesto risk of metabolic syndrome. Furthermore, the array of moleculesand pathways involved in its generation—representing theentire molecular infrastructure of energy metabolism and itsregulation—underscore the many candidate sites. A detailedlisting is beyond the scope of this review. Instead, selectiveexamples highlight major pathophysiologic pathways. Virtuallyall genetic mechanisms described involve interaction with environmentalfactors (e.g., nutrient abundance, sedentary lifestyle) to createmetabolic disease. In the Quebec Family Study, Tremblay et al.(113) described in older children and adolescents a glucocorticoidreceptor polymorphism that predicted twofold increase in visceraladiposity in girls >12 yr (a similar trend in boys was NS).Similarly, abdominal visceral fat was linked with an RFLP atthe glucocorticoid receptor locus (114). As predicted from itsantidiabetic efficacy, human adiponectin mutants have also beenassociated with diabetes: Waki et al. (115) reported two mutantsthat failed to form the high-molecular-weight multimers requiredfor adiponectin secretion from the adipocyte. Genetic predispositionto insulin resistance has also received attention in relationto PPAR-2. A Gly483Ser missense mutation in the PPAR- coactivator1 gene was associated with reduced lipid oxidation, larger abdominaladipocyte size, and higher plasma FFA concentration in PimaIndians and in Danish populations (116). Muller et al. (117)found that a functional variant in the PPAR-2 promoter withreduced transcriptional activity also predicted obesity andinsulin resistance in the high-risk Pima Indian population.A Pro12Ala polymorphism in PPAR-2 also predicted insulin resistancein Pima Indians and in other populations (117). Of special note,the effects of the Pro12Ala polymorphism on lipid metabolismwas apparent only in individuals with low birth weight (118),a fascinating example of an interaction between a classic geneticfactor and early environmental programming.
Renal Injury in Obesity-Initiated Metabolic Syndrome: Epidemiologic Studies
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Introduction
Metabolic Syndrome Defined: A...
130/85 (2)] and the typical pattern of atherogenic dyslipidemia—hypertriglyceridemia, low HDL cholesterol, and increase in small dense LDL particles (2)—are also likely downstream consequences of insulin resistance with identifiable contributions from specific organs. Clinical criteria also do not emphasize the role of disordered skeletal muscle metabolism in this syndrome or highlight for the clinician the therapeutic power of regular exercise to offset insulin resistance. Finally, concepts now evolving from research advances suggest that the current clinical definition identifies individuals at a relatively advanced stage, well beyond onset of irreversible organ/tissue injury. Consequently, one immediate research challenge is to define, in the temporal evolution of metabolic syndrome, where interventions can both reverse metabolic derangements and prevent the tissue damage that conveys long-term risk. 
cells, cardiomyocytes, gastrointestinal enterocytes, and vascular endothelial cells (23,24); insulin resistance in (at least) the same list of tissues; and reduced functional activity of two insulin-sensitizing adipokines that promote tissue fuel oxidation, adiponectin (25–27), and leptin (27). As abdominal fat expands, adiponectin is progressively reduced (25) while leptin levels are progressively elevated (28), the latter reflecting tissue leptin resistance (20,29). Although not yet included in formal clinical definitions, additional features are increasingly considered integral to obesity-initiated metabolic syndrome: macrocytic infiltration of WAT (30,31), increase in local and circulating inflammatory markers [C-reactive protein (32), TNF-
(33), plasminogen activator inhibitor-1 (34,35), and IL-6 (36)] and hyperhomocysteinemia (37). How do we integrate these diverse elements into a coherent process that permits rational clinical interventions? New data suggest that excess visceral fat mass alone is sufficient to generate all elements of the metabolic syndrome. 
(PKC
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in mediating tissue-specific actions of adiponectin and leptin—and their alterations in metabolic syndrome—are addressed separately in this series. 
5.5 lb to 6% of those who were 
30% reduction in nephron number, undergo 100% catch-up growth of body and organ sizes, and develop hypertension as young adults (6 mo) (104). In adults, renal weight and function are normal, but glomerular volume is increased, compatible with nephron hypertrophy and hyperfiltration. Woods et al. (94) reported similar findings in rat offspring of protein-restricted dams. We further proposed that this mismatch of excretory load to excretory capacity would induce compensatory nephron hyperfiltration via activation of the renin/Ang II system. In examining plasma components of renin/Ang II activity (105), we find no differences among low-protein versus normal-protein offspring for Ang II, plasma renin activity, or renin substrate concentration. In contrast, intrarenal Ang II levels are elevated in hypertensive adult low-protein offspring (106). This pattern of normal renin/Ang II status in plasma but activated status intrarenally is reminiscent of that observed in the diabetic kidney (107). In our 6-mo-old young-adult offspring of maternal protein restriction, glomerulomegaly and intrarenal Ang II excess are present in the absence of proteinuria (106). To distinguish between body mass excess and developmental programming of the renin/Ang II system as causes of these changes, we are currently examining whether prevention of catch-up growth by early postnatal caloric restriction modifies the renal adaptations, intrarenal Ang II, and hypertension. 
