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What is metabolic syndrome, and why are children getting it?
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PMID:  23356701     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Metabolic syndrome comprises a cluster of cardiovascular risk factors (hypertension, altered glucose metabolism, dyslipidemia, and abdominal obesity) that occur in obese children. However, metabolic syndrome can also occur in lean individuals, suggesting that obesity is a marker for the syndrome, not a cause. Metabolic syndrome is difficult to define, due to its nonuniform classification and reliance on hard cutoffs in the evaluation of disorders with non-Gaussian distributions. Defining the syndrome is even more difficult in children, owing to racial and pubertal differences and lack of cardiovascular events. Lipid partitioning among specific fat depots is associated with insulin resistance, which can lead to mitochondrial overload and dysfunctional subcellular energy use and drive the various elements of metabolic syndrome. Multiple environmental factors, in particular a typical Western diet, drive mitochondrial overload, while other changes in Western society, such as stress and sleep deprivation, increase insulin resistance and the propensity for food intake. These culminate in an adverse biochemical phenotype, including development of altered glucose metabolism and early atherogenesis during childhood and early adulthood.
Authors:
Ram Weiss; Andrew A Bremer; Robert H Lustig
Publication Detail:
Type:  Journal Article; Review     Date:  2013-01-28
Journal Detail:
Title:  Annals of the New York Academy of Sciences     Volume:  1281     ISSN:  1749-6632     ISO Abbreviation:  Ann. N. Y. Acad. Sci.     Publication Date:  2013 Apr 
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Created Date:  2013-04-04     Completed Date:  2013-06-03     Revised Date:  2014-04-28    
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Nlm Unique ID:  7506858     Medline TA:  Ann N Y Acad Sci     Country:  United States    
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Languages:  eng     Pagination:  123-40     Citation Subset:  IM    
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© 2013 New York Academy of Sciences.
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MeSH Terms
Descriptor/Qualifier:
Age Factors
Body Mass Index
Child
Humans
Insulin Resistance / physiology
Metabolic Syndrome X / diagnosis*,  epidemiology,  metabolism*
Obesity / diagnosis,  epidemiology,  metabolism
Reactive Oxygen Species / metabolism
Risk Factors
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ID/Acronym/Agency:
T32 DK007161/DK/NIDDK NIH HHS
Chemical
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0/Reactive Oxygen Species
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Journal ID (nlm-ta): Ann N Y Acad Sci
Journal ID (iso-abbrev): Ann. N. Y. Acad. Sci
Journal ID (publisher-id): nyas
ISSN: 0077-8923
ISSN: 1749-6632
Publisher: Blackwell Publishing Ltd
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© 2013 The New York Academy of Sciences
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Print publication date: Month: 4 Year: 2013
Electronic publication date: Day: 28 Month: 1 Year: 2013
Volume: 1281 Issue: 1
First Page: 123 Last Page: 140
PubMed Id: 23356701
ID: 3715098
DOI: 10.1111/nyas.12030

What is metabolic syndrome, and why are children getting it?
Ram Weiss1
Andrew A Bremer2
Robert H Lustig34
1Department of Pediatrics, Hadassah Hebrew University School of MedicineJerusalem, Israel
2Department of Pediatrics, Vanderbilt University School of MedicineNashville, Tennessee
3Department of Pediatrics, University of CaliforniaSan Francisco
4The Philip R. Lee Institute for Health Policy Studies, University of CaliforniaSan Francisco
Correspondence: Address for correspondence: Robert H. Lustig, M.D., Division of Pediatric Endocrinology, Box 0434, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0434. rlustig@peds.ucsf.edu

Introduction

The rise in the prevalence of obesity in children and adolescents is one of the most alarming public health issues facing the world today.1 While this rise seems to have leveled in some parts of the world,2 in many others (especially developing countries) it has not, and the prevalence of pediatric metabolic syndrome appears to be increasing.

Childhood obesity can be a harbinger of future health disorders. Childhood obesity tends to track into adulthood: 85% of obese children become obese adults.3,4 Obese toddlers have an odds ratio of 1.3 for becoming obese adults, while obese teenagers have an odds ratio of 17.5.5 Childhood obesity is associated with significant health problems and is an early risk factor for much of adult morbidity and mortality.6,7 While children rarely develop true cardiovascular events, early evidence of accelerated atherogenesis can be detected. Those who remain obese as adults have a significant risk for the development of type 2 diabetes (T2DM), hypertension, dyslipidemia, and atherosclerotic cardiovascular disease (CVD). This cluster of diseases and disorders is collectively termed metabolic syndrome.

Metabolic syndrome affects over 25% of the adult population of the United States.8 Controversy exists regarding the various definitions of the syndrome and the ability of the syndrome to predict future adverse cardiometabolic events in a manner surpassing other well-described risk factors. Despite this, there can be little controversy regarding the current national and worldwide epidemic of obesity, and the links between risk factors in youth and subsequent adult cardiometabolic disease.9,10 Metabolic syndrome is associated with many clinical conditions besides CVD and T2DM, including chronic low-grade inflammation, oxidative stress, hyperuricemia, hypertension, dyslipidemia, hyperandrogenism and polycystic ovary syndrome, hepatic steatosis and nonalcoholic fatty liver disease (NAFLD), impaired glucose tolerance, obstructive sleep apnea (OSA), hypogonadism, vascular dementia and Alzheimer's disease, and certain forms of cancer.11,12 These diseases constitute the overwhelming majority of health care expenditures in the United States,13 and the United Nations Secretary General has declared noncommunicable diseases to be a greater threat to the developing world than acute infectious diseases, including human immunodeficiency virus (HIV).14

However, it should be noted that 20% of morbidly obese individuals are metabolically healthy and have normal life spans,15,16 while up to 40% of adults of normal weight harbor metabolic perturbations typically associated with obesity, including hypertension, dyslipidemia, NAFLD, and CVD.17,18 Thus, obesity may not be a primary cause of metabolic syndrome; rather, it may be another marker for the underlying metabolic dysfunction that potentially drives its development. Aging does not explain metabolic syndrome either, as young children can manifest these same biochemical processes, especially dyslipidemia, NAFLD, and T2DM.19 Thus, metabolic syndrome should be considered a marker for the presence of increased CVD risk rather than a specific phenotype, and metabolic syndrome is now as much a pediatric condition as an adult condition.20 How can children experience this degree of metabolic dysfunction?


Definition of metabolic syndrome
Adults

The notion that cardiovascular risk factors cluster in certain individuals has been known for several decades. However, it was not until the early 1980s that the relationship between obesity, dyslipidemia (particularly hypertriglyceridemia), and hypertension was recognized.21 In the late 1980s–early 1990s, the central roles of insulin resistance (specifically resistance to insulin-stimulated glucose uptake) and abdominal obesity in the syndrome became apparent.22 Our current paradigm of metabolic syndrome was established in 1988, when Reaven described the role of insulin resistance in human disease and the interrelation between insulin resistance, hypertension, T2DM, and CVD.11 Although Reaven used the term Syndrome X to describe the interrelationships of these conditions, many other terms, including the deadly quartet, the cardiometabolic syndrome, and the insulin resistance syndrome have been and continue to be used in the medical literature. Due to the collection of different components, and the reliance of cutoff thresholds of different non-Gaussian distributions, several organizations have established different diagnostic criteria for metabolic syndrome. Nonetheless, the same clustering of CVD risk factors that had been first observed in adults in the early 1920s23 became evident in obese children by the mid-1990s.24

Children

Although many attempts have been made to define metabolic syndrome in the pediatric population, to date no consensus definition exists. Indeed, a writing committee of the American Heart Association in 2009 refused to define it (RHL was a committee member).25 In 2007, the International Diabetes Federation (IDF) attempted a definition of pediatric metabolic syndrome using age-specific diagnostic criteria26 and proposed that metabolic syndrome be considered in (1) children aged 6–10 years who are obese (defined as waist circumference (WC) ≥90th percentile) and have other relevant risk factors (such as family history of cardiometabolic disease) and in (2) children aged 10–16 years who are obese (defined as WC ≥90th percentile) and meet the adult metabolic syndrome criteria for triglycerides (TGs), HDL-cholesterol (HDL-C), blood pressure (BP), and glucose concentrations. Using the IDF definition in the pediatric population and data from the National Health and Nutrition Examination Survey (NHANES) database, the reported prevalence of metabolic syndrome in U.S. adolescents for the period 1999–2004 was approximately 4.5%; it increased with age, was higher among males (6.7%) than females (2.1%), and was highest among Mexican-American adolescents (7.1%).27

Several methodological and physiological limitations complicate the establishment of a definition for pediatric metabolic syndrome. For example, children develop transient physiologic insulin resistance during puberty,28,29 and normal lipid levels vary by age, sex, and race.30 Reliance on a fasting blood sample makes diagnosis and detection simple and cheap yet prevents the utilization of a postglucose load sample to detect impaired glucose tolerance (which is a better marker of peripheral insulin resistance in this age group than is a fasting sample). Other barriers include the lack of standardized central obesity measures in children, the lack of normal ranges for insulin assays and concentrations across childhood, and the fact that disturbances in many of the metabolic perturbations associated with metabolic syndrome in children are usually moderate. Children and adolescents with metabolic syndrome may not have the same degree of laboratory abnormalities as those seen in adults.25 While laboratory values for some of these phenotypes reflect a risk factor continuum, conventional definitions of metabolic syndrome employ threshold values, creating a false binary system that may obscure important information. One promising approach to overcome this barrier is to use the measurements of metabolic syndrome elements as continuous variables and to sum the z-scores of each component in order to quantify the risk.31 It has been shown that children of different ethnic backgrounds differ in patterns of lipid partitioning, the major contributor to the development of insulin resistance, and in their metabolic profiles of specific risk markers such as lipids.32 Thus, youths of African American origin seem to be “protected” from the syndrome when standard definitions are used, in contrast to the overall worse cardiovascular outcome seen in adults of this ethnic background.

As such, the criteria for metabolic syndrome used in most pediatric studies to date have been variably adapted from adult definitions and standards with the use of available sex- and age-dependent normative values. As in the adult definitions of metabolic syndrome, almost all of them include the following five elements: (1) an elevated TG level, (2) a reduced HDL-C level, (3) a raised BP, (4) an elevated fasting plasma glucose concentration, and (5) an increased WC. Furthermore, most definitions allow for a partial combination of the above factors rather than a requirement that all five be present in order to define metabolic syndrome.

The stability of metabolic syndrome definitions in childhood has been questioned, specifically when assessing the less stringent criteria in obese and normal weight children. Indeed, upon testing normal weight children, the signal to noise ratio of these definitions is low and minor changes induced by normal growth may result in a change in the metabolic syndrome status of an individual.33 In contrast, when such definitions are tested in the population at risk (i.e., obese children), weight reduction may still affect their stability yet weight maintenance or gain leads to a stable and reproducible definition.34

Currently, 17% of all children and adolescents in the United States are obese,35 and childhood obesity is associated with insulin resistance,3638 abnormal glucose metabolism,39 elevated BP,40 dyslipidemia,41 inflammation,27 and compromised vascular function42—all components of metabolic syndrome.25 Obesity and its metabolic complications also track from childhood to adulthood.43 So, not only is childhood obesity a strong predictor of subsequent obesity, insulin resistance, and dyslipidemia in adulthood, but weight gain in excess of normal growth during childhood is also a determinant of adult cardiovascular risk.12

However, the body mass index (BMI), a calculation (kg/m2) based on weight and height that is used to define “overweight” and “obesity,” does not account for all variances in insulin sensitivity and cardiometabolic risk.44 Furthermore, there is considerable debate as to the metabolic differences between visceral and subcutaneous fat and the role of these fat depots in cardiometabolic disease. As such, obesity does not automatically indicate the presence of metabolic syndrome. Lipid partitioning (i.e., the distribution of fat among its potential depots) is much more related to the metabolic phenotype of obese children and adolescents than the degree of obesity.10 Thus, lipid partitioning is a major determinant of peripheral insulin sensitivity and is strongly associated with other metabolic biomarkers such as systemic inflammation and free fatty acid fluxes. These elements determine the metabolic milieu and phenotype of the individual much more than the degree of obesity per se. Again, obesity is a marker for metabolic dysfunction, not the cause.

An early marker of cardiovascular disease in childhood is intimal–medial thickness (IMT), a surrogate of early atherogenesis. When the various published definitions of metabolic syndrome were tested in overweight and obese adolescents along with IMT measurements, only the most conservative definitions were significantly correlated with the degree of IMT, and the presence of impaired glucose tolerance had a strong positive predictive value for the top quartile of IMT.45 These observations suggest that the definition of metabolic syndrome should probably be more conservative (e.g., the extreme 5% vs. 10%) in children than in adults, and that the presence of impaired glucose tolerance—-the early sign of altered glucose metabolism—-should be interpreted as a generalized proatherogenic metabolic state. While some investigators suggest that actual carotid plaques (rather than overall arterial wall thickening) are the true expression of atherosclerosis in this age group, carotid plaques have not been sufficiently studied as outcome variables in children. While standard definitions of metabolic syndrome, along with weight changes, have also been shown to predict the development of prediabetes and type 2 diabetes at the age of 24 years,46 the presence of impaired glucose tolerance in adolescents (a component of metabolic syndrome in some definitions) is the best predictor of progression to overt diabetes in adolescence.47


Pathogenesis of metabolic syndrome
Insulin resistance

The association and clustering of T2DM, hypertension, dyslipidemia, and CVD in adults has led to the hypothesis that the various phenotypes of metabolic syndrome arise from a common antecedent. The World Health Organization (WHO) argues that this antecedent is insulin resistance.11,4850

Insulin resistance is defined as the decreased tissue response to insulin-mediated cellular actions and is the inverse of insulin sensitivity. The term insulin resistance, as generally applied, refers to whole-body reduced glucose uptake in response to physiological insulin levels and its consequent effects on glucose and other insulin-driven metabolic pathways. However, it is now clear that not all tissues in such individuals show equal resistance to insulin. Generalized marked insulin resistance results in global metabolic dysfunction, such as Donohue syndrome or Rabson–Mendenhall syndrome. Thus, the insulin resistance of obesity must of necessity affect different tissues and even different signal transduction pathways within the same tissue differently.

Hepatic insulin resistance

The liver plays a major role in substrate metabolism and is the primary target of insulin action. After insulin is released from the β cell following a glucose load, it travels directly to the liver via the portal vein, where it binds to the insulin receptor and elicits two key actions at the level of gene transcription. First, insulin stimulates the phosphorylation of FoxO1, preventing it from entering the nucleus51,52 and diminishing the expression of genes required for gluconeogenesis, principally phosphoenolpyruvate carboxy-kinase and glucose 6-phosphatase. The net effect is diminished hepatic glucose output. Second, insulin activates the transcription factor sterol regulatory element-binding protein (SREBP)-1c, which, in turn, increases the transcription of genes required for fatty acid and TG biosynthesis, most notably ATP-citrate lyase, acetyl-coenzyme A carboxylase, and fatty acid synthase, which together promote the process of de novo lipogenesis (DNL). TGs synthesized by DNL are then packaged with apoliprotein B (apoB) into very low-density lipoproteins (VLDL), which are then exported to the periphery for storage. VLDLs can then be utilized by reciprocal activation of lipoprotein lipase (LPL) on the surfaces of endothelial cells in adipose or muscle tissues.53

For reasons that remain unclear, insulin resistant subjects typically have selective or dissociated hepatic insulin resistance; that is, they have impaired insulin-mediated glucose homeostasis (mediated by the FoxO1 pathway) but enhanced insulin-mediated hepatic DNL (mediated by the SREBP-1c pathway).54 The increase in free fatty acid (FFA) flux within the liver, either by DNL or FFA delivery via the portal vein, impairs hepatic insulin action,55,56 which, in turn, leads to increases in hepatic glucose output, the synthesis of proinflammatory cytokines, excess TG, low HDL-cholesterol secretion by the liver, and an elevated number of relatively cholesterol-depleted small dense LDL particles.57 This intrahepatic accumulation of FFA and lipids is also detrimental to liver insulin sensitivity, as it leads to the generation of toxic lipid-derived metabolites, such as diacyglycerol (DAG), fatty acyl CoA, and ceramides. These, in turn, trigger activation of protein kinase C-ɛ (PKCɛ,) and serine/threonine phosphorylation of IRS-1, which attenuates hepatic insulin signal transduction.58

Adipose tissue insulin resistance

The expanded adipose tissue mass that accompanies obesity often leads to increased lipolysis and FFA turnover. Normally, insulin inhibits adipose tissue lipolysis; however, in the insulin resistant state, the process is accelerated, leading to increased FFA release into the circulation. Moreover, visceral adipocytes are more sensitive to catecholamine-stimulated lipolysis than subcutaneous adipocytes, further increasing FFA flux.59 Macrophages also infiltrate into adipose tissue and contribute to both adipocyte hypertrophy and cytokine release.60,61 These circulating cytokines also affect insulin action in other tissues, such as liver and muscle.

Muscle insulin resistance

Downstream of an insulin resistant liver, increased plasma FFA levels disrupt the glucose-fatty acid or Randle cycle and insulin-mediated glucose uptake by skeletal muscle,62,63 facilitating the development of hyperglycemia. The ectopic deposition in skeletal muscle of fat as intramyocellular lipid may also play a direct role in the pathogenesis of insulin resistance and metabolic syndrome via lipid metabolite-induced activation of protein PKCɛ with subsequent impairment of insulin signaling.58

The two most important biological effectors associated with insulin resistance in childhood are ethnicity and puberty. Studies show that African American, Hispanic, Pima Indian, and Asian children are less insulin sensitive compared to BMI-matched Caucasian children.64 The insulin resistance in minority ethnic groups is manifested as lower insulin-stimulated glucose uptake, concomitant with hyperinsulinemia (evidence of increased insulin secretion from the β cell) and decreased insulin clearance.65 During puberty, there is a 25–50% decline in insulin sensitivity with recovery when pubertal development is complete.66 However, the compensatory increase in insulin secretion during puberty may be blunted in African American and Hispanic youth, thus increasing their risk for T2DM.67

Lipid partitioning

The term lipid partitioning refers to the distribution of body fat in various organs and compartments. The majority of excess fat is stored in its conventional subcutaneous depot, yet other potential storage sites exist as well, such as the intraabdominal (visceral) fat compartment and insulin-responsive tissues such as muscle and liver. Although still debated, one potential etiology of metabolic syndrome is shown in Figure 1. According to this paradigm, the impact of obesity is determined by the pattern of lipid partitioning (i.e., the specific depots in which excess fat is stored). This pattern of lipid storage determines the secretion profile of adipocytokines and its effect on circulating concentrations of inflammatory cytokines and FFA flux. The combined effects of these factors determine the sensitivity of insulin-mediated pathways within target organs (such as muscle and liver) and influence the vascular system by affecting endothelial function.

One hypothesis to explain the relationship between obesity and insulin resistance is the portal-visceral paradigm,68 which suggests that increased adiposity causes accumulation of fat in the visceral depot, leading to an increased portal and systemic FFA flux69 (Fig. 1). Associations between visceral adiposity, insulin resistance, and comorbidities have been demonstrated across most age groups and ethnicities.70 However, studies of in vivo FFA fluxes from the visceral and the subcutaneous truncal and abdominal depots have failed to demonstrate a substantial difference in net fluxes between these depots.71

Subcutaneous fat, which does not drain into the portal system, is strongly related to insulin resistance in both healthy obese and diabetic men.72 Similarly, truncal subcutaneous fat mass has been demonstrated to independently predict insulin resistance in obese women. Visceral and subcutaneous fat differ in their biologic properties,73 as visceral fat is more resistant to insulin and has increased sensitivity to catecholamines. These observations emphasize that both visceral and subcutaneous abdominal fat can contribute to insulin resistance, possibly by different mechanisms.74

Recent studies performed in obese adolescents highlight the fact that the ratio of visceral to subcutaneous fat, rather than the absolute quantity of body fat, may be the determinant of metabolic impact. Indeed, obese adolescents with a high ratio, relative to even more obese individuals with lower ratios, demonstrate a markedly adverse metabolic phenotype of severe insulin resistance and alterations in glucose and lipid metabolism.75 Moreover, intrahepatic fat, while strongly associated with high levels of visceral fat, is independently associated with the insulin-resistant state in obese adolescents, independent of all other fat depots.76

An alternative theory to explain the relationship between obesity and insulin resistance is the “ectopic lipid deposition” paradigm.77 This theory is based on the observations that lipid content of insulin responsive tissues such as liver and/or muscle is increased in obesity and in T2DM and is a strong predictor of insulin resistance.78,79 Moreover, in conditions such as lipodystrophies, all fat is stored in liver and muscle due to lack of subcutaneous fat tissue, causing severe insulin resistance and diabetes.80 In obese adults (BMI > 30 kg/m2), muscle attenuation on computed tomography (CT), representing lipid content, is a stronger predictor of insulin resistance than is visceral fat.81 Studies performed in vivo using 1H-NMR spectroscopy also demonstrated increased intramyocellular lipid (IMCL) content to be a strong determinant of insulin resistance in adults82 and in obese adolescents.83 Furthermore, lipid deposition in hepatocytes and the production of intrahepatocellular lipid (IHCL) are highly predictive of insulin resistance, even more so than visceral fat.84 Thus, morbidity may begin when the subcutaneous fat depot reaches its storage capacity and begins to shunt lipid to ectopic tissues, such as liver and muscle, leading to peripheral insulin resistance,85 or alternatively when the liver or muscle accumulates fat produced by DNL in response to dietary factors (see below).

Another postulated cause of IMCL and IHCL accumulation is not lipid shunting from adipose depots, but rather de novo lipogenesis along with a reduction of β-oxidation of fat86 due to low aerobic capacity, a reduced number or malfunction of mitochondria, or reduced sympathetic tone. The effects of IMCL or IHCL accumulation on peripheral insulin sensitivity are postulated to result from an alteration of the insulin signal transduction pathway, caused by derivates of fat such as long chain fatty acyl-CoA and DAG in the hepatocyte or myocyte. In muscle, these derivatives activate the serine/threonine kinase cascade and cause serine phosphorylation of IRS-1, which inhibits insulin signaling.87 A comparable mechanism has been demonstrated in the liver, where accumulation of lipids, DAG in particular, activates the inflammatory cascade by inducing c-jun N-terminal kinase (JNK-1), which causes serine rather than tyrosine phosphorylation of IRS-1 and leads to inhibition of hepatic insulin signaling.88,89

Adipocytokines
Leptin

The discovery of leptin in 1994 dramatically changed the view of adipose tissue in the regulation of energy balance.90 Adipocytes secrete several proteins that act as regulators of glucose and lipid homeostasis.91 These proteins have been collectively referred to as adipocytokines because of their structural similarities with cytokines. Circulating leptin levels serve as an adiposity sensor to protect against starvation and correlate with the degree of obesity. Leptin probably has a permissive role in high-energy metabolic processes such as puberty, ovulation, and pregnancy, but its role in states of energy excess is less known. In obesity, the development of leptin resistance may result in a breakdown of the normal partitioning of surplus lipids in the adipocyte compartment.92

Adiponectin

Adiponectin is peculiar because, in contrast to the other adipocytokines, its level is reduced in obesity.93 The adiponectin gene is located on chromosome 3q27, a location previously linked to the development of T2DM and metabolic syndrome. Several single nucleotide polymorphisms (SNPs) in the adiponectin gene have been reported to be associated with the development of T2DM in populations around the world, suggesting that adiponectin plays a major role in glucose and lipid metabolism.94 Adiponectin circulates in plasma in three major forms: a low molecular weight trimer, a middle molecular weight hexamer, and a high molecular weight 12- to 18-mer.95 Circulating plasma adiponectin concentrations demonstrate a sexual dimorphism (females have higher concentrations), suggesting a role for sex hormones in the regulation of adiponectin production or clearance. Dietary factors such as linoleic acid or fish oil versus a high carbohydrate diet or increased oxidative stress have been shown to increase or decrease adiponectin concentrations, respectively. These observations suggest that the circulating levels of adiponectin are regulated by complex interactions between genetic and environmental factors.96

Two adiponectin receptors, named ADIPOR1 and ADIPOR2, have been characterized. ADIPOR1 is expressed in numerous tissues including muscle, while ADIPOR2 is mostly restricted to the liver. Both receptors are bound to the cell membrane, yet are unique in comparison to other G protein–coupled receptors in the fact that the C-terminus is extracellular while the N-terminus is intracellular.97 Both ADIPOR1 and ADIPOR2 are receptors for the globular head of adiponectin and serve as initiators of signal transduction pathways that lead to increased peroxisome proliferator-activated receptor (PPAR)-α and AMP kinase activities, which promote glucose uptake and fatty acid oxidation. Adiponectin has also been shown to have potent antiatherogenic functions, as it accumulates in the subendothelial space of injured vascular walls, reducing the expression of adhesion molecules and the recruitment of macrophages.98

Studies in obese children and adolescents have shown that adiponectin levels are inversely related to the degree of obesity, insulin resistance, visceral adiposity, IHCL, and IMCL, while weight loss increases adiponectin concentrations. A fall in adiponectin levels has also been shown to coincide with the onset of insulin resistance99 and the development of diabetes in monkeys.100 All of these observations, along with human clinical data, support a pivotal role for adiponectin in the prevention of the comorbidities of metabolic syndrome.

Inflammatory cytokines

Accumulating evidence indicates that obesity is associated with subclinical chronic inflammation.101 Thus, the adipose tissue serves not merely as a simple reservoir of energy, but also as an active secretory organ releasing many peptides, including inflammatory cytokines, into the circulation. In obesity, the balance between these peptides is altered, such that larger adipocytes and macrophages embedded within them produce more inflammatory cytokines (i.e., TNF-α and IL-6) and fewer anti-inflammatory peptides such as adiponectin.102 One theory posits that as energy accumulates in adipocytes, the perilipin border of the fat vacuole breaks down, causing the adipocyte to die.103 Cell death then recruits macrophages in the adipose tissue, especially the visceral compartment, that in the process of clearing debris also secrete inflammatory cytokines, initiating a proinflammatory cascade that predates and possibly drives the development of systemic insulin resistance, diabetes, and endothelial dysfunction.104,105 Systemic concentrations of C-reactive protein (CRP) and IL-6, two major markers of inflammation, are increased in obese children and adolescents. Indeed, CRP levels within the high-normal range have been shown to predict CVD106 and the development of T2DM107 in adults. Elevated levels of CRP also correlate with other components of metabolic syndrome in obese children.108,109 Thus, inflammation may be one of the links between obesity and insulin resistance, and may also promote endothelial dysfunction and early atherogenesis.

Most of the aforementioned molecules have been associated with elements of metabolic syndrome and its characteristic pattern of lipid partitioning. Specifically, low adiponectin levels have been associated with insulin resistance, low-grade inflammation and increased intramyocellular fat.110 High leptin concentrations have also been shown to be associated with metabolic syndrome in adults.111 Moreover, factor analyses of plasma leptin concentrations and the variables that are considered relevant to metabolic syndrome revealed a clustering of plasma leptin concentrations with insulin resistance and hyperinsulinemia.112

Reactive oxygen species

The free radical theory holds that an imbalance between reactive oxygen species (ROS) generation and antioxidant defenses is a major factor in the determination of lipid peroxidation and protein misfolding, with resultant DNA and cellular damage.113 Excessive intracellular ROS formation occurs via three pathways: (1) inflammatory cytokines derived from visceral fat accumulation;114 (2) dysfunctional mitochondrial energetics;115 and (3) glycation (see below). Excessive nutrient processing by mitochondria can result in uncoupling of oxidative phosphorylation and an increased generation of ROS; this, in turn, leads to altered mitochondrial function and further ROS generation.116 ROS accumulation can also impair endoplasmic reticulum (ER) function, causing ER stress and the compensatory unfolded protein response (UPR). The UPR can itself be overwhelmed by persistent excessive nutrient processing and ROS generation, leading to cellular shutdown, defective insulin secretion, and T2DM117,118 (Fig. 2).

As ROS generation is an inherent by-product of cellular metabolism, endogenous cellular antioxidants (e.g., catalase and glutathione) quench the ROS before they have a chance to promote peroxidation. These antioxidants are found primarily in peroxisomes, which abut the mitochondria, and support ROS processing. A reduction in peroxisomal activity results in mitochondrial dysfunction and ER stress. Cytokines such as TNF-α can reduce peroxisomal number and function, rendering cells even more vulnerable.119,120

ER stress and the UPR

Excessive ROS that are not quenched by peroxisomes find their way to the adjacent ER, where they alter the redox environment crucial for proper protein folding.121 Accumulation of ROS and misfolded proteins within the ER activates the UPR,122 which is designed to decrease protein synthesis in order to allow for their clearance.123 However, excessive ROS levels impair the ability of a cell to clear misfolded proteins and activate the enzyme caspase-3, leading to even further ROS generation, apoptosis, and cellular demise.124 ER stress in the liver is a specific mechanism of hepatic injury in NAFLD,125 and ER stress in the pancreas reduces β-cell number and promotes diabetes.126


Environmental antecedents

If obesity is not the cause of metabolic syndrome, what is? Although many investigators have searched for genetic predispositions, it has been estimated that only 10% of metabolic syndrome cases can be explained by genetics.127 Alternatively, numerous environmental correlates have been identified. However, most of these associations are cross-sectional rather than longitudinal; and in many cases mechanisms remain undiscovered.128

Stress and cortisol

In humans, elevated cortisol or markers of hypothalamic–pituitary–adrenal (HPA) axis dysregulation correlate with abdominal fat distribution and metabolic syndrome.129 Although circulating cortisol is clearly important in determining visceral adiposity, the reduction of circulating cortisone to cortisol within visceral fat tissue by the enzyme 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) has also recently been linked to metabolic syndrome.130,131 These data suggest that cortisol is important both in increasing visceral adiposity and in promoting metabolic syndrome.

In adults, job stress and depression stress are associated with increased cortisol secretion,132 which leads to insulin resistance and metabolic syndrome. Psychosocial stresses correlate with an elevated risk of myocardial infarction in adults,133 and it is assumed that such patients exhibit increased HPA axis activation.134 Even exogenous glucocorticoid administration is a risk factor for CVD events.135 Evidence of associations between elevated cortisol and psychological distress with abdominal fat distribution in adults is compelling. For instance, urinary glucocorticoid excretion is linked to aspects of metabolic syndrome, including BP, fasting glucose, insulin, and WC.129 The role of cortisol in mediating visceral fat accumulation, insulin resistance, and T2DM has been elegantly demonstrated by transgenic knockout and overexpression models of 11β-HSD1.130,131 It appears that some individuals are high responders to stress stimuli and demonstrate higher cortisol secretion. These individuals seem more prone to alterations in satiety recognition and consume larger amounts of calories following the stress exposure. Thus, cortisol appears to be important both in increasing visceral adiposity and promoting metabolic syndrome—equivalent to Cushing's syndrome of the abdomen.136 However, the role of stress and cortisol in childhood obesity is currently speculative.

Sleep deprivation

Americans get significantly less sleep than they did three decades ago. Adults in the United States currently average less than seven hours of sleep per night—almost two hours less than in 1980—and about one-third of them get less than six hours per night.137 Analyses of data from NHANES I revealed that adults (32–49 years old) who slept less than seven hours per night were more likely to be obese five to eight years later than those who slept seven or more hours.138 Similarly, a 13-year prospective cohort study in which participants were interviewed at 27, 29, 34, and 40 years of age found that sleep duration correlated negatively with obesity.139 The link between short sleep duration and obesity has also been observed among children.140 Like adults, increasing numbers of children are chronically sleep deprived. This is especially true of obese children, who have been found to get less sleep than normal weight children. In addition to its other effects, sleep is one of the most powerful cross-sectional141 and longitudinal142 predictors of obesity in prepubertal children. Obesity is a major risk factor for OSA at all ages and OSA is tightly linked mechanistically to insulin resistance and low-grade inflammation, the drivers of metabolic syndrome.143 Although relatively little is known about the mechanism(s) for the sleep–obesity relationship,144 especially among children, there are reasons to suspect increased stress and altered activity of various hormones, such as leptin, ghrelin, and cortisol.

Dietary factors

While the primary focus regarding obesity has been on total calories ingested, an emerging evidence base suggests that the quality of those calories play an important role in the pathogenesis of the metabolic syndrome by increasing hepatic insulin resistance and/or increasing ROS formation.

Dietary fat versus carbohydrate

Fat is generally considered more obesogenic than other macronutrients, given that it has greater energy density, is highly palatable, and is more effectively converted to body fat.145 A high-fat diet induces decreased thermogenesis and a higher positive fat balance than an isocaloric and isoproteic low-fat meal.146 Excessive fat intake is believed to cause weight gain,147 but the relationship between dietary fat intake and childhood adiposity remains controversial.148

The prevalence of overweight individuals in the United States has increased despite a decreased percentage of dietary energy derived from fat. A meta-analysis of 12 studies in overweight or obese adults who were given dietary advice on a low-fat diet and followed for 6–18 months suggested that low-fat diets are no more effective than calorie-restricted diets for long-term weight loss.149 Similarly, in children, total fat consumption expressed as a percentage of energy intake has decreased.150 This decrease in fat consumption has been paralleled by an increase in total energy intake, mostly in the form of carbohydrates. Much of this imbalance is attributed to changing beverage consumption patterns, characterized by declining milk intakes and substantial increases in soft-drink consumption,151 which may have its own etiopathogenesis to metabolic syndrome (see below). Moreover, most interventions with a low-fat, heart-healthy diet have not been successful in childhood overweight prevention.152

Reduction in carbohydrate intake is taken to the extreme in the Atkins diet, which restricts adult subjects to less than 25 gm/day of ingested carbohydrate. Adult evaluations of the diet have been disappointing long term, 153,154 and there is currently a single study regarding the effect of the modified carbohydrate diet on obesity in children or adolescents that demonstrated short-term efficacy yet difficulties in adherence.155 However, it should be noted that the ketogenic diet used for seizure control is similar in composition to the Atkins diet. A two-year study of the ketogenic diet demonstrated persistent decreases in weight z-scores in children who were above average upon diet initiation, without significant compromise in general nutrition or in height.156

Fructose

The most commonly used sweetener in the U.S. diet is the disaccharide sucrose (e.g., table sugar), which contains 50% fructose and 50% glucose. However, in North America and many other countries, nondiet soft drinks are sweetened with high-fructose corn syrup (HFCS), which contains up to 55% of the monosaccharide fructose. HFCS is found in processed foods ranging from soft drinks and candy bars to crackers, hot dog buns, and ketchup. Average daily fructose consumption has increased by over 25% over the past 30 years, and the growing dependence on fructose in the Western diet may be fueling the obesity and T2DM epidemics.157 The highest fructose loads are soda (1.7 gm/oz) and juice (1.8 gm/oz). Although soda has received most of the attention,158,159 high fruit juice intake is also associated with childhood obesity, especially in lower income families.160

Animal models demonstrate that high-fructose diets lead to increased energy intake, decreased resting energy expenditure, excess fat deposition, and insulin resistance,161,162 which also suggest that fructose consumption is playing a role in the epidemics of insulin resistance, obesity, and T2DM in humans.163,164

Fructose in the gut is transported into the enterocyte via the fructose transporter, Glut5, independent of ATP hydrolysis and sodium absorption. Once inside the enterocyte, a small portion of the fructose load is converted to lactic acid and released in the portal circulation, another small portion may also be converted to glucose. However, the majority of ingested fructose is secreted into the portal circulation and delivered to the liver. There, fructose is rapidly metabolized to fructose-1-phosphate (F1P) via fructokinase, an insulin-independent process that also bypasses the negative feedback regulation of phosphofructokinase in the glycolytic pathway. Thus, fructose metabolism generates lipogenic substrates (e.g., glyceraldehyde-3-phosphate and acetyl-CoA) in an unregulated fashion, which are delivered straight to the mitochondria. This excessive mitochondrial substrate then drives hepatic DNL, which can then overwhelm apoB and the lipid export machinery, leading to intrahepatic lipid deposition and steatosis.165 Hepatic DNL also limits further fatty acid oxidation in the liver via excess production of malonyl-CoA, which reduces entry of fatty acids into the mitochondria by inhibiting carnitine palmitoyl transferase-1 (CPT-1). F1P activates dual-specificity mitogen-activated protein kinase 7 (MKK7), which subsequently stimulates JNK-1, a hepatic enzyme considered to act as a bridge between hepatic metabolism and inflammation.166 In addition, the lipogenic intermediate DAG (formed during fructose metabolism in the liver) activates PKC-ɛ, which leads to serine phosphorylation of IRS-1 that inactivates it and leads to hepatic insulin resistance.165 This impairs insulin-mediated phosphorylation of FoxO1, leading to increased expression of the genes required for gluconeogenesis and promoting increased hepatic glucose output, which subsequently contribute to hyperglycemia and the development of T2DM. The excess TGs secreted from the liver into the circulation as fat-laden VLDL particles following the ingestion of fructose, coupled with a fructose-induced reduction in LPL activity, cause sustained postprandial dyslipidemia, thereby augmenting the risk for CVD167,168 (Fig. 3).

Fructose also does not suppress secretion of the so-called hunger hormone ghrelin, levels of which correlate with perceived hunger.169 In sum, fructose consumption has metabolic and hormonal consequences that facilitate development of obesity and the metabolic syndrome.164

Due to its unique stereochemistry, the ring form of fructose is under a great deal of ionic strain, which favors the linear form of the molecule, exposing the reactive 2-keto group, which can readily engage in the nonenzymatic fructosylation of exposed amino moieties of proteins via the Maillard reaction in the same way that the 1-aldehyde position of glucose is reactive.165 Each Maillard reaction generates one ROS, which must be quenched by an antioxidant at the risk of cellular damage. In an in vitro study, incubation of hepatocytes with fructose yielded no direct damage; however, when these hepatocytes were preincubated with sublethal doses of hydrogen peroxide to reduce their peroxisomal ROS-quenching ability, fructose then became as hepatotoxic as other organic aldehydes.170 Furthermore, an in vivo study in antioxidant-deficient mice demonstrated that intrahepatic lipid toxicity and hepatocellular death occurred following sucrose administration.171 These data thus suggest that excessive ROS, in combination with micronutrient insufficiencies that impair antioxidant reserves, can lead to cellular damage and promote the metabolic syndrome.

Branched-chain amino acids

Branched-chain amino acids (BCAAs: valine, leucine, and isoleucine) are essential amino acids that account for more than 20% of the amino acids in the typical Western diet.172 Although normally utilized for protein biosynthesis and cell growth, when provided in excess they are diverted away from protein synthesis and toward energy utilization.173

In the liver, BCAAs increase transcription of ChREBP and SREBP-1c,174 facilitating DNL. Furthermore, BCAAs limit insulin-induced PI3K signaling and stimulate the activation of the mammalian target of rapamycin (mTOR), promoting the serine phosphorylation of IRS-1 and impairment of insulin signaling. In addition, just as there are obesity-related changes in adipokines and cardiovascular risk markers, there also appear to be obesity-associated changes in BCAA metabolism and resulting serum levels. In particular, valine and leucine/isoleucine levels have been reported to be 20% and 14% higher, respectively, in obese compared to lean subjects.173 Mechanistically, this appears to be accounted for by a high rate of flux through the BCAA catabolic pathway, resulting in the increased production of alanine. Since alanine is a highly gluconeogenic amino acid, increased BCAA catabolism may thus contribute to increased hepatic glucose output.175 Furthermore, the increased α-ketoacids generated by increased flux of the BCAAs through their catabolic pathways also potentially suppress mitochondrial β-oxidation.

Furthermore, chronic BCAA elevation impairs the transport of aromatic amino acids into the brain; the reduced production of serotonin (derived from tryptophan) and catecholamines (derived from phenylalanine and tyrosine) may drive hunger.173 The BCAA overload hypothesis suggests that in the context of a dietary pattern that includes high fat consumption, BCAAs may make an independent contribution to the development of insulin resistance, a hypothesis supported by metabolomic studies demonstrating high BCAA levels in normoglycemic individuals that subsequently develop insulin resistance and diabetes.176,177 Although the data supporting a role of BCAAs in the development of metabolic syndrome components are currently only correlative in nature, the BCAA overload hypothesis is intriguing and relevant.

Ethanol

Although adult epidemiological studies associate light to moderate ethanol consumption with improved insulin sensitivity and wine consumption with reduced cardiovascular risk, other cross-sectional and prospective studies implicate a dose-dependent effect of alcohol in metabolic syndrome, and suggest that chronic consumption of large amounts of ethanol worsen insulin sensitivity. Ethanol bypasses glycolysis by being converted by alcohol dehydrogenase-1B into acetaldehyde, which promotes ROS formation and must also be quenched by hepatic antioxidants such as glutathione or ascorbic acid to prevent cellular damage. Acetaldehyde is then metabolized by the enzyme aldehyde dehydrogenase-2 to acetic acid, which, in turn, is metabolized by the enzyme acyl-CoA synthetase short-chain family member 2 to form acetyl-CoA. The acetyl-CoA can then enter the mitochondria; or, in the presence of other caloric substrates, it is preferentially used for the synthesis of fatty acids through DNL. The excess malonyl-CoA produced from ethanol metabolism inhibits CPT-1, limiting mitochondrial fatty acid β-oxidation. Ethanol also blocks fatty acid β-oxidation by inhibiting PPAR-α, which suppresses microsomal triglyceride transfer protein, thereby altering the liver's lipid export machinery.178181 Buildup of intrahepatic lipid metabolites leads to subsequent activation of the enzyme JNK-1 and serine phosphorylation of IRS-1, driving further hepatic insulin resistance. Thus, ethanol metabolism results in intrahepatic lipid accumulation and liver injury, driving hepatic insulin resistance and promoting metabolic syndrome.182 However, while clearly a concern in adults, the likelihood that ethanol contributes significantly to metabolic syndrome in children is highly suspect.

How are these four dietary foodstuffs similar? They share the following biochemical properties: (1) they are metabolized for energy primarily within the liver; (2) they are not insulin regulated; and (3) they do not have a threshold mechanism to form glycogen for storage. Although the kinetics of their metabolism may differ, virtually all their intermediates are delivered directly to the mitochondria, which cannot process the volume of substrate, resulting in a backlog of metabolic intermediates, ROS generation, excessive DNL, and impaired β-oxidation, driving insulin resistance and the downstream comorbidities of the metabolic syndrome.


Conclusions

Metabolic syndrome is a complex phenotype that correlates with obesity, but nonetheless appears to be distinct from it. The fact that children can develop metabolic syndrome suggests that while obesity and aging contribute to the syndrome, it is unlikely that they are initiating factors. The fact that children around the world are getting heavier183 and developing the syndrome argues against genetics. More likely, the environment plays a major role, in particular the typical Western diet, which has now been adopted globally due to palatability and price. This review outlines the potential instigators and their pathophysiological mechanisms, which starts with mitochondrial overload and results in de novo lipogenesis, insulin resistance, ROS formation, peroxisomal dysfunction, and ER stress and the UPR.184,185 Sadly, there does not appear to be a likely drug target in this pathway to reduce mitochondrial overload. While medications can treat the various disease states associated with metabolic syndrome, prevention is paramount. We proffer the notion that an overhaul of the typical Western diet will be required to beat metabolic syndrome once and for all.


Conflicts of interest

The authors declare no conflicts of interest.


References
1. Wijnhoven TM,van Raaij JM,Spinelli A,et al. WHO European Childhood Obesity Surveillance Initiative 2008: weight, height and body mass index in 6–9-year-old childrenPediatr. Obesity in press. 012 Sep 21. doi: 10.1111/j.2047-6310.2012.00090.x. [Epub ahead of print].
2. Ogden CL,Carroll MD,Kit BK,Flegal KM. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999–2010JAMAYear: 201230748348322253364
3. Dietz WH. Health consequences of obesity in youth: childhood predictors of adult diseasePediatricsYear: 199810151852512224658
4. Must A,Strauss RS. Risks and consequences of childhood and adolescent obesityInt. J. ObesYear: 199923S2S11
5. Styne DM. Childhood and adolescent obesity: prevalence and significancePediatr. Clin. N. AmYear: 200148823854
6. Dietz WH. Health consequences of obesity in youth: childhood predictors of adulthood diseasePediatricsYear: 1998101supp. 351852512224658
7. Tirosh A,Shai I,Afek A,et al. Adolescent BMI trajectory and risk of diabetes versus coronary diseaseN. Engl. J. MedYear: 20113641315132521470009
8. Ford ES,Giles WH,Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination SurveyJAMAYear: 200228735635911790215
9. Must A,Jacques PF,Dallal GE,et al. Long-term morbidity and mortality of overweight adolescents. A follow-up of the Harvard Growth Study of 1922 to 1935N. Engl. J. MedYear: 1992327135013551406836
10. Weiss R,Dziura J,Burgert TS,et al. Obesity and the metabolic syndrome in children and adolescentsN. Engl. J. MedYear: 20043502362237415175438
11. Reaven GM. Banting lecture 1988. Role of insulin resistance in human diseaseDiabetesYear: 198837159516073056758
12. Cornier MA,Dabelea D,Hernandez TL. The metabolic syndromeEndocr. RevYear: 20082977782218971485
13. Finkelstein EA,Khavjou OA,Thompson H,et al. Obesity and severe obesity forecasts through 2030Am. J. Prev. MedYear: 20124256357022608371
14. U.N. General AssemblyPrevention and control of non-communicable diseasesU.N. General AssemblyYear: 2010New York
15. Chan JM,Rimm EB,Colditz GA,et al. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in menDiabetes CareYear: 1994179619697988316
16. McLaughlin T,Abbasi F,Cheal K,et al. Use of metabolic markers to identify overweight individuals who are insulin resistantAnn. Int. MedYear: 200313980280914623617
17. Abbasi F,Chu JW,Lamendola C,et al. Discrimination between obesity and insulin resistance in the relationship with adiponectinDiabetesYear: 20045358559014988241
18. Voulgari C,Tentolouris N,Dilaveris P,et al. Increased heart failure risk in normal-weight people with metabolic syndrome compared with metabolically healthy obese individualsJ. Am. Coll. CardiolYear: 2011581343135021920263
19. Wiegand S,Maikowski U,Blankenstein O,et al. Type 2 diabetes and impaired glucose tolerance in European children and adolescents with obesity—a problem that is no longer restricted to minority groupsEur. J. EndocrinolYear: 200415119920615296475
20. Biltoft CA,Muir A. The metabolic syndrome in children and adolescents: a clinician's guideAdolesc. Med. State Art RevYear: 20092010912019492694
21. Albrink MJ,Krauss RM,Lindgrem FT,et al. Intercorrelations among plasma high density lipoprotein, obesity and triglycerides in a normal populationLipidsYear: 1980156686767421421
22. Despres JP. Abdominal obesity as important component of insulin-resistance syndromeNutritionYear: 199394524598286886
23. Kylin E. Studien uber das hypertonie-hyperglyka “mie-hyperurika” miesyndromZentralbl. Inn. MedYear: 192344105127
24. Luciano A,Zoppi G. Blood insulin values after the oral glucose tolerance test (OGTT) and the body composition in 30 obese childrenPediatr. Med. ChirYear: 1994164714737885957
25. Steinberger J,Daniels SR,Eckel RH,et al. Progress and challenges in Metabolic Syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and MetabolismCirculationYear: 200911962864719139390
26. Zimmet P,Alberti G,Kaufman F,et al. International Diabetes Federation Task Force on Epidemiology and Prevention of Diabetes. The metabolic syndrome in children and adolescentsLancetYear: 20073692059206117586288
27. Ford ES,Li C,Zhao G,et al. Prevalence of the metabolic syndrome among U.S. adolescents using the definition from the International Diabetes FederationDiab. CareYear: 200831587589
28. Hannon TS,Janosky J,Arslanian SA. Longitudinal study of physiologic insulin resistance and metabolic changes of pubertyPed. ResearchYear: 200660759763
29. Moran A,Jacobs DRJ,Steinberger J,et al. Changes in insulin resistance and cardiovascular risk during adolescence: establishment of differential risk in males and femalesCirculationYear: 20081172361236818427135
30. Dai S,Fulton JE,Harrist RB,Grunbaum JA,et al. Blood lipids in children: age-related patterns and association with body-fat indices: project HeartBeat!Am. J. Prev. MedYear: 200937suppl 1S56S6419524157
31. Eisenmann JC. On the use of a continuous metabolic syndrome score in pediatric researchCardiovasc. DiabetolYear: 200871718534019
32. Liska D,Dufour S,Zern TL,et al. Interethnic differences in muscle, liver and abdominal fat partitioning in obese adolescentsPLoS OneYear: 200727e56917593968
33. Goodman E,Daniels SR,Meigs JB,Dolan LM. Instability in the diagnosis of metabolic syndrome in adolescentsCirculationYear: 20071152316232217420347
34. Weiss R,Shaw M,Savoye M,Caprio S. Obesity dynamics and cardiovascular risk factor stability in obese adolescentsPediatr. DiabetesYear: 20091036036719490496
35. Ogden CL,Carroll MD,Kit BK,Flegal KM. Prevalence of obesity and trends in body mass index among US children and adolescents, 1999–2010JAMAYear: 201230748349022253364
36. Sinaiko AR,Caprio S. Insulin resistanceJ. PediatrYear: 2012161111522336575
37. Arslanian S,Suprasongsin C. Differences in the in vivo insulin secretion and sensitivity of healthy black versus white adolescentsJ. PediatrYear: 19961294404438804335
38. Caprio S,Hyman LD,McCarthy S,et al. Fat distribution and cardiovascular risk factors in obese adolescent girls: importance of the intraabdominal fat depotAm. J. Clin. NutrYear: 19966412178669407
39. Sinha R,Fisch G,Teague B,et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesityN. Engl. J. MedYear: 200234680281011893791
40. Sorof JM,Lai D,Turner J,et al. Overweight, ethnicity, and the prevalence of hypertension in school-aged childrenPediatricsYear: 200411347548214993537
41. Steinberger J,Daniels SR. Obesity, insulin resistance, diabetes, and cardiovascular risk in childrenCirculationYear: 20031071448145312642369
42. Mimoun E,Aggoun Y,Pousset M,et al. Association of arterial stiffness and endothelial dysfunction with metabolic syndrome in obese childrenJ. PediatrYear: 2008153657018571538
43. Ode KL,Frohnert BI,Nathan BM. Identification and treatment of metabolic complications in pediatric obesityRev. Endocr. Metab. DisordYear: 20091016718819809879
44. Abbasi F,Brown BWB,Lamendola C,et al. Relationship between obesity, insulin resistance, and coronary heart disease riskJ. Am. Coll. CardiolYear: 20024093794312225719
45. Reinehr T,Wunsch R,de Sousa G,Toschke AM. Relationship between metabolic syndrome definitions for children and adolescents and intima-media thicknessAtherosclerosisYear: 200819919320018031749
46. Morrison JA,Glueck CJ,Umar M,et al. Hyperinsulinemia and metabolic syndrome at mean age of 10 years in black and white schoolgirls and development of impaired fasting glucose and type 2 diabetes mellitus by mean age of 24 yearsMetabolismYear: 201160243120096893
47. Weiss R,Taksali SE,Tamborlane WV,et al. Predictors of changes in glucose tolerance status in obese youthDiab. CareYear: 200528902909
48. Haffner SM. Epidemiology of insulin resistance and its relation to coronary artery diseaseAm. J. CardiolYear: 19998411J14J
49. Hu FB,Stampfer JM,Haffner SM,et al. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetesDiab. CareYear: 20022511291134
50. Alberti KG,Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultationDiabet. MedYear: 1998155395539686693
51. Matsumoto M,Han S,Kitamura T,Accili D. Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolismJ. Clin. InvestYear: 20061162464247216906224
52. Naïmi M,Gautier N,Chaussade C,et al. Nuclear forkhead box O1 controls and integrates key signaling pathways in hepatocytesEndocrinolYear: 200714824242434
53. Lewis GF,Uffelman KD,Szeto LW,Steiner G. Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individualsDiabetesYear: 1993428338428495807
54. Brown MS,Goldstein JL. Selective versus total insulin resistance: a pathogenic paradoxCell MetabYear: 20087959618249166
55. Bergman RN,Kim SP,Hsu IR,et al. Abdominal obesity: role in the pathophysiology of metabolic disease and cardiovascular riskAm. J. MedYear: 2007120Suppl 1S3S817296343
56. Ross MG,Huber I,Desai M. Lustig RHIntrauterine growth restriction, small for gestational age, and experiemental obesityObesity Before Birth: Maternal and Prenatal Effects on the OffspringYear: 2010New YorkSpringer215239
57. Ginsberg HN,Zhang YL,Hernandez-Ono A. Regulation of plasma triglycerides in insulin resistance and diabetesArch. Med. ResYear: 20053623224015925013
58. Samuel VT,Petersen KF,Shulman GI. Lipid-induced insulin resistance: unravelling the mechanismLancetYear: 20103752267227720609972
59. Large V,Arner P. Regulation of lipolysis in humans. Pathophysiological modulation in obesity, diabetes, and hyperlipidaemiaDiabetes Metab. ResYear: 199824409418
60. Gustafson B,Hammarstedt A,Andersson CX,Smith U. Inflamed adipose tissue: a culprit underlying the metabolic syndrome and atherosclerosisArterioscler. Thromb. Vasc. BiolYear: 2007272276228317823366
61. Heilbronn LK,Campbell LV. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesityCurr. Pharm. DesYear: 2008141225123018473870
62. Roden M,Krssak M,Stingl H,et al. Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humansDiabetesYear: 19994835836410334314
63. Petersen KF,Dufour SSD,Bilz S,et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndromeProc. Natl. Acad. SciYear: 2007104125871259417640906
64. Whincup PH,Gilg JA,Papacosta O,et al. Early evidence of ethnic differences in cardiovascular risk: cross sectional comparison of British South Asian and white childrenBr. Med. JYear: 200232463511895820
65. Weiss R,Dziura JD,Burgert TS,et al. Ethnic differences in beta cell adaptation to insulin resistance in obese children and adolescentsDiabetologiaYear: 20064957157916456682
66. Moran A,Jacobs DR,Steinberger J,et al. Insulin resistance during puberty: results from clamp studies in 357 childrenDiabetesYear: 1999482039204410512371
67. Saad RJ,Danadian K,Lewy V,Arslanian SA. Insulin resistance of puberty in African-American children: lack of a compensatory increase in insulin secretionPediatr. DiabetesYear: 200234915016168
68. Bjorntorp P. Portal adipose tissue as a generator of risk factors for cardiovascular disease and diabetesArteriosclerosisYear: 1990104934962196039
69. Arner P. Insulin resistance in type 2 diabetes: role of fatty acidsDiab. Metab. Res. RevYear: 200218Supp. 2S5S9
70. Bonora E. Relationship between regional fat distribution and insulin resistanceInt. J. ObesYear: 200024Supp. 2S32S35
71. Koutsari C,Jensen MD. Thematic review series: patient-oriented research. Free fatty acid metabolism in human obesityJ. Lipid ResYear: 2006471643165016685078
72. Abate N,Garg A,Peshock RM,et al. Relationship of generalized and regional adiposity to insulin sensitivity in men with NIDDMDiabetesYear: 199645168416938922352
73. Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndromeEndocr. RevYear: 20002169773811133069
74. Montague CT,O'Rahilly S. The perils of portliness: causes and consequences of visceral adiposityDiabetesYear: 20004988388810866038
75. Taksali SE,Caprio S,Dziura J,et al. High visceral and low abdominal subcutaneous fat stores in the obese adolescent: a determinant of an adverse metabolic phenotypeDiabetesYear: 20085736737117977954
76. D'Adamo E,Cali AM,Weiss R,et al. Central role of fatty liver in the pathogenesis of insulin resistance in obese adolescentsDiab. CareYear: 20103318171822
77. Ravussin E,Smith SR. Increased fat intake, impaired fat oxidation, and failure of fat cell proliferation result in ectopic fat storage, insulin resistance, and type 2 diabetes mellitusAnn. N.Y. Acad. SciYear: 200296736337812079864
78. Sung KC,Kim SH. Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetesJ. Clin. Endocrinol. MetabYear: 2011961093109721252243
79. Krssak M,Falk Petersen K,Dresner A,et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy studyDiabetologiaYear: 19994211311610027589
80. Garg A. Acquired and inherited lipodystrophiesN. Engl. J. MedYear: 20043501220123415028826
81. Goodpaster BH,Thaete FL,Simoneau JA,Kelley DE. Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fatDiabetesYear: 199746157915859313753
82. Perseghin G,Scifo P,De Cobelli F,et al. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parentsDiabetesYear: 1999481600160610426379
83. Sinha R,Dufour S,Petersen KF,et al. Assessment of skeletal muscle triglyceride content by (1)H nuclear magnetic resonance spectroscopy in lean and obese adolescents: relationships to insulin sensitivity, total body fat, and central adiposityDiabetesYear: 2002511022102711916921
84. Fabbrini E,Magkos F,Mohammed BS,et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesityProc. Natl. Acad. SciYear: 2009106154301543519706383
85. Unger RH. Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndromeEndocrinologyYear: 20031445159516512960011
86. Dobbins RL,Szczepaniak LS,Bentley B,et al. Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in ratsDiabetesYear: 20015012313011147777
87. Morino K,Petersen KF,Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunctionDiabetesYear: 200655Supp. 2S9S1517130651
88. Samuel VT,Liu ZX,Qu X,et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver diseaseJ. Biol. ChemYear: 2004279323453235315166226
89. Hirosumi J,Tuncman G,Chang L,et al. A central role for JNK in obesity and insulin resistanceNatureYear: 200242033333612447443
90. Zhang Y,Proenca R,Maffei M,et al. Positional cloning of the mouse obese gene and its human homologueNatureYear: 1994393372425
91. Saltiel AR. You are what you secreteNat. MedYear: 2001788788011479613
92. Unger RH. The hyperleptinemia of obesity-regulator of caloric surplusesCellYear: 200411714514615084251
93. Arita Y,Kihara S,Ouchi N,et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesityBiochem. Biophys. Res. CommYear: 1999257798310092513
94. Kondo H,Shimomura I,Matsukawa Y,et al. Association of adiponectin mutation with type 2 diabetes: a candidate gene for the insulin resistance syndromeDiabetesYear: 2002512325232812086969
95. Pajvani UB,Du X,Combs TP,et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivityJ. Biol. ChemYear: 20032789073908512496257
96. Kadowaki T,Yamauchi T. Adiponectin and adiponectin receptorsEndocr. RevYear: 20052643945115897298
97. Yamauchi T,Kamon J,Ito Y,et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effectsNatureYear: 200342376276912802337
98. Ouchi N,Kihara S,Arita Y,et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathwayCirculationYear: 20001021296130110982546
99. Yatagai T,Nagasaka S,Taniguchi A,et al. Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitusMetabolismYear: 2003521274127814564678
100. Hotta K,Funahashi T,Bodkin NL,et al. Circulating concentrations of the adipocyte protein adiponectin: a decrease in parallel with reduced insulin sensitivity during the progression of type 2 diabetes in Rhesus monkeysDiabetesYear: 2001501126113311334417
101. Weisberg SP,McCann D,Desai M,et al. Obesity is associated with macrophage accumulation in adipose tissueJ. Clin. InvestYear: 200311216731808
102. Matsuzawa Y,Funahashi T,Nakamura T. Molecular mechanism of metabolic syndrome X: contribution of adipocytokines adipocyte-derived bioactive substancesAnn. N.Y. Acad. SciYear: 199989214615410842660
103. Cinti S,Mitchell G,Barbatelli G,et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humansJ. Lipid ResYear: 2005462347235516150820
104. Yudkin JS,Kumari M,Humphries SE,Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the linkAtherosclerosisYear: 200014820921410657556
105. Pickup JC,Crook MA. Is type 2 diabetes mellitus a disease of the innate immune systemDiabetologiaYear: 199841124112489794114
106. Ridker PM,Hennekens CH,Buring JE,Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in womenN. Engl. J. MedYear: 200034283684310733371
107. Pradhan AD,Manson JE,Rifai N,et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitusJAMAYear: 200128632733411466099
108. Cook DG,Mendall MA,Whincup PH,et al. C-reactive protein concentration in children: relationship to adiposity and other cardiovascular risk factorsAtherosclerosisYear: 200014913915010704625
109. Ford ES,Galuska DA,Gillespie C,et al. C-reactive protein and body mass index in children: findings from the Third National Health and Nutrition Examination Survey, 1988–1994J. PediatrYear: 200113848649211295710
110. Winer JC,Zern TL,Taksali SE,et al. Adiponectin in childhood and adolescent obesity and its association with inflammatory markers and components of the metabolic syndromeJ. Clin. Endocrinol. MetabYear: 2006914415442316926246
111. Martins MD,Lima Faleiro L,Fonseca A. Relationship between leptin and body mass and metabolic syndrome in an adult populationRev. Port. CardiolYear: 20123171171923040870
112. Leyva F,Godsland IF,Ghatei M,et al. Hyperleptinemia as a component of a metabolic syndrome of cardiovascular riskArterioscler. Thromb. Vasc. BiolYear: 1998189289339633933
113. Civitarese AE,Ravussin E. Mitochondrial energetics and insulin resistanceEndocrinologyYear: 200814995095418202132
114. Subasinghe W,Syed I,Kowluru A. Phagocyte-like NADPH oxidase promotes cytokine-induced mitochondrial dysfunction in pancreatic beta-cells: evidence for regulation by Rac1Am. J. Physiol. Regul. Integr. Comp. PhysiolYear: 2011300R12R2020943855
115. Turrens JF. Mitochondrial formation of reactive oxygen speciesJ. PhysiolYear: 200355233534414561818
116. Fan X,Hussien R,Brooks GA. H2O2-induced mitochondrial fragmentation in C2C12 myocytesFree Radic. Biol. MedYear: 2010491646165420801212
117. de Ferranti S,Mozaffarian D. The perfect storm: obesity, adipocyte dysfunction, and metabolic consequencesClin. ChemYear: 20085494595518436717
118. Bremer AA,Mietus-Snyder ML,Lustig RH. Toward a unifying hypothesis of metabolic syndromePediatricsYear: 201212955757022351884
119. Schrader M,Fahimi HD. Peroxisomes and oxidative stressBiochim. Biophys. ActaYear: 200617631755176617034877
120. Dirkx R,Vanhorebeek I,Martens K,et al. Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalitiesHepatologyYear: 20054186887815732085
121. Kapoor A,Sanyal AJ. Endoplasmic reticulum stress and the unfolded protein responseClin. Liver DisYear: 20091358159019818306
122. Merksamer PI,Trusina A,Papa FR. Real-time redox measurements during endoplasmic reticulum stress reveal interlinked protein folding functionsCellYear: 200813593394719026441
123. Haynes CM,Titus EA,Cooper AA. Degradation of misfolded proteins prevents ER-derived oxidative stress and cell deathMol. CellYear: 20041576777615350220
124. Santos CX,Tanaka LY,Wosniak J,Laurindo FR. Mechanisms and implications of reactive oxygen species generation during the unfolded protein response: roles of endoplasmic reticulum oxidoreductases, mitochondrial electron transport, and NADPH oxidaseAntioxid. Redox SignalYear: 2009112409242719388824
125. Mollica MP,Lionetti L,Putti R,et al. From chronic overfeeding to hepatic injury: role of endoplasmic reticulum stress and inflammationNutr. Metab. Cardiovasc. DisYear: 20112122223021277757
126. Hummasti S,Hotamisligil GS. Endoplasmic reticulum stress and inflammation in obesity and diabetesCirc. ResYear: 201010757959120814028
127. Lusis AJ,Attie AD,Reue K. Metabolic syndrome: from epidemiology to systems biologyNat. Rev. GenetYear: 2008981983018852695
128. Keith SW,Redden DT,Katzmaryk PT,et al. Putative contributors to the secular increase in obesity: exploring the roads less traveledInt. J. ObesYear: 20063015851594
129. Andrew R,Gale CR,Walker BR,et al. Glucocorticoid metabolism and the metabolic syndrome: associations in an elderly cohortExp. Clin. Endocrinol. DiabYear: 2002110284290
130. Kotelevtsev YV,Holmes MC,Burchell A,et al. 11β-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid inducible responses and resist hyperglycaemia on obesity and stressProc. Nat. Acad. SciYear: 19979414924149299405715
131. Masuzaki H,Paterson J,Shinyama H,et al. A transgenic model of visceral obesity and the metabolic syndromeScienceYear: 20012942166217011739957
132. Chandola T,Brunner E,Marmot M. Chronic stress at work and the metabolic syndrome: prospective studyBr Med JYear: 200633252152516428252
133. Rosengren A,Hawken S,Ounpuu S,et al. Association of psychosocial risk factors with risk of acute myocardial infarction in 11,119 cases and 13,648 controls from 52 countries (the INTERHEART study): case-control studyLancetYear: 200436495396215364186
134. Brunner EJ,Hemingway H,Walker BR,et al. Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control studyCirculationYear: 20021062659266512438290
135. Souverein PC,Berard A,Van Staa TP,et al. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control studyHeartYear: 20049085986515253953
136. Bujalska IJ,Kumar S,Stewart PM. Does central obesity reflect “Cushing's disease of the omentum”LancetYear: 1997349121012139130942
137. Spiegel K,Sheridan JF,Van Cauter E. Effect of sleep deprivation on response to immunizationJAMAYear: 20022881471147212243633
138. Gangwisch JE,Malaspina D,Boden-Albala B,Heymsfield SB. Inadequate sleep as a risk factor for obesity: analyses of the NHANES ISleepYear: 2005281217122016295203
139. Hasler G,Buysse DJ,Klaghofer R,et al. The association between short sleep duration and obesity in young adults: a 13-year prospective studySleepYear: 20042760260315282992
140. Taheri S. The link between short sleep duration and obesity: we should recommend more sleep to prevent obesityArch. Dis. ChildYear: 20069188188417056861
141. Sekine M,Yamagami T,Hamanishi S,et al. Parental obesity, lifestyle factors and obesity in preschool children: results of the Toyama birth cohort studyJ. EpidemiolYear: 200212333911848182
142. Reilly JJ,Armstrong J,Dorosty AR,et al. Early life risk factors for obesity in childhood: cohort studyBr. Med. JYear: 2005330135715908441
143. Waters KA,Mast BT,Vella S,et al. Structural equation modeling of sleep apnea, inflammation, and metabolic dysfunction in childrenJ. Sleep ResYear: 20071638839518036084
144. Penev PD. Update on energy homeostasis and insufficient sleepJ. Clin. Endocrinol. MetabYear: 2012971792180122442266
145. Parsons TJ,Power C,Logan S,Summerbell CD. Childhood predictors of adult obesity: a systematic reviewInt. J. ObesYear: 199923supp 8S1S107
146. Maffeis C,Schutz Y,Grezzani A,et al. Meal-induced thermogenesis and obesity: is a fat meal a risk factor for fat gain in childrenJ. Clin. Endocrinol. MetabolYear: 200186214219
147. Jequier E. Is fat intake a risk factor for fat gain in childrenJ. Clin. Endocrinol. MetabolYear: 200186980983
148. Tucker LA,Seljaas GT,Hager RL. Body fat percentage of children varies according to their diet compositionJ. Am. Dietetic. AssocYear: 199797981986
149. Pirozzo S,Summerbell C,Cameron C,Glasziou P. Advice on low-fat diets for obesityCochrane Database Sys. RevYear: 2002CD003640
150. Kennedy E,Powell R. Changing eating patterns of American children: a view from 1996J. Am. Coll. NutriYear: 199716524529
151. Harnack L,Stang J,Story M. Soft drink consumption among US children and adolescents: nutritional consequencesJ. Am. Dietetic AssocYear: 199999436441
152. Center for Weight and HealthYear: 2001 Pediatric overweight: a review of the literature June 2001: http://www.cnr.berkeley.edu/cwh/news/announcements.shtml-lit_review.
153. Foster GD,Wyatt HR,Hill JO,et al. A randomized trial of a low-carbohydrate diet for obesityN. Engl. J. MedYear: 20033482082209012761365
154. Stern L,Iqbal N,Seshadri P,et al. The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trialAnn. Int. MedYear: 200414077878515148064
155. Kirk S,Brehm B,Saelens BE,et al. Role of carbohydrate modification in weight management among obese children: a randomized clinical trialJ. PediatrYear: 201216132032722381024
156. Vining EP,Pyzik P,McGrogan J,et al. Growth of children on the ketogenic dietDev. Med. Child. NeurolYear: 20024479680212455855
157. Gross LS,Li S,Ford ES,Liu S. Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessmentAm. J. Clin. NutrYear: 20047977477915113714
158. Ludwig DS,Peterson KE,Gortmaker SL. Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysisLancetYear: 200135750550811229668
159. Warner ML,Harley K,Bradman A,et al. Soda consumption and overweight status of 2-year-old Mexican-American children in CaliforniaObesityYear: 2006141966197417135613
160. Faith MS,Dennison BA,Edmunds LS,Stratton HH. Fruit juice intake predicts increased adiposity gain in children from low-income families: weight status-by-environment interactionPediatricsYear: 20061182066207517079580
161. Jurgens H,Haass W,Castaneda TR,et al. Consuming fructose-sweetened beverages increases body adiposity in miceObes. ResYear: 2005131146115616076983
162. Bremer AA,Stanhope KL,Graham JL,et al. Fructose-fed rhesus monkeys: a nonhuman primate model of insulin resistance, metabolic syndrome, and type 2 diabetesClin. Transl. SciYear: 2011424325221884510
163. Havel PJ. Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolismNutr. RevYear: 20056313315715971409
164. Le KA,Tappy L. Metabolic effects of fructoseCurr. Opin. Nutr. Metab. CareYear: 20069469475
165. Lim JS,Mietus-Snyder M,Valente A,et al. The role of fructose in the pathogenesis of NAFLD and the metabolic syndromeNat. Rev. Gastroenterol. HepatolYear: 2010725126420368739
166. Tuncman G,Hirosumi J,Solinas G,et al. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistanceProc. Natl. Acad. Sci. USAYear: 2006103107411074616818881
167. Stanhope KL,Schwarz JM,Keim NL,et al. Consuming fructose-, not glucose-sweetened beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humansJ. Clin. InvestYear: 20091191322133419381015
168. Teff KL,Grudziak J,Townsend RR,et al. Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: influence of insulin resistance on plasma triglyceride responsesJ. Clin. Endocrinol. MetabYear: 2009941562156919208729
169. Teff KL,Elliott SS,Tschop M,et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in womenJ. Clin. Endocrinol. MetabYear: 2004892963297215181085
170. Lee O,Bruce WR,Dong Q,et al. Fructose and carbonyl metabolites and endogenous toxinsChem. Biol. InteractYear: 200917833233919000661
171. Pickens MK,Yan JS,Ng RK,et al. Dietary sucrose is essential to the development of liver injury in the MCD model of steatohepatitisJ. Lipid ResYear: 2009502072208219295183
172. Layman DK,Walker DA. Potential importance of leucine in treatment of obesity and the metabolic syndromeJ. NutrYear: 2006136Suppl319S323S16365106
173. Newgard CB,An J,Bain JR,et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistanceCell MetabYear: 2009931132619356713
174. Higuchi N,Kato M,Miyazaki M,et al. Potential role of branched-chain amino acids in glucose metabolism through the accelerated induction of the glucose-sensing apparatus in the liverJ. Cell. BiochemYear: 2011112303820506195
175. Eaton S. Control of mitochondrial beta-oxidation fluxProg. Lipid ResYear: 20024119723911814524
176. Wang TJ,Larson MG,Vasan RS,et al. Metabolic profiles and the risk of developing diabetesNat. MedYear: 20111744845321423183
177. Tai ES,Tan ML,Stevens RD,et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian menDiabetologiaYear: 20105375778720076942
178. Steinberg D,Pearson TA,Kuller LH. Alcohol and atherosclerosisAnn. Intern. MedYear: 19911149679762024865
179. Suter PM,Schutz Y. The effect of exercise, alcohol or both combined on health and physical performanceInt. J. ObesYear: 200832suppl. 6S48S52
180. Schneider J,Tesdorfpf M,Kaffarnik H,et al. Alteration of plasma lipids and intermediates of lipid metabolism in healthy fasting volunteers by ethanol and fructoseRes. Exp. MedYear: 1976167159170
181. Sozio M,Crabb DW. Alcohol and lipid metabolismAm. J. Physiol. Endocrinol. MetabYear: 2008295E10E1618349117
182. Yokoyama H,Hiroshi H,Ohgo H,et al. Effects of excessive ethanol consumption on the diagnosis of the metabolic syndrome using its clinical diagnostic criteriaIntern. MedYear: 2007461345135217827831
183. Gupta N,Goel K,Bhatt SP,Misra A. Childhood obesity in developing countries: epidemiology, determinants, and preventionEndocr. RevYear: 201233487022240243
184. Lustig RH,Weiss R. Sperling MADisorders of energy balanceTextbook of Pediatric EndocrinologyYear: 2008New YorkElsevier688713
185. Lustig RH. Fructose: metabolic, hedonic, and societal parallels with ethanolJ. Am. Diet. AssocYear: 20101101307132120800122

Figures

[Figure ID: fig01]
Figure 1 

An hypothesis on the relationship between obesity and metabolic syndrome. The metabolic impact of obesity is determined by the pattern of lipid partitioning. Lipid storage in insulin-sensitive tissues, such as liver or muscle, and in the visceral compartment is associated with a typical metabolic profile characterized by elevated free fatty acids and inflammatory cytokines alongside reduced levels of adiponectin. This combination can independently lead to peripheral insulin resistance and to endothelial dysfunction. The combination of insulin resistance and early atherogenesis (manifested as endothelial dysfunction) drives the development of altered glucose metabolism and of cardiovascular disease. (With permission from Ref. 184.)



[Figure ID: fig02]
Figure 2 

Mechanisms of subcellular metabolic dysfunction, using fructose as an example. The formation of acetyl-CoA leads to lipid deposition and activation of inflammatory pathways, including serine phosphorylation of IRS-1, which leads to insulin resistance. Furthermore, metabolic processing in the mitochondria, the glycation of protein ɛ-amino groups via the Maillard reaction, and circulating inflammatory cytokines due to their receptor-mediated activation of NADPH oxidase, all increase intracellular levels of ROS. In the absence of sufficient peroxisomal quenching and degradation, the ROS moieties lead to endoplasmic reticulum stress, promoting the unfolded protein response, and cause either cell death (apoptosis) or cellular/metabolic dysfunction. (With permission from Ref. 18.) Courtesy of the American Academy of Pediatrics. Abbreviations: ATP, adenosine triphosphate; CoA, coenzyme A; JNK-1, c-jun N-terminal kinase 1; NADPH, nicotinamide adenine dinucleotide phosphate; PKCɛ, protein kinase C-ɛ; pSer-IRS-1, serine phosphorylated IRS-1; ROS, reactive oxygen species; UPR, unfolded protein response.



[Figure ID: fig03]
Figure 3 

Hepatic fructose metabolism. In contrast to glucose, fructose induces (1) substrate-dependent hepatocellular phosphate depletion, which increases uric acid and contributes to hypertension through inhibition of endothelial nitric oxide synthase and reduction of nitric oxide (NO); (2) excess citrate production; (3) stimulation of de novo lipogenesis and excess production of VLDL and serum TG, promoting dyslipidemia; (4) accumulation of intrahepatic lipid droplets, promoting hepatic steatosis; (5) lack of phosphorylation of FoxO1, leading to increased gluconeogenesis; (6) delivery of triglycerides to muscle, promoting muscle insulin resistance; (7) CNS hyperinsulinemia, which antagonizes leptin signaling and promotes continued energy intake; (8) JNK-1 activation, which causes serine phosphorylation of the hepatic insulin receptor rendering it inactive and contributing to hepatic insulin resistance; and (9) production of reactive oxygen species (ROS), which lead to protein instability.



Article Categories:
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Keywords: metabolic syndrome, obesity, diet, insulin resistance, reactive oxygen species.

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