J Am Soc Nephrol 15: 2775–2791, 2004

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

Metabolic syndrome, originally described in 1988 as “syn- (Table 1): abdominal obesity, impaired fasting glucose (reflect- drome X” by Reaven et al. (1), has evolved in our collective ing insulin resistance), hypertension, hypertriglyceridemia, and thinking from a vague association of common chronic disease low HDL cholesterol. In addition, the NCEP ATPIII recog- states to a formally defined cluster of clinical traits with ad- nizes prothrombotic and proinflammatory states as character- verse impact on cardiovascular risk (2). The cause is incom- istic of metabolic syndrome (2). Importantly, as subsequent pletely understood but represents a complex interaction among paragraphs detail, these simple clinical criteria for diagnosis genetic, environmental, and metabolic factors, clearly includ- belie the emerging complexity of the underlying metabolic ing diet (3,4) and level of physical activity (4,5). These abnor- derangements (6). Thus, insulin resistance is viewed as the malities are mediated by—and interconnected by—complex essential common denominator of metabolic syndrome, regard- pathways that affect energy homeostasis at cellular, organ, and less of cause. Abdominal obesity, now identified solely by whole-body levels. This review focuses on obesity-initiated waist circumference criteria (Table 1), is the single most com- metabolic syndrome, first to provide a pathogenetic overview mon cause of insulin resistance, and key mechanisms that of extrarenal metabolic derangements; second to consider pre- mediate this pathway are becoming clear (6). Hypertension disposing conditions shaped by genetic or environmental fac- [defined in this high-risk context as Ն130/85 (2)] and the tors, including growth constraints in utero; and finally to typical pattern of atherogenic dyslipidemia—hypertriglyceri- consider the impact of metabolic syndrome on the kidney in its demia, low HDL cholesterol, and increase in small dense LDL prediabetic phase. The pathogenesis of hypertension in the particles (2)—are also likely downstream consequences of context of metabolic syndrome is considered separately in this insulin resistance with identifiable contributions from specific series. Similarly, central nervous system pathways that con- organs. Clinical criteria also do not emphasize the role of tribute to disordered energy homeostasis is addressed in detail disordered skeletal muscle metabolism in this syndrome or by others. The mechanisms of irreversible renal injury from highlight for the clinician the therapeutic power of regular hypertension and overt diabetes are well documented and are exercise to offset insulin resistance. Finally, concepts now beyond the scope of this review; nonetheless, they loom large evolving from research advances suggest that the current clin- in the long-term renal future of the patient with metabolic ical definition identifies individuals at a relatively advanced syndrome. The current worldwide epidemic of obesity-initiated stage, well beyond onset of irreversible organ/tissue injury. metabolic syndrome, with its potential for renal damage, man- Consequently, one immediate research challenge is to define, dates our commitment to early renal protection in the obese and in the temporal evolution of metabolic syndrome, where inter- to vigorous prevention of obesity in both pediatric and adult ventions can both reverse metabolic derangements and prevent populations. the tissue damage that conveys long-term risk.

Metabolic Syndrome Defined: A Work in Prevalence and Cardiovascular Risks of Progress Metabolic Syndrome The Adult Treatment Panel III (ATPIII) of the National On the basis of the Third National Health and Nutrition Cholesterol Education Program (NCEP) (2) defines metabolic Examination Survey (NHANES III; 1988 to 1994), the preva- syndrome clinically as any three of the following five traits lence of metabolic syndrome in the U.S. population Ն20 yr of age is 23.7% (7), rising to Ͼ40% in those Ն60 yr of age and in those from specific geographic regions (e.g., south Texas) Correspondence to Dr. Susan P. Bagby, Departments of Medicine and Phys- (8). This compares with a 30.5% prevalence of obesity (body iology/Pharmacology, Division of Nephrology & Hypertension, Oregon mass index [BMI] Ն30) and a 64.5% prevalence of overweight Health & Sciences University, 3314 SW US Veterans Hospital Road (PP262), Ն Portland, OE 97239-2940. Phone: 503-494-8490; Fax: 503-494-5330; E-mail: (BMI 25) in the NHANES III U.S. population sample, re- [email protected] flecting marked increases of 7 to 10%, respectively, in the 1046-6673/1511-2775 previous decade (9). Among non-U.S. populations, prevalence Journal of the American Society of Nephrology ranges from 49.4% of 1625 hypertensive individuals in Spain Copyright © 2004 by the American Society of Nephrology (10), 19.8% in Greece (11), and 17.8% in older Italians (12). DOI: 10.1097/01.ASN.0000141965.28037.EE The last cohort exhibited a stepwise increase in insulin resis- 2776 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 2775–2791, 2004

Table 1. Clinical criteria for diagnosis of metabolic syndrome this system are (1) exogenous fuel overload, (2) ectopic accu- mulation of lipid in nonadipose cells (21), and (3) insulin Risk Factor Defining Level resistance (3,16). Abdominal obesity Waist circumference To summarize concepts to be detailed below, the evolution Men Ͼ102 cm (Ͼ40 in) of metabolic syndrome seems to proceed not as a linear se- Women Ͼ88 cm (Ͼ35 in) quence of events but along a matrix of interconnected path- Triglycerides Ն150 mg/dL ways that mediate interactions among multiple organs and also HDL cholesterol link these organs as a functional unit to regulate total-body Men Ͻ40 mg/dl energy homeostasis (Figure 1). Each organ/cell type is typi- Women Ͻ50 mg/dl cally both a target and an effector within this matrix. Further- BP Ն130/85 mmHg more, disturbance within this matrix of pathways can be initi- Fasting glucose Ն110 mg/dl ated by stimuli acting at any one of multiple sites in the matrix (e.g., in adipocytes, in hepatocytes, in skeletal myocytes), each independently capable of disturbing whole-body fuel ho- meostasis. However, initiation of metabolic syndrome by obe- tance severity (by Homeostasis Model Assessment) with in- sity, in keeping with the now-recognized role of adipose tissue creasing numbers of metabolic syndrome features (12). Impor- as an endocrine organ, is characterized by powerful systemic tantly, overt metabolic syndrome is not limited to adults (13). stimuli that together impair energy homeostasis in multiple Cruz et al. (14) examined 126 overweight Hispanic children organs simultaneously, leaving no room for protective com- who were aged 8 to 13 and had a family history of type 2 diabetes; 62% exhibited abdominal obesity, and 30% met criteria for metabolic syndrome. As in adults, obesity in the pediatric population is increasing, with Hispanic and non- Hispanic black adolescents at greatest risk (15). The 2002 NCEP ATPIII panel rated metabolic syndrome equivalent to cigarette smoking in magnitude of risk for pre- mature coronary heart disease (2). In epidemiologic studies, metabolic syndrome increases risk of developing overt diabetes (16), cardiovascular disease (17,18), and cardiovascular mor- tality (17). In a prospective Finnish cohort, both NCEP ATPIII and World Health Organization criteria for defining metabolic syndrome predicted a five- to ninefold increase in risk of new diabetes over 4 yr (16). Lakka et al. (17), in a cohort of 1209 disease-free Finnish men who were aged 42 to 60 yr and followed for Ͼ11 yr, found that the presence of metabolic syndrome conferred a three- to fourfold increased risk for death from coronary heart disease. Using NHANES III data, Ni- nomiya et al. (7) described an approximately twofold increase in myocardial infarction and stroke risk in the presence of metabolic syndrome. Figure 1. Pathogenesis of obesity-initiated metabolic syndrome. In- creased abdominal fat mass yields high circulating free fatty acids Pathogenesis of Obesity-Initiated Metabolic (FFA), which drives increased cellular FFA uptake. Reduced release Syndrome of adiponectin from expanding abdominal white adipose tissue The NCEP panel identifies the root causes of metabolic (WAT) reduces mitochondrial FA uptake/oxidation in multiple tis- syndrome as overweight/obesity, physical inactivity, and ge- sues. Despite increased release of leptin from WAT, which normally netic factors (2). Unraveling underlying mechanisms has been also enhances FA oxidation, tissue resistance to leptin further pro- complicated by the unique multiorgan complexity of this trait motes cytosolic FA build-up. As a result, excess intracellular FA and cluster. Fundamentally, the metabolic syndrome reflects disor- its metabolites (fatty acyl CoA, diacylglyceride) accumulate, causing dered energy homeostasis. Just as evolution prepared us well insulin resistance (see pathway, Figure 2). Organ-specific conse- for surviving hypotension but poorly for combating hyperten- quences include increased hepatic gluconeogenesis and reduced skel- sion, it has apparently equipped us for surviving the fast but not etal muscle glucose uptake; the latter raises plasma glucose content and stimulates pancreatic insulin release, and hyperinsulinemia en- the feast. Unger (19,20) described metabolic syndrome as “a sues. The newly available glucose plus high insulin now comes back failure of the system of intracellular lipid homeostasis which full circle to stimulate further WAT lipogenesis. Increasing fat cell prevents lipotoxicity in organs of overnourished individuals,” a size induces release of chemotactic molecules (e.g., monocyte che- system that normally acts “by confining the lipid overload to moattractant protein-1) with macrophage infiltration plus TNF-␣ and cells specifically designed to store large quantities of surplus IL-6 generation. These cytokines generate an inflammatory reaction calories, the white adipocytes.” Central to the breakdown of and enhance adipocyte insulin resistance in WAT. J Am Soc Nephrol 15: 2775–2791, 2004 Obesity-Initiated Metabolic Syndrome and the Kidney 2777

mits rational clinical interventions? New data suggest that excess visceral fat mass alone is sufficient to generate all elements of the metabolic syndrome.

Role of Abdominal Obesity Most studies support the view that the metabolic syndrome that now confronts U.S. physicians in epidemic proportions is largely initiated by abdominal obesity. The four most crucial elements that link abdominal obesity to other features of the metabolic syndrome seem to be elevated FFA, reduction in circulating insulin-sensitizing adiponectin, peripheral-tissue re- sistance to the insulin-sensitizing actions of leptin, and en- hanced macrophage infiltration in fat tissue with release of proinflammatory cytokines (Figure 1). Abdominal fat is unique in its metabolic features as compared with peripheral fat de- pots, exhibiting larger adipocytes that contain more triglycer- ide (TG) and exhibit greater insulin resistance than smaller Figure 2. Intracellular pathways of insulin resistance. Accumulation adipocytes. Adipocyte resistance to the lipogenic effect of of FA and its metabolites (fatty acyl CoA and diacylglycerol) induce insulin yields higher basal rates of lipolysis with increased protein kinase C isoforms, leading to serine/threonine phosphorylation of insulin receptor substrate-1 (IRS-1) on serine 302. This renders the release of FFA into the portal venous system. This direct IRS-1 resistant to tyrosine phosphorylation by the activated insulin access to the liver (see below) may also contribute to the receptor. As a result, downstream effects of insulin receptor activa- unique impact of visceral fat on energy homeostasis. Abdom- tion—Akt activation and translocation of the glucose transporter Glut inal fat may also secrete less leptin than subcutaneous fat. Thus 4 to the plasma membrane—is reduced. Glucose uptake is thereby Cnop et al. (28), comparing lean-insulin resistant, lean insulin- diminished, secondarily decreasing both glucose-derived glycogen sensitive, and obese insulin-resistant adults, found that leptin synthesis and glucose-dependent lipogenesis. Activation of the JNK levels correlated with increasing subcutaneous—but not vis- pathway by elevated cytoplasmic FA may provide an additional pathway ceral—fat mass, proposing yet another metabolic distinction for induction of insulin resistance. Adapted from reference 52. between these two compartments. Abdominal fat mass expan- sion is also coupled with reciprocally reduced release of adi- ponectin, a multifunctional collagen-like molecule with potent pensation. This multiplicity of pathways and targets likely capacity to stimulate fuel oxidation in peripheral tissues (25). explains the efficacy of obesity as the major generator of Abdominal fat additionally expresses higher levels of renin- metabolic syndrome. angiotensin system components: increased angiotensinogen and increased angiotensin II (Ang II) AT1 receptors (38). Generation of Obesity-Associated Metabolic Finally, epidemiologic studies confirm the unique significance Syndrome: Reversible Derangements of the of abdominal fat mass in predicting microalbuminuria, diabe- Metabolic Matrix tes, and overall cardiovascular risk (39). It was this compelling Obesity-initiated metabolic syndrome is consistently as- evidence for a unique role of central or visceral obesity—in sociated with specific metabolic abnormalities: high circu- contradistinction to subcutaneous obesity—that prompted the lating free fatty acids (FFA) (22); increased intracellular NCEP ATPIII decision to specify abdominal obesity in the lipid content of not only white adipose tissue (WAT) but clinical definition of metabolic syndrome. also hepatocytes, skeletal myocytes, pancreatic ␤ cells, car- These phenomena originating in abdominal adipose tissue diomyocytes, gastrointestinal enterocytes, and vascular en- generate the clinical picture that we recognize as metabolic dothelial cells (23,24); insulin resistance in (at least) the syndrome. The roles of FFA excess and adiponectin deficiency same list of tissues; and reduced functional activity of two are reviewed below in the context of their actions in individual insulin-sensitizing adipokines that promote tissue fuel oxida- organs; the role of leptin is addressed subsequently to compare tion, adiponectin (25–27), and leptin (27). As abdominal fat and integrate prevailing views of how insulin resistance expands, adiponectin is progressively reduced (25) while leptin evolves. levels are progressively elevated (28), the latter reflecting tissue leptin resistance (20,29). Although not yet included in Liver formal clinical definitions, additional features are increasingly Under conditions of normal energy homeostasis, the liver considered integral to obesity-initiated metabolic syndrome: serves as a short-term energy reservoir, taking up absorbed macrocytic infiltration of WAT (30,31), increase in local and dietary glucose and FFA, synthesizing/storing glycogen, syn- circulating inflammatory markers [C-reactive protein (32), thesizing/storing TG, and packaging TG into VLDL. During TNF-␣ (33), plasminogen activator inhibitor-1 (34,35), and fasting, the liver must sustain a continuous supply of plasma IL-6 (36)] and hyperhomocysteinemia (37). How do we inte- glucose, acutely by glycogenolysis and later in the fasting grate these diverse elements into a coherent process that per- period by gluconeogenesis. Secreted VLDL provides ongoing 2778 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 2775–2791, 2004

TG and ultimately FA fuel to skeletal muscle, heart, and other low plasma HDL are pathogenetically linked manifestations of peripheral tissues via lipoprotein lipase activity in the vascular altered lipid regulation in metabolic syndrome. space. Effect of Adiponectin Deficiency on Liver Effect of Excess FFA on Liver In addition to the effects of elevated FFA load, the energy- Intracellular FFA content is a function of substrate delivery related functions of the liver are profoundly affected by the from the plasma and FFA utilization (efflux into mitochondria reduced circulating levels of the adipokine adiponectin. The for oxidation or cytosolic synthesis of intracellular lipids). actions of this multifunctional protein are organ specific and With abdominal obesity, the increased FFA released into the uniformly insulin sensitizing. Adiponectin normally promotes portal vein from excess visceral fat lipolysis have direct access insulin sensitivity in liver in part by enhancing FA oxidation to the liver. Because cellular FA uptake is substrate dependent, (46); this reduces accumulation of cytoplasmic FA, thereby increased hepatocyte FFA uptake ensues (23). Elevated cyto- reducing intracellular FA levels and enhancing insulin action plasmic FA content leads to hepatic insulin resistance. This via IRS-1 availability to the insulin receptor. Second, like process involves competition of FA and glucose for access to insulin, adiponectin normally suppresses hepatic gluconeo- mitochondrial oxidative metabolism. The molecular mecha- genic enzymes and induces glycogenetic enzymes. Increase in nism was recently described by Shulman et al. (40,41) (Figure 5'-AMP-activated kinase mediates these effects of adiponectin 2), wherein elevated intracellular fatty acyl CoA activates (46,47). Conversely, deficiency of adiponectin in states of protein kinase C␪ (PKC␪), causing phosphorylation of serine- abdominal obesity directly contributes to insulin resistance by 302 of insulin receptor substrate-1 (IRS-1). This renders IRS-1 further enhancing accumulation of intracellular FA and FA unavailable for tyrosine phosphorylation by the activated in- metabolites and by stimulating hepatic glucose output. The sulin receptor and reduces all downstream actions of insulin. impact of insulin-sensitizing adipokines is apparent from trans- As a result, the fasting state is simulated and hepatocyte genic mouse models that completely lack fat (and thus both enzymatic machinery is shifted to favor enhanced hepatic adiponectin and leptin) (48). Animals are insulin resistant; the gluconeogenesis at the expense of glycogen synthesis. The provision of physiologic levels of both adiponectin and leptin consequent increase in liver-derived glucose in plasma leads to fully restores normal energy homeostasis, whereas either alone hyperinsulinemia, a hallmark of metabolic syndrome in its is only partially effective (48). These studies underscore the earliest stage and a marker of insulin resistance. regulatory role of fat-derived adipokines and lend logic to the The capacity of the insulin-resistant liver to impair second- seeming paradox that either too little or too much adipose arily systemic energy homeostasis is illustrated by transgenic tissue can lead to insulin resistance (21). studies introducing an insulin-resistant form of the rate-limit- ing enzyme of liver gluconeogenesis: phosphoenolpyruvate carboxykinase (42). Creating isolated hepatic insulin resistance Skeletal Muscle led to systemic hyperglycemia, hyperinsulinemia, and a mod- Increased circulating FFA also have an impact on skeletal erate increase in fat mass (42). The last reflects WAT utiliza- muscle energy homeostasis. Skeletal muscle is normally a tion of surplus circulating glucose for insulin-induced lipogen- major site of glucose and FA uptake, accounting for the bulk of esis. In effect, this represents a redistribution of fuel away from total-body glucose utilization and deriving 60% of resting the liver to adipose fat stores. These findings emphasize the energy from FA. As in the hepatocyte, increase in intramyo- potential for activating the abnormal metabolic matrix simply cellular FA in skeletal muscle has been shown to impair insulin by inducing hepatic insulin resistance and also illustrate the receptor signaling by PKC-dependent serine phosphorylation dual role of the liver as target and effector in metabolic of IRS-1; this leads to reduced IRS-1 availability for tyrosine syndrome derangements. In dogs that were fed an isocaloric phosphorylation, reducing Glut 4 translocation to the myocyte moderate-fat diet, striking visceral obesity was associated with plasma membrane with consequent reduction in glucose uptake marked reduction in the ability of insulin to suppress hepatic (6). Secondarily, glucose-driven lipogenesis and glycogen syn- gluconeogenesis, even before any reduction in insulin-stimu- thesis in skeletal myocytes are also reduced. Accordingly, lated glucose uptake appeared; investigators concluded that elevated circulating FFA contribute to insulin resistance in hepatic insulin resistance plays a dominant role in the patho- both liver and skeletal muscle. physiologic cascade initiated by abdominal obesity (43). As in the hepatocyte, reduced adiponectin secretion second- FFA overload also provides substrate for increased hepatic ary to increased visceral fat mass augments insulin resistance TG synthesis and for TG-rich VLDL assembly and secretion. in skeletal muscle, also in part via reducing FA oxidation rate, Although details are beyond the scope of this review, the further increasing intramyocellular FA content and impairing peripheral metabolism of these VLDL generate a small, dense insulin action (48). Using magnetic resonance spectroscopy in form of highly atherogenic LDL [reviewed by Avramoglu et insulin-resistant offspring of patients with type 2 diabetes, al. (44)] along with an increase in plasma TG. In addition, Petersen et al. (49) found evidence of a 30% reduction in increased hepatic lipase activity in the insulin-resistant state mitochondrial oxidative phosphorylation together with im- reduces levels of protective HDL-2 cholesterol (45), which is paired muscle FA oxidation and an 80% increase in intramyo- essential to the transport of cholesterol from tissues back to the cellular lipid content. Overt diabetes has also been associated liver. Thus, hepatic insulin resistance, high plasma TG, and with impaired muscle oxidative capacity (50,51). Finally, the J Am Soc Nephrol 15: 2775–2791, 2004 Obesity-Initiated Metabolic Syndrome and the Kidney 2779 insulin resistance of aging is associated with impaired mito- Role of Leptin Resistance in Peripheral Organs chondrial FA oxidative capacity in skeletal muscle (52). In addition to FFA excess and adiponectin deficiency, Impaired energy production is a particularly important con- functional leptin deficiency in peripheral tissues is believed sequence of insulin resistance in skeletal muscle. Diabetic and to play a significant role in the evolution of obesity-initiated prediabetic patients have impaired maximal exercise capacity, insulin resistance. Leptin is secreted in proportion to body reduced maximal oxygen consumption, and slower oxygen fat mass and, under normal circumstances, signals via cen- uptake at initiation of low-level exercise, potentially contrib- tral nervous system receptors to attenuate appetite and to uting to the fatigue and reduced physical activity typical of enhance sympathetic outflow, the latter stimulating energy obesity/insulin resistance (53). Exercise stimulates skeletal utilization and thermogenesis. Increase in fat-derived muscle oxidative enzymes and activates mitochondrial biogen- plasma leptin seen with abdominal obesity states is para- esis (54). Inactivity would be predicted to reduce basal meta- doxically coupled with poorly understood leptin resistance bolic rate both by reducing muscle mass and by augmenting to central appetite-suppressing and to peripheral insulin- defective muscle energy production. The practical physical sensitizing effects of leptin (see below), thus a functional consequences of these skeletal muscle metabolic abnormalities leptin deficiency. Central pathways of adipocytokines are have not yet been widely studied in metabolic syndrome but addressed separately in this series. Unger and colleagues are likely to reinforce the vicious cycle of ongoing weight gain (62) proposed, on the basis of compelling experimental and sedentary lifestyle. evidence, that peripheral-tissue leptin resistance is a crucial factor leading to insulin resistance in metabolic syndrome Pancreas (19). They contended that leptin’s major role in normal The pancreas is the ultimate arbiter of insulin availability, energy homeostasis is not prevention of obesity, as origi- determining the point at which overt diabetes will occur. Early nally conceived, but rather protection of nonadipocytes in the course of metabolic syndrome, hepatic gluconeogenesis against the cytotoxicity of intracellular lipid overload during stimulates the pancreas to hypersecrete insulin, yielding nor- periods of nutrient excess (21,24). Leptin potently activates moglycemic hyperinsulinemia. Increased FFA uptake by pan- cellular fuel consumption by stimulating FA oxidation, re- creatic cells also increases glucose-induced insulin secretion ducing lipogenesis, enhancing glucose entry and metabo- and modifies expression of peroxisome proliferator–activated lism, and dramatically shrinking fat stores in adipose tissue receptor-␣ (PPAR-␣), glucokinase, and Glut 2 transporter (23). (63) as well as in muscle and liver cells (24). Accumulation In the spontaneously obese captive rhesus monkey, hyperinsu- of cytoplasmic FA thus could reflect functional leptin defi- linemia is sustained and progressively increases, eventually ciency acting via impaired mitochondrial oxidative capacity falling as overt hyperglycemia appears (55). Once hyperglyce- and concomitantly enhanced lipogenesis. The ensuing insu- mia ensues, insulin-secreting ␤ cells become targets of gluco- lin resistance could be viewed as a compensatory cytopro- toxicity: reduction in insulin-stimulated insulin secretion, late tective response to prevent further accumulation of intracel- increase in mitochondrial free-radical production, and lipid lular lipid, i.e., reduced glucose entry attenuates glucose- overload–induced apoptosis (lipotoxicity; see also below) with derived lipogenesis (21). The mechanisms of peripheral progressive loss of ␤ cell mass (56–58). Adverse effects of resistance to the fuel-burning actions of leptin are not yet hyperinsulinemia per se on organ structure and function in the known. In reality, excess FFA in the circulation, leptin prehyperglycemic phase of metabolic syndrome are not well resistance, and adiponectin deficiency are likely acting in defined but are relevant to establishing optimum timing of concert to generate intracellular FA excess, although their intervention. It is worthy of emphasis that lifestyle interven- precise sequence and relative importance remain to be de- tions that reduce hyperglycemia can markedly decrease pro- termined. The biochemical pathways involved in these in- gression to overt diabetes (59). tracellular processes have been reviewed in detail by Unger (19,21), Petersen and Shulman (64), and Shulman (6). The Vascular Endothelium crucial participation of PPAR-␥,-␣, and -␦ in mediating Available evidence indicates that the insulin-receptor signal- tissue-specific actions of adiponectin and leptin—and their ing pathway mediating glucose uptake in vascular endothelium alterations in metabolic syndrome—are addressed separately in requires stimulation of endothelial nitric oxide (NO) synthase this series. and NO production (60), a potent vasodilatory and antithrom- botic stimulus. Comparable endothelial responses—enhanced Meanwhile, Back to Fat NO production with vasodilation—are induced by adiponectin Although excess abdominal fat serves to initiate dysfunc- (61). These actions mediate a hemodynamic component of tional energy homeostasis in multiple other organs, it eventu- energy distribution, enhancing tissue blood flow to optimize ally becomes also a target tissue. It is first a target of excess nutrient delivery. When insulin resistance ensues, insulin-in- glucose in the vascular space. Increased glucose availability duced NO production is concomitantly impaired, representing from liver-based gluconeogenesis and from muscle-based re- one of several mechanisms linking abdominal obesity/insulin duction in glucose uptake, together with pancreas-dependent resistance and hypertension. Implications of endothelial dys- hyperinsulinemia, promote lipogenesis in WAT (42) (Figure function for hypertension in metabolic syndrome are addressed 1). This poses the disturbing possibility that abdominal obesity in detail by Dr. Sowers elsewhere in this issue. creates a self-perpetuating cycle. 2780 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 2775–2791, 2004

Excess cortisol activity is known to shift fat from peripheral Once again, a change confined to fat tissue induces systemic (gluteal and subcutaneous) to central visceral depots and to metabolic dysregulation. mimic many aspects of metabolic syndrome. It thus is not Expanding WAT also becomes the primary target of an surprising that glucocorticoid excess has been suspected in the inflammatory process. Recent studies in mice and human cause of metabolic syndrome. Recently, increased activity (65) adipose tissue elegantly documented this process and impli- and a twofold increased expression of 11 ␤ hydroxy steroid cated the role of macrophage infiltration and macrophage- dehydrogenase 1 (11␤HSD1) in adipose tissue of nondiabetic derived inflammatory mediators in obesity and metabolic centrally obese women (66) were reported. This enzyme acts syndrome (30,31). Weisberg et al. (31) demonstrated that predominantly to convert inactive cortisone to the active cor- increasing body mass and increasing fat-cell volume (i.e., tisol form, thus generating glucocorticoid at a tissue level. fat content) each correlates linearly with bone marrow– Expression levels of 11␤HSD1 were directly proportional to derived macrophage infiltration in WAT and linearly with waist circumference and insulin resistance (66). Supporting the increased expression of macrophage-linked proinflamma- relevance of locally generated glucocorticoid in WAT, trans- tory genes (Figure 3). Xu et al. (30) similarly found that genic mice overexpressing 11␤HSD1 in adipocytes faithfully upregulated genes in WAT of obese mouse models were reproduced the metabolic syndrome (67,68), whereas deficient primarily inflammatory genes linked to macrophage infil- mice were metabolically resistant to high-fat feeding (69). tration/activation; furthermore, in diet-induced obesity, this

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 F4/80ϩ/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). J Am Soc Nephrol 15: 2775–2791, 2004 Obesity-Initiated Metabolic Syndrome and the Kidney 2781 inflammatory process within WAT preceded insulin resis- in central fat mass and hypertension as adults; all features were tance. TNF-␣ and IL-6 have been shown to induce insulin exaggerated by a highly palatable “cafeteria” diet (81). Human resistance in vitro and to contribute to insulin resistance in epidemiologic studies based on large longitudinal databases mouse models of obesity (36,70). This in situ inflammatory from diverse countries now demonstrate that rapid compensa- reaction within WAT therefore may induce/augment insulin tory growth in childhood is a significant enhancer of adult resistance in the adipocytes per se, coming full circle in cardiovascular disease risk in offspring with intrauterine generation of multiorgan energy dysregulation. growth restriction (IUGR), specifically including central obe- sity (76,82,83), diabetes (84–86), hypertension (87,88), and Predisposition to Obesity-Initiated Metabolic coronary disease (79,80). Specific patterns of postnatal growth Syndrome after IUGR influence the magnitude of risk for specific ele- ments of the metabolic syndrome. Thus, in a South African A number of factors influence risk for development of cohort, low-birth-weight children who were exposed to nutri- obesity-initiated metabolic syndrome. The increasing risk with ent abundance and catch-up growth exhibited increased pro- age (4,71) parallels the declining muscle mass and muscle pensity for fat more than lean mass deposition and increased oxidative capacity of aging (52). Hormonal changes with aging risk of obesity and insulin resistance by age 7 as compared with are also involved: the compensatory increase in T3-mediated those who did not undergo catch-up growth (89). In a Finnish thermogenesis induced by dietary fat in young rats is lost with cohort that contained extensive longitudinal growth data in aging (72). Lifestyle factors are similarly influential. In cohorts childhood, the subset of individuals who subsequently devel- followed prospectively, regular physical activity and adherence oped hypertension as adults exhibited a distinct pattern of to the Mediterranean diet significantly reduced risk (10). In the childhood growth: low birth weight followed by an exaggerated Framingham Offspring Cohort, diets with low glycemic index growth rate in weight greater than height to attain increased BMI and high whole-grain attributes also decreased risk of devel- levels by 12 yr (88) (Figure 4). When the population was subdi- oping metabolic syndrome (3). In addition to demographic and vided, children who were destined to develop only hypertension lifestyle modulators, recent interest has focused on two mech- exhibited exaggerated growth to attain average-for-age BMI by anisms of predisposition operative early in life: environmental age 7, which remained constant thereafter; children who were “programming” by adverse events operative during early destined to develop both hypertension and diabetes as adults growth and development and genetic factors. Both can perma- exhibited a similar pattern between birth and age 7 but differed by nently modify postnatal organ functional capacity, permanently continuing rapid growth between 7 and 15 yr of age to reach alter gene expression patterns and homeostatic setpoints, and also exhibit maternal transmission across generations (73,74); as a result, the distinction between classic genetic inheritance and environmentally programmed effects can no longer rely solely on maternal phenotype.

Lessons from Intrauterine Growth Restriction Asymmetric Intrauterine Growth Restriction Produces the “Thrifty Phenotype” Epidemiologic studies over the past 15 yr have uncovered a consistent relationship between low birth weight and increased risk for developing adult metabolic syndrome (75), a phenom- enon now known as developmental “programming.” For ex- ample, in the Hertfordshire Study, prevalence of metabolic syndrome according to birth weight fell stepwise from 30% of subjects who were Յ5.5 lb to 6% of those who were Ն9.5 lb (76). A key feature that conveys risk in programming is not low birth weight per se but rather a form of asymmetric growth restriction wherein weight is disproportionately impaired rela- tive to height, and sizes of kidney, liver, pancreas, and skeletal muscle are disproportionately reduced relative to heart and brain (77,78). When asymmetrically growth-restricted infants encounter nutrient abundance postnatally, there is spontaneous Figure 4. Pattern of infant and childhood growth in children who “compensatory” or “catch-up” growth such that body weight developed hypertension as adults. Growth rates are expressed as SD units increase is accelerated and crosses percentiles during child- (z scores) from the overall population average (set at zero). The 1404 of hood (79,80). In a rat model of global maternal calorie restric- 8760 children who subsequently required antihypertensive medications tion, offspring that were weaned to normal diets postnatally as adults exhibited low birth weight and low birth BMI but exaggerated were permanently hyperphagic, hyperinsulinemic, and hyper- growth in weight and BMI between 5 and 12 yr of age. (Reproduced by leptinemic; exhibited catch-up growth; and developed increase permission from Barker DJ, et al., J Hypertens 20: 1951-1956, 2002). 2782 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 2775–2791, 2004 excess BMI (87). Thus, early growth restriction in an asymmetric pattern leads to “programmed” increase in appetite, excess food intake when available, exaggerated childhood “catch-up” growth with a propensity for accruing fat more than lean body mass, and preferential deposition of abdominal more than peripheral fat (89,90). Hales (91) termed this constellation of traits the “thrifty phenotype.”

Asymmetric IUGR Permanently Impairs Organ Structure and Maximal Functional Capacity Another consequence of IUGR that predisposes to metabolic syndrome derives from unique developmental patterns of kid- ney, pancreas, and muscle in utero and their impact postnatally when structurally impaired at critical windows of development. Because each organ develops its respective functional units before birth, no additional units can form postnatally; maximal organ capacity thus is fixed at birth. Fetal undernutrition, Figure 5. Proposed interaction between thrifty phenotype behaviors depending on the developmental period of exposure, can lead and fixed reduction in nephron number after intrauterine growth to permanently reduced nephron number (78,92–95), perma- ␤ restriction. Fetal nutrient deprivation of any cause encompassing the nently reduced pancreatic insulin-secreting cells (96–98), last half of pregnancy typically impairs renal development and re- and permanently reduced skeletal muscle fiber number duces nephron number. No new nephrons form after birth in humans. (99,100) and mitochondrial mass (101). Following the original Nutrient deprivation also “programs” the fetus to utilize energy more hypothesis of Brenner and Chertow (92), Eriksson et al. (88) efficiently, optimizing survival. Postnatally, the offspring exhibit hy- proposed for kidney—and others for pancreas (98)—that post- perphagia on the basis of ad libitum food intake, increased efficiency natal increase in body size beyond the birth weight percentile in utilization of calories, and metabolic changes that reduce maximum will impose metabolic and excretory demands that exceed capacity for energy consumption (reduced muscle mass, smaller mi- organ capacities. These structurally based functional limits in tochondria). If food is available in the environment, then hyperphagia key organs after IUGR would be expected to predispose to drives caloric intake to yield rapid compensatory growth in weight more than height, crossing centiles to achieve typically normal BMI. metabolic syndrome derangements at multiple sites simulta- Even in the absence of overt obesity, this now-normal body mass is neously. In the face of abundant nutrients, the thrifty phenotype relatively excessive for the fixed reduction in nephron number. In a generates body size excess relative to organ capacity, deposits microswine model, catch-up growth is associated with intrarenal excess abdominal fat, and promotes abdominal obesity. Re- angiotensin II excess and hypertension in young adults. This may be duced pancreatic insulin secretory mass/capacity may hasten analogous to the increased risk of hypertension and proteinuria when transition from hyperinsulinemia to overt diabetes. Lower mus- obesity precedes unilateral nephrectomy. cle mass—which persists in adults who experienced IUGR (102)—could promote obesity via low basal metabolic rate and biologically based inactivity; the reduced skeletal muscle oxi- 5). To test this, we developed a microswine model of IUGR dative capacity and smaller mitochondria described in off- using maternal protein restriction during the window of spring with IUGR (101) could increase susceptibility to insulin nephrogenesis (in swine, the last one third or gestation plus resistance by favoring accumulation of intramyocellular FFA. first 2 wk postnatally). Offspring of low-protein sows, as From the renal perspective, Lackland et al. (103), comparing compared with control offspring, exhibit a typical asymmetric 1230 young ESRD subjects (70% caused by diabetes or hy- pattern of growth restriction, have evidence of ~30% reduction pertension) with 2460 matched control subjects in South Caro- in nephron number, undergo 100% catch-up growth of body lina, showed that low birth weight increased relative risk of and organ sizes, and develop hypertension as young adults (6 early-onset ESRD. mo) (104). In adults, renal weight and function are normal, but glomerular volume is increased, compatible with nephron hy- Studies in a Microswine Model of IUGR: Reduced pertrophy and hyperfiltration. Woods et al. (94) reported sim- Nephron Number, Intrarenal Ang II Excess, and ilar findings in rat offspring of protein-restricted dams. We Hypertension in Adult Offspring further proposed that this mismatch of excretory load to ex- Our investigative group has pursued the hypothesis that cretory capacity would induce compensatory nephron hyper- exaggerated postnatal increase in body mass in the face of filtration via activation of the renin/Ang II system. In examin- developmentally fixed nephron deficit would favor nephron ing plasma components of renin/Ang II activity (105), we find adaptations of hypertrophy and hyperfiltration and increase in no differences among low-protein versus normal-protein off- glomerular capillary pressure independent of obesity. That is, spring for Ang II, plasma renin activity, or renin substrate two independent consequences of IUGR—nephron deficit and concentration. In contrast, intrarenal Ang II levels are elevated thrifty-phenotype traits—interact to create imbalance between in hypertensive adult low-protein offspring (106). This pattern metabolic/excretory load and renal excretory capacity (Figure of normal renin/Ang II status in plasma but activated status J Am Soc Nephrol 15: 2775–2791, 2004 Obesity-Initiated Metabolic Syndrome and the Kidney 2783 intrarenally is reminiscent of that observed in the diabetic the array of molecules and pathways involved in its genera- kidney (107). In our 6-mo-old young-adult offspring of mater- tion—representing the entire molecular infrastructure of en- nal protein restriction, glomerulomegaly and intrarenal Ang II ergy metabolism and its regulation—underscore the many excess are present in the absence of proteinuria (106). To candidate sites. A detailed listing is beyond the scope of this distinguish between body mass excess and developmental pro- review. Instead, selective examples highlight major pathophys- gramming of the renin/Ang II system as causes of these iologic pathways. Virtually all genetic mechanisms described changes, we are currently examining whether prevention of involve interaction with environmental factors (e.g., nutrient catch-up growth by early postnatal caloric restriction modifies abundance, sedentary lifestyle) to create metabolic disease. In the renal adaptations, intrarenal Ang II, and hypertension. the Quebec Family Study, Tremblay et al. (113) described in older children and adolescents a glucocorticoid receptor poly- Developmental Programming of Postnatal Gene morphism that predicted twofold increase in visceral adiposity Expression in girls Ͼ12 yr (a similar trend in boys was NS). Similarly, A third way in which IUGR may predispose to metabolic abdominal visceral fat was linked with an RFLP at the glu- syndrome is fetal programming of gene expression that then cocorticoid receptor locus (114). As predicted from its antidi- persists to impair postnatal homeostatic functions. In the IUGR abetic efficacy, human adiponectin mutants have also been that results from severe maternal diabetes (in contrast to asym- associated with diabetes: Waki et al. (115) reported two mu- metric macrosomia of milder maternal diabetes) (108), off- tants that failed to form the high-molecular-weight multimers spring exhibit reduced insulin secretion and low insulin recep- required for adiponectin secretion from the adipocyte. Genetic tor density in utero; this persists postnatally to generate insulin predisposition to insulin resistance has also received attention resistance and diabetes. Another important example of perma- in relation to PPAR-␥2. A Gly483Ser missense mutation in the nently altered gene expression has been described for the PPAR-␥ coactivator 1 gene was associated with reduced lipid hypothalamic-pituitary-adrenal axis in rats (73). Maternal nu- oxidation, larger abdominal adipocyte size, and higher plasma trient restriction has been associated with decrease in placental FFA concentration in Pima Indians and in Danish populations 11␤OHSD2, which normally functions to inactivate maternal (116). Muller et al. (117) found that a functional variant in the cortisol and keep fetal cortisol levels at less than one tenth of PPAR-␥2 promoter with reduced transcriptional activity also maternal levels. Fetal exposure to excess glucocorticoid per- predicted obesity and insulin resistance in the high-risk Pima manently reduces adult hippocampal glucocorticoid receptor Indian population. A Pro12Ala polymorphism in PPAR-␥2 mRNA and increases adult corticosterone levels, suggesting a also predicted insulin resistance in Pima Indians and in other programmed reduction in postnatal sensitivity to cortisol feed- populations (117). Of special note, the effects of the Pro12Ala back (109). polymorphism on lipid metabolism was apparent only in indi- viduals with low birth weight (118), a fascinating example of Programming Can Occur after Birth and Can Be an interaction between a classic genetic factor and early envi- Transmitted to Offspring ronmental programming. Nutritional programming of postnatal homeostasis during periods of developmental plasticity is not confined to the fetal period. Srinivasan et al. (110) showed metabolic programming Renal Injury in Obesity-Initiated Metabolic in neonatal rats in response to high-carbohydrate versus normal Syndrome: Epidemiologic Studies high-fat milk formula during postnatal days 4 to 24. Adapta- Evidence linking metabolic syndrome and renal disease has tions in the high-carbohydrate pups included life-long hyper- only recently emerged. In the Modification of Diet in Renal insulinemia, increased number and size of pancreatic islets, and Disease study, a low HDL cholesterol independently predicted adult-onset obesity (110). It is especially noteworthy that the renal disease progression in 840 patients (119). In the Athero- high-carbohydrate-fed female rats transmit this phenotype to sclerosis Risk in Communities study of Ͼ12,000 subjects, their progeny (110), much as diabetic mothers transmit risk of Muntner et al. (120) observed that, in individuals who had diabetes to offspring via the intrauterine environment (108). baseline creatinine Ͻ2.0 and were followed for 2.9 yr, high TG Similarly, female IUGR offspring deliver low birth weight increased (adjusted relative risk, 1.65) whereas high HDL babies (73), another example of a transgenerational effect that cholesterol reduced (adjusted relative risk, 0.47) the probability may confound interpretation of studies in which transmission of developing renal dysfunction. of maternal traits has been viewed as “genetic.” This transgen- However, these observations did not directly address the erational reach of fetal programming (111,112) is not currently impact of the full metabolic syndrome as currently defined. To understood but potentially relates to factors such as develop- that end, Chen et al. (121) recently compiled data from the mentally impaired vascularization of the uterus and/or nutri- NHANES III survey to examine the association between met- tional effects on a female infant’s developing ova. abolic syndrome and the respective risks for chronic kidney disease (CKD) and microalbuminuria in U.S. adults. CKD was Genetic Predisposition to Metabolic Syndrome defined as GFR (Modification of Diet in Renal Disease for- In addition to age, demographic factors, and developmental mula) of Ͻ60 ml/m per 1.73 m2; microalbuminuria as protein: programming, germline transmission of predisposing factors creatinine ratio of 30 to 300 mg/g, and clinical proteinuria as clearly contributes to risk of metabolic syndrome. Furthermore, ratio Ͼ300 mg/g. Not only was each element of the metabolic 2784 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 2775–2791, 2004 syndrome associated with increased prevalence of CKD and dogs on high-fat intake, renal structural changes appeared after microalbuminuria, but also there was a graded relationship only 7 to 9 wk and included glomerulomegaly with Bowman’s between the number of components present and the corre- capsule expansion, glomerular cell proliferation, mesangial sponding prevalence of CKD or microalbuminuria (P Ͻ 0.001 matrix expansion, and glomerular and tubular basement mem- for each; Figure 6). Also using NHANES III data, Palaniappan brane thickening (125). Risk of death for the hyperinsulinemic et al. (122) found that the presence of metabolic syndrome was (but not yet hyperglycemic) monkeys was 3.7-fold higher than associated with an increased risk of microalbuminuria: odds that for diet-restricted (nonobese) controls (126). Placed on a ratio, 2.2 (1.4–3.3) in women and 4.1 (2.5–6.7) in men. Fi- human scale, whereby insulin resistance and hyperinsulinemia nally, Chen et al. (123) found that insulin resistance and precede overt diabetes by 10 to 20 yr, these important obser- hyperinsulinemia in individuals without diabetes strongly and vations suggest that structural changes long precede clinical positively predicted CKD and suggested that intervention to disease manifestations. However, neither the full spectrum of ameliorate insulin resistance could lower CKD risk. To date, early prehyperglycemia lesions and their time of onset nor their however, there are no clinical trials addressing whether treating degree of reversibility are fully characterized. metabolic syndrome elements other than hypertension or dia- betes will reduce risk of renal disease onset or progression; Mechanisms of Renal Injury neither are there trials defining optimum target levels of treated Although hypertensive and diabetic modes of injury are well components in these settings. described and beyond our scope, we can speculate on mecha- nisms of early renal damage in obesity-initiated metabolic Potential Mechanisms of Early Renal Injury syndrome. Several possibilities—acting singly or in combina- Renal changes occur early in the natural history of obesity- tion—deserve consideration: (1) adverse effects of adaptations initiated metabolic syndrome. Studies in the captive rhesus to increase body mass/excretory load, (2) adverse effects of monkey, in which spontaneous obesity evolves to fully devel- adaptations to obesity-induced sodium retention (127), (3) di- oped metabolic syndrome (55), have shed light on the sequence rect or indirect effects of hyperinsulinemia/insulin resistance, and time course of disease progression. In these prospectively and (4) renal lipotoxicity [see recent reviews by Hall et al. observed animals, progressive weight gain is followed in se- (127), Adelman (128), and Praga (129)]. quence by a sustained period of increasing hyperinsulinemia without hyperglycemia. This is followed by overt hyperglyce- Excess Excretory Load mia and subsequently by declining insulin levels (55). Of note, Obesity is associated with an excess excretory load on the the earliest evidence of structural change—glomerular hyper- basis of increased body mass and the increased energy intake trophy—appears before the onset of hyperglycemia (124). In and tissue turnover required to maintain it. Fat-free body mass (130) is also increased in obesity; in keeping with functional overload, the organomegaly of obesity includes both the heart and the kidneys (131). Chagnac et al. (132) confirmed renal hyperperfusion and hyperfiltration in severe obesity, averaging 51 and 31% increases, respectively. The reduced renal resis- tance with increased filtration fraction was compatible with net afferent dilation and glomerular capillary hypertension (132), the classic recipe for eventual glomerulosclerotic damage. Fur- thermore, in keeping with glomerular hypertension, the first clinical evidence of renal disease in obesity is proteinuria (see below); weight loss can strikingly reduce proteinuria as a result of obesity per se or of other underlying causes (133,134). In effect, obesity induces—even at normal nephron capacity—the single-nephron adaptations typical of the reduced nephron number accompanying CKD. Nephron overwork and risk of intraglomerular hypertension in obesity would be exaggerated if nephron number is already low, as would be predicted in offspring with IUGR (103) or after uninephrectomy (135). Increased glomerular risk as a result of transmission of sys- temic hypertension is also likely to apply. If chronic intrarenal Ang II excess proves typical of load adaptation, then Ang II could further enhance renal risk by proinflammatory mecha- Figure 6. Risk for chronic kidney disease (CKD; top) and microalbu- minuria (bottom) according to number of metabolic syndrome ele- nisms and by promoting proteinuria-related renal damage. Of ments. A significant graded relationship was apparent between num- interest in relation to load-induced nephron adaptation, ber of components and corresponding prevalence of CKD or Schwimmer et al. (136) reported focal segmental glomerulo- microalbuminuria (P Ͻ 0.001 for each comparison). (Adapted with sclerosis (FSGS) and glomerulomegaly in three nonobese pa- permission from Chen J, et al., Ann Intern Med 140: 167–174, 2004). tients with markedly increased muscle mass, as evidenced by J Am Soc Nephrol 15: 2775–2791, 2004 Obesity-Initiated Metabolic Syndrome and the Kidney 2785

BMI of 30 to 32, body fat of only 13 to 17%, and nonnephrotic perglycemia with low insulin—was associated with an altered proteinuria Ն1 g/d. GFR of 113 to 208 suggested hyperfiltra- ratio of insulin receptor splice variants in liver and skeletal tion; FSGS affected a minority of glomeruli, and foot process muscle (145). Finally, although hyperinsulinemia may achieve effacement was minimal. Because insulin resistance/hyperin- normal insulin action in insulin-resistant organs, it could lead sulinemia would not be expected in this setting, the changes— to excess insulin action/glucose uptake and promote lipogen- albeit in only three patients—conceptually support the view esis/lipotoxicity in sites with persistent insulin sensitivity. The that excess excretory load—whether derived from lean or fat evidence that hyperinsulinemia—in conjunction with increased tissue—is an important factor in inducing glomerulomegaly glucose availability—actively promotes adiposity in WAT via and glomerulonephropathy. just such a mechanism has already been discussed (Figure 1). These considerations underscore the importance of learning Adverse Adaptations to Excess Renal Na more about the structural and functional effects on specific Retention tissues during the hyperinsulinemic, prehyperglycemic phase of metabolic syndrome. Whether injury at this early stage Hall et al. (127) proposed that, in response to the reduced Na reflects insulin resistance and/or hyperinsulinemia, therapeutic excretion capacity acting at sites proximal to the macula densa intervention in metabolic syndrome could ultimately prove to in obesity (via Ang II and sympathetic activation), reduced be necessary at a much earlier stage than currently considered. NaCl delivery to the macula densa site induces afferent vaso- dilation and renin release to produce compensatory glomerular hyperfiltration, thereby restoring normal distal delivery. A Renal Lipotoxicity? similar scenario has been proposed by Thomson et al. (137) for A well-documented form of multiorgan injury associated hyperglycemia-induced increase in proximal tubular Na reab- with progression of metabolic syndrome is lipotoxicity sorption in frank diabetes. As with hyperfiltration driven by (21,23,24). This cytotoxic process, marking advanced stages of excess excretory load, the ensuing intraglomerular hyperten- intracellular lipid overload, involves intracellular shunting of sion and proteinuria represent the final common pathway lead- excess FA toward synthesis of lipid products that are capable ing to chronic glomerular and tubular injury. of inducing cell damage: e.g., diacylglycerol, TG, and cer- amide (Figure 2). Diacylglyeride enhances PKC activities; Adverse Renal Effects of Hyperinsulinemia/ ceramide is a major candidate mediator of apoptosis (19). Insulin Resistance Evidence indicates that lipotoxicity affects liver (hepatic ste- Recent evidence supports early development of pathophys- atosis), skeletal muscle, cardiomyocytes, pancreatic ␤ cells, iologic functional and structural changes. Thus, in the captive and potentially endothelial cells (24). This process not only rhesus monkey with spontaneous obesity, glomerular hypertro- impairs function in the individual cell but also reduces cell phy appears in the prediabetic hyperinsulinemic phase despite mass via apoptosis in multiple organs, each with important no hyperglycemia, no hypertension, no renal dysfunction, and functional consequences. Lipotoxicity in proximal tubular no increase in mesangial matrix deposition (124). However, cells—with its associated tubulointerstitial inflammation—is these observations do not distinguish between effects of insulin now a recognized consequence of heavy proteinuria as a result resistance and hyperinsulinemia. Hall et al. (127) summarized of accumulation of excess albumin-bound FFA (146,147). evidence that high insulin per se has no adverse impact on BP However, no studies have systematically addressed whether in the normal or in the obese insulin-resistant dog. However, FFA lipotoxicity afflicts renal cell types in obesity-initiated insulin—although a weak vasodilator—augments endothelial- metabolic syndrome, particularly in the absence of (or inde- dependent vasodilation; thus, hyperinsulinemia could contrib- pendent of) proteinuria. The mesangial cell would seem at ute to preglomerular vasodilation and glomerular hypertension particular risk for exposure to high circulating FFA bound to and require time to manifest damage. On the basis of in vitro albumin in the face of intraglomerular hypertension. observations, hyperinsulinemia could induce glomerular hy- In the presence of proteinuria—whether as a result of obesity pertrophy either directly (138) or by stimulating the IGF-1 per se or of other nephropathies—elevated plasma FFA in receptor (138). IGF-1 actions (or actions of high insulin levels metabolic syndrome would be expected to enhance the number at the IGF-1 receptor) also include vasodilation (139) and may of FFA moieties bound to albumin and thus to enhance the increase glomerular capillary permeability (140). Hyperinsu- FFA available for proximal uptake. Therapeutic lowering of linemia could further interact with elevated intrarenal Ang II FFA could potentially ameliorate proteinuria-associated prox- levels to augment Ang II contraction of glomerular mesangial imal tubular lipotoxicity and tubulointerstitial nephritis. Oxi- cells (141). In addition, Abrass et al. (142) showed that high- dative stress is another potential mechanism of FFA toxicity: dose insulin exerts direct pathologic effects on renal mesangial reactive oxygen scavengers block FFA-induced apoptosis in cells in culture, stimulating expression of inflammatory colla- vitro (19). FFA both upregulate inducible NO synthase and gens typical of the diabetic phenotype. Importantly, the latter generate reactive intermediates as byproducts of oxidative was not reversible on subsequent withdrawal of insulin phosphorylation. High FFA per se during early metabolic (143,144), suggesting permanently altered gene expression af- syndrome, independent of intracellular TG accumulation, may ter exposure to high insulin. Again in the rhesus monkey, be an important co-factor in epidemiologic linkage of abdom- hyperinsulinemia—with or without hyperglycemia but not hy- inal obesity and microalbuminuria (148). 2786 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 2775–2791, 2004

Obesity-Associated Glomerulonephropathy importance and the feasibility of lifestyle change. Growing Weisinger et al. (149) first reported massive proteinuria understanding of the direct skeletal muscle benefits of regular associated with obesity in 1974. Subsequent reports have con- exercise to offset insulin resistance, even in the absence of sistently confirmed the presence of proteinuria and glomeru- weight loss, makes this a mandatory recommendation well lomegaly in obesity, often with FSGS (131,134,150,151). worthy of the education and counseling time invested. Thus, Verani et al. (131) reported an autopsy study of 22 Pharmacologic interventions with well-established benefit kidneys from obese subjects: glomerulomegaly was a consis- include angiotensin-converting enzyme inhibitors and angio- tent feature; FSGS was present in seven with no predilection tensin receptor blockers, which increase insulin sensitivity for juxtamedullary sites. In 15 obese individuals with FSGS, (155) and ameliorate microalbuminuria in addition to their Praga et al. (151) further emphasized absence of clinical ne- well-documented cardiovascular and renal protections (156); phrosis despite heavy proteinuria and a 46% rate of renal their use with BP Ͼ130/80 complies with the BP goal for progression. In 2001, D’Agati and colleagues (150) reported a metabolic syndrome (2). Statins are currently under study in striking 10-fold increase in incidence of a similar histopatho- prospective trials to assess their contribution to renal protection logic entity that they termed obesity-related glomerulopathy. and are clearly indicated in the presence of hypercholesterol- Seventy-one renal biopsies from obese patients (BMI Ͼ30 emia. Evidence that statins have anti-inflammatory benefit kg/m2) were compiled from 6818 consecutive biopsies over 10 independent of lipid lowering suggests that clinical trials of yr. All were associated with glomerulomegaly, and all exhib- their use in normocholesterolemic metabolic syndrome will be ited proteinuria (48% nephrotic range). Two histologic types forthcoming. Metformin has been shown to be effective in were identified: FSGS and glomerulomegaly only. The obese preventing development of diabetes in prediabetic individuals FSGS group (n ϭ 57) differed from classic idiopathic FSGS (n (59), reducing incidence by 31%; however, it unfortunately is ϭ 50 in a comparison group) via concomitant presence of contraindicated with impaired renal function. There is at this glomerulomegaly, less clinical nephrosis, less severe protein- time no long-term outcome data justifying use of the insulin- uria, less podocyte injury, less cholesterol elevation, and more sensitizing thiazolidinediones in nonhyperglycemic metabolic indolent progression (150). Also of note, these FSGS lesions syndrome. Moreover, the increased adiposity associated with occurred across the spectrum of obesity, not just in class III these PPAR-␥ agonists is intuitively concerning despite its (morbid) obesity. Of equal interest were the 14 proteinuric putative nonabdominal localization. Although the PPAR-␣ and obese patients who exhibited only glomerulomegaly on biopsy PPAR-␤␦ agonists seem superficially ideal, the risk that an (150), suggesting the possibility that glomerular hypertrophy increased metabolic rate—especially without concomitant cal- alone in hyperinsulinemic obesity may induce or be associated orie restriction—may reduce life span is not trivial, backed by with macroproteinuria (150). Although sampling error could a large body of literature, including primates (126). What can not be excluded, the previous autopsy report of Verani et al. and should be aggressively addressed in metabolic syndrome at (131) supported the view that apparent absence of FSGS did all stages is pharmacologic management of hypertriglyceride- not reflect a predominantly juxtamedullary localization. mia and low HDL cholesterol. Newer statins are more effective Whether glomerulomegaly is a cause or simply an associated in reducing TG as well as LDL cholesterol, although cost will feature of proteinuria in obesity-related glomerulomegaly is be the perennial drawback. Fenofibrate (a PPAR-␣ agonist) unknown. Similarly, whether glomerulomegaly is a precursor and niacin are effective tools for hypertriglyceridemia and can of the obesity-related FSGS lesion remains to be demonstrated. each (but not both) be combined with a statin when needed. These findings again raise the issue of where in the course of Management issues in metabolic syndrome have been recently obesity/metabolic syndrome renal injury is initiated and when reviewed (45). intervention should be considered to prevent irreversible dis- In summary, hand in hand with the ongoing epidemic of ease. [Excellent recent reviews of obesity and renal disease are obesity, the prevalence of obesity-initiated metabolic syn- available by Adelman (128), Hall et al. (127), and Praga (129).] drome—with its increased risk for diabetes, cardiovascular Our growing understanding of the pathogenesis of metabolic disease, and CKD—has reached alarming proportions. Its im- syndrome provides the rationale for management strategies to pact on renal disease is ensured if only because hypertension achieving long-term renal and cardiovascular protection. As and insulin resistance/diabetes are defining components of the clearly demonstrated by primate studies (126,152,153), obesi- syndrome. However, our challenge is to define and ultimately ty-associated metabolic syndrome and its entire cascade of prevent obesity-related renal injury before onset of irreversible consequences can be resolved by weight loss and prevented by damage. Evidence reviewed supports the concept that obesi- caloric restriction. Intensive programs of exercise and weight ty—via excess body mass and consequently excretory load loss in individuals with metabolic syndrome also achieve dra- and/or via sodium retaining forces requiring compensation— matic improvement (59,154). In the Diabetes Prevention Pro- co-opts the kidneys to serve those demands, driving nephro- gram Research study (59), the lifestyle intervention achieved a megaly and glomerulomegaly, inducing hyperperfusion/hyper- 58% reduction in the incidence of diabetes in individuals who filtration, and creating intraglomerular changes that mimic already exhibited hyperglycemia. As difficult as these changes those of reduced nephron number. In effect, the kidney in may be, there is no intervention more powerful. There is also obesity has the hemodynamic equivalent of CKD. In addition no motivator more effective than a knowledgeable and con- to the injury susceptibilities that this confers, the systemic cerned physician who is willing to convey personally the signals that mediate metabolic derangement in abdominal obe- J Am Soc Nephrol 15: 2775–2791, 2004 Obesity-Initiated Metabolic Syndrome and the Kidney 2787 sity are likely to have an impact on renal glomerular and 11. 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