Obesity-Initiated Metabolic Syndrome and the Kidney

Metabolic syndrome, originally described in 1988 as "syndrome X" by Reaven et al. (1), has evolved in our collective thinking from a vague association of common chronic disease states to a formally defined cluster of clinical traits with adverse impact on cardiovascular risk (2). The cause is incompletely understood but represents a complex interaction among genetic, environmental, and metabolic factors, clearly including diet (3,4) and level of physical activity (4,5). These abnormalities are mediated by—and interconnected by—complex pathways that affect energy homeostasis at cellular, organ, and whole-body levels. This review focuses on obesity-initiated metabolic syndrome, first to provide a pathogenetic overview of extrarenal metabolic derangements; second to consider predisposing conditions shaped by genetic or environmental factors, including growth constraints in utero; and finally to consider the impact of metabolic syndrome on the kidney in its prediabetic phase. The pathogenesis of hypertension in the context of metabolic syndrome is considered separately in this series. Similarly, central nervous system pathways that contribute to disordered energy homeostasis is addressed in detail by others. The mechanisms of irreversible renal injury from hypertension and overt diabetes are well documented and are beyond the scope of this review; nonetheless, they loom large in the long-term renal future of the patient with metabolic syndrome. The current worldwide epidemic of obesity-initiated metabolic syndrome, with its potential for renal damage, mandates our commitment to early renal protection in the obese and to vigorous prevention of obesity in both pediatric and adult populations. Metabolic Syndrome Defined: A Work in Progress The Adult Treatment Panel III (ATPIII) of the National Cholesterol Education Program (NCEP) (2) defines metabolic syndrome clinically as any three of the following five traits (Table 1): abdominal obesity, impaired fasting glucose (reflecting insulin resistance), hypertension, hypertriglyceridemia, and low HDL cholesterol. In addition, the NCEP ATPIII recognizes prothrombotic and proinflammatory states as characteristic of metabolic syndrome (2). Importantly, as subsequent paragraphs detail, these simple clinical criteria for diagnosis belie the emerging complexity of the underlying metabolic derangements (6). Thus, insulin resistance is viewed as the essential common denominator of metabolic syndrome, regardless of cause. Abdominal obesity, now identified solely by waist circumference criteria (Table 1), is the single most common cause of insulin resistance, and key mechanisms that mediate this pathway are becoming clear (6). Hypertension defined in this high-risk context as ≥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. Table 1: Clinical criteria for diagnosis of metabolic syndromePrevalence and Cardiovascular Risks of Metabolic Syndrome On the basis of the Third National Health and Nutrition Examination Survey (NHANES III; 1988 to 1994), the prevalence of metabolic syndrome in the U.S. population ≥20 yr of age is 23.7% (7), rising to >40% in those ≥60 yr of age and in those from specific geographic regions (e.g., south Texas) (8). This compares with a 30.5% prevalence of obesity (body mass index BMI ≥30) and a 64.5% prevalence of overweight (BMI ≥25) in the NHANES III U.S. population sample, reflecting marked increases of 7 to 10%, respectively, in the previous decade (9). Among non-U.S. populations, prevalence ranges from 49.4% of 1625 hypertensive individuals in Spain (10), 19.8% in Greece (11), and 17.8% in older Italians (12). The last cohort exhibited a stepwise increase in 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 children 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 premature coronary heart disease (2). In epidemiologic studies, metabolic syndrome increases risk of developing overt diabetes (16), cardiovascular disease (17,18), and cardiovascular mortality (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 >11 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, Ninomiya et al. (7) described an approximately twofold increase in myocardial infarction and stroke risk in the presence of metabolic syndrome. Pathogenesis of Obesity-Initiated Metabolic Syndrome The NCEP panel identifies the root causes of metabolic syndrome as overweight/obesity, physical inactivity, and genetic factors (2). Unraveling underlying mechanisms has been complicated by the unique multiorgan complexity of this trait cluster. Fundamentally, the metabolic syndrome reflects disordered energy homeostasis. Just as evolution prepared us well for surviving hypotension but poorly for combating hypertension, it has apparently equipped us for surviving the fast but not the feast. Unger (19,20) described metabolic syndrome as "a failure of the system of intracellular lipid homeostasis which prevents lipotoxicity in organs of overnourished individuals," a system that normally acts "by confining the lipid overload to cells specifically designed to store large quantities of surplus calories, the white adipocytes." Central to 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 of metabolic syndrome seems to proceed not as a linear sequence of events but along a matrix of interconnected pathways that mediate interactions among multiple organs and also link these organs as a functional unit to regulate total-body energy homeostasis (Figure 1). Each organ/cell type is typically both a target and an effector within this matrix. Furthermore, disturbance within this matrix of pathways can be initiated 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 homeostasis. However, initiation of metabolic syndrome by obesity, in keeping with the now-recognized role of adipose tissue as an endocrine organ, is characterized by powerful systemic stimuli that together impair energy homeostasis in multiple organs simultaneously, leaving no room for protective compensation. This multiplicity of pathways and targets likely explains the efficacy of obesity as the major generator of metabolic syndrome. 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-α 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 associated with specific metabolic abnormalities: high circulating free fatty acids (FFA) (22); increased intracellular lipid content of not only white adipose tissue (WAT) but also hepatocytes, skeletal myocytes, pancreatic β 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-α (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. 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 resistance to the insulin-sensitizing actions of leptin, and enhanced 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 depots, exhibiting larger adipocytes that contain more triglyceride (TG) and exhibit greater insulin resistance than smaller adipocytes. Adipocyte resistance to the lipogenic effect of insulin yields higher basal rates of lipolysis with increased release of FFA into the portal venous system. This direct access to the liver (see below) may also contribute to the unique impact of visceral fat on energy homeostasis. Abdominal fat may also secrete less leptin than subcutaneous fat. Thus Cnop et al. (28), comparing lean-insulin resistant, lean insulin-sensitive, and obese insulin-resistant adults, found that leptin levels correlated with increasing subcutaneous—but not visceral—fat mass, proposing yet another metabolic distinction between these two compartments. Abdominal fat mass expansion is also coupled with reciprocally reduced release of adiponectin, a multifunctional collagen-like molecule with potent capacity to stimulate fuel oxidation in peripheral tissues (25). Abdominal fat additionally expresses higher levels of renin-angiotensin system components: increased angiotensinogen and increased angiotensin II (Ang II) AT1 receptors (38). Finally, epidemiologic studies confirm the unique significance of abdominal fat mass in predicting microalbuminuria, diabetes, and overall cardiovascular risk (39). It was this compelling evidence for a unique role of central or visceral obesity—in contradistinction to subcutaneous obesity—that prompted the NCEP ATPIII decision to specify abdominal obesity in the clinical definition of metabolic syndrome. These phenomena originating in abdominal adipose tissue generate the clinical picture that we recognize as metabolic syndrome. The roles of FFA excess and adiponectin deficiency are reviewed below in the context of their actions in individual organs; the role of leptin is addressed subsequently to compare and integrate prevailing views of how insulin resistance evolves. Liver Under conditions of normal energy homeostasis, the liver serves as a short-term energy reservoir, taking up absorbed dietary glucose and FFA, synthesizing/storing glycogen, synthesizing/storing TG, and packaging TG into VLDL. During fasting, the liver must sustain a continuous supply of plasma glucose, acutely by glycogenolysis and later in the fasting period by gluconeogenesis. Secreted VLDL provides ongoing TG and ultimately FA fuel to skeletal muscle, heart, and other peripheral tissues via lipoprotein lipase activity in the vascular space. Effect of Excess FFA on Liver Intracellular FFA content is a function of substrate delivery from the plasma and FFA utilization (efflux into mitochondria for oxidation or cytosolic synthesis of intracellular lipids). With abdominal obesity, the increased FFA released into the portal vein from excess visceral fat lipolysis have direct access to the liver. Because cellular FA uptake is substrate dependent, increased hepatocyte FFA uptake ensues (23). Elevated cytoplasmic FA content leads to hepatic insulin resistance. This process involves competition of FA and glucose for access to mitochondrial oxidative metabolism. The molecular mechanism was recently described by Shulman et al. (40,41) (Figure 2), wherein elevated intracellular fatty acyl CoA activates protein kinase Cθ (PKCθ), causing phosphorylation of serine-302 of insulin receptor substrate-1 (IRS-1). This renders IRS-1 unavailable for tyrosine phosphorylation by the activated insulin receptor and reduces all downstream actions of insulin. As a result, the fasting state is simulated and hepatocyte enzymatic machinery is shifted to favor enhanced hepatic gluconeogenesis at the expense of glycogen synthesis. The consequent increase in liver-derived glucose in plasma leads to hyperinsulinemia, a hallmark of metabolic syndrome in its earliest stage and a marker of insulin resistance. The capacity of the insulin-resistant liver to impair secondarily systemic energy homeostasis is illustrated by transgenic studies introducing an insulin-resistant form of the rate-limiting enzyme of liver gluconeogenesis: phosphoenolpyruvate carboxykinase (42). Creating isolated hepatic insulin resistance led to systemic hyperglycemia, hyperinsulinemia, and a moderate increase in fat mass (42). The last reflects WAT utilization of surplus circulating glucose for insulin-induced lipogenesis. In effect, this represents a redistribution of fuel away from the liver to adipose fat stores. These findings emphasize the potential for activating the abnormal metabolic matrix simply by inducing hepatic insulin resistance and also illustrate the dual role of the liver as target and effector in metabolic syndrome derangements. In dogs that were fed an isocaloric moderate-fat diet, striking visceral obesity was associated with marked reduction in the ability of insulin to suppress hepatic gluconeogenesis, even before any reduction in insulin-stimulated glucose uptake appeared; investigators concluded that hepatic insulin resistance plays a dominant role in the pathophysiologic cascade initiated by abdominal obesity (43). FFA overload also provides substrate for increased hepatic TG synthesis and for TG-rich VLDL assembly and secretion. Although details are beyond the scope of this review, the peripheral metabolism of these VLDL generate a small, dense form of highly atherogenic LDL reviewed by Avramoglu et al. (44) along with an increase in plasma TG. In addition, increased hepatic lipase activity in the insulin-resistant state reduces levels of protective HDL-2 cholesterol (45), which is essential to the transport of cholesterol from tissues back to the liver. Thus, hepatic insulin resistance, high plasma TG, and low plasma HDL are pathogenetically linked manifestations of altered lipid regulation in metabolic syndrome. Effect of Adiponectin Deficiency on Liver In addition to the effects of elevated FFA load, the energy-related functions of the liver are profoundly affected by the reduced circulating levels of the adipokine adiponectin. The actions of this multifunctional protein are organ specific and uniformly insulin sensitizing. Adiponectin normally promotes insulin sensitivity in liver in part by enhancing FA oxidation (46); this reduces accumulation of cytoplasmic FA, thereby reducing intracellular FA levels and enhancing insulin action via IRS-1 availability to the insulin receptor. Second, like insulin, adiponectin normally suppresses hepatic gluconeogenic enzymes and induces glycogenetic enzymes. Increase in 5′-AMP-activated kinase mediates these effects of adiponectin (46,47). Conversely, deficiency of adiponectin in states of abdominal obesity directly contributes to insulin resistance by further enhancing accumulation of intracellular FA and FA metabolites and by stimulating hepatic glucose output. The impact of insulin-sensitizing adipokines is apparent from transgenic mouse models that completely lack fat (and thus both adiponectin and leptin) (48). Animals are insulin resistant; the provision of physiologic levels of both adiponectin and leptin fully restores normal energy homeostasis, whereas either alone is only partially effective (48). These studies underscore the regulatory role of fat-derived adipokines and lend logic to the seeming paradox that either too little or too much adipose tissue can lead to insulin resistance (21). Skeletal Muscle Increased circulating FFA also have an impact on skeletal muscle energy homeostasis. Skeletal muscle is normally a major site of glucose and FA uptake, accounting for the bulk of total-body glucose utilization and deriving 60% of resting energy from FA. As in the hepatocyte, increase in intramyocellular FA in skeletal muscle has been to impair insulin receptor by serine phosphorylation of this leads to reduced IRS-1 availability for tyrosine reducing Glut 4 translocation to the plasma with consequent reduction in glucose uptake (6). and glycogen synthesis in skeletal are also reduced. elevated circulating FFA contribute to insulin resistance in both liver and skeletal As in the hepatocyte, reduced adiponectin to increased visceral fat mass insulin resistance in skeletal muscle, also in part via reducing FA oxidation further increasing intramyocellular FA content and insulin action (48). Using in insulin-resistant of with type 2 diabetes, et al. found evidence of a 30% reduction in mitochondrial oxidative phosphorylation together with impaired muscle FA oxidation and an increase in intramyocellular lipid diabetes has also been associated with impaired muscle oxidative capacity Finally, the insulin resistance of is associated with impaired mitochondrial FA oxidative capacity in skeletal muscle energy is a of insulin resistance in skeletal and prediabetic have impaired exercise reduced and uptake at initiation of to the and reduced physical activity typical of resistance stimulates skeletal muscle oxidative enzymes and activates mitochondrial be predicted to basal metabolic both by reducing muscle mass and by muscle energy The physical consequences of these skeletal muscle metabolic abnormalities have not yet been in metabolic syndrome but are likely to the of ongoing and The is the of insulin the at which overt diabetes in the of metabolic syndrome, hepatic gluconeogenesis stimulates the to insulin, Increased FFA uptake by pancreatic cells also increases insulin and of and Glut 2 transporter (23). In the obese hyperinsulinemia is and progressively as overt β cells targets of reduction in insulin-stimulated insulin increase in mitochondrial and lipid also below) with of β cell mass effects of hyperinsulinemia on organ and function in the of metabolic syndrome are not well defined but are to of It is of that interventions that can to overt diabetes evidence that the pathway glucose uptake in vascular of endothelial and a potent and endothelial with by adiponectin These actions mediate a of energy enhancing tissue to insulin resistance insulin-induced is one of mechanisms abdominal resistance and of endothelial for hypertension in metabolic syndrome are addressed in detail by in this Role of in In addition to FFA excess and adiponectin functional leptin deficiency in peripheral tissues is to a role in the evolution of obesity-initiated insulin resistance. is in to fat mass normal via central nervous system receptors to and to enhance the latter stimulating energy utilization and Increase in fat-derived plasma leptin with abdominal obesity states is coupled with poorly understood leptin resistance to central and to peripheral insulin-sensitizing effects of leptin (see thus a functional leptin Central pathways of are addressed separately in this series. Unger and on the basis of compelling that peripheral-tissue leptin resistance is a crucial leading to insulin resistance in metabolic syndrome that major role in normal energy homeostasis is not prevention of obesity, as originally but protection of the of intracellular lipid overload of excess activates cellular fuel by stimulating FA oxidation, reducing enhancing glucose and and fat in adipose tissue as well as in muscle and liver cells Accumulation of cytoplasmic FA thus functional leptin deficiency acting via impaired mitochondrial oxidative capacity and enhanced lipogenesis. The insulin resistance be viewed as a to prevent further accumulation of intracellular reduced glucose glucose-derived (21). The mechanisms of peripheral resistance to the actions of leptin are not yet In excess FFA in the leptin resistance, and adiponectin deficiency are likely acting in to generate intracellular FA their sequence and to be The pathways in these intracellular have been reviewed in detail by Unger and Shulman and Shulman (6). The crucial of and in actions of adiponectin and their in metabolic addressed separately in this series. to Although excess abdominal fat serves to energy homeostasis in multiple other it also a target It is first a target of excess glucose in the vascular space. Increased glucose availability from gluconeogenesis and from reduction in glucose uptake, together with hyperinsulinemia, promote in WAT (Figure 1). This the disturbing that abdominal obesity a Excess activity is to fat from peripheral and to central visceral and to of metabolic syndrome. It thus is not that excess has been in the cause of metabolic syndrome. increased activity and a twofold increased of β in adipose tissue of obese were This enzyme acts to to the thus at a tissue levels of were directly to waist circumference and insulin resistance the of in WAT, transgenic in adipocytes the metabolic syndrome whereas were resistant to a to fat tissue induces systemic metabolic WAT also the target of an inflammatory studies in and adipose tissue documented this process and the role of macrophage infiltration and inflammatory in obesity and metabolic syndrome et al. that increasing mass and increasing fat each with macrophage infiltration in WAT and with increased of proinflammatory (Figure et al. found that in WAT of obese mouse models were inflammatory linked to macrophage in obesity, this inflammatory process within WAT insulin resistance. TNF-α and IL-6 have been to induce insulin resistance in and to contribute to insulin resistance in mouse models of obesity This in inflammatory reaction within WAT may insulin resistance in the adipocytes full circle in of multiorgan energy Figure : infiltration in WAT with mass index and adipocyte content In subcutaneous