Fat distribution and storage: how much, where, and how?

 
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European Journal of Endocrinology (2007) 157 S39–S45                                                                          ISSN 0804-4643

Fat distribution and storage: how much, where, and how?
Ram Weiss
The Diabetes Center and the Department of Pediatrics, Hadassah Hebrew University School of Medicine, PO Box 12000, Jerusalem 91120, Israel
(Correspondence should be addressed to R Weiss; Email: weissr@hadassah.org.il)

                             Abstract
                             Obesity does not necessarily imply disease and similarly obese individuals may manifest obesity-related
                             morbidity or seemingly be in reasonably good health. Recent studies have shown that patterns of lipid
                             partitioning are a major determinant of the metabolic profile and not just obesity per se. The underlying
                             mechanisms and clinical relevance of lipid deposition in the visceral compartment and in insulin-
                             sensitive tissues are described. Increased intramyocellular lipid deposition impairs the insulin signal
                             transduction pathway and is associated with insulin resistance. Increased hepatic lipid deposition is
                             similarly associated with the majority of the components of the insulin resistance syndrome. The roles
                             of increased circulating fatty acids in conditions of insulin resistance and the typical pro-inflammatory
                             milieu of specific obesity patterns are provided. Insights into the patterns of lipid storage within the cell
                             are provided along with their relation to changes in insulin sensitivity and weight loss.

                             European Journal of Endocrinology 157 S39–S45

The prevalence of obesity among adults as well as                         compartments such as the intra-abdominal (visceral)
children is on the rise and gaining epidemic proportions                  compartment, and in insulin-sensitive tissues that are
(1). There is an overall consensus based on numerous                      prone to deposition of lipid in specific clinical scenarios.
longitudinal studies that obesity poses a significant risk                This may cause deposition of lipid within skeletal
factor for the development of cardiovascular disease,                     muscle and the liver, affecting their normal metabolic
alterations in glucose metabolism, certain cancers,                       pathways.
intellectual deterioration, and reduces life expectancy.                     This review focuses on the metabolic impact of overall
Despite these observations, a significant proportion of                   adiposity and specifically lipid partitioning in the s.c.
obese individuals can achieve longevity without devel-                    tissue, visceral compartment, muscle and liver on
oping any of the morbidities previously mentioned. One                    metabolic complications of obesity. The importance
hypothesis to explain this observation is that total body                 and clinical relevance of each compartment are high-
fat is not the sole source of the adverse health                          lighted with regards to the metabolic manifestations
complications of obesity; rather the fat distribution or                  associated with each partitioning profile. Insights into
the relative proportion of lipids in various potential lipid              the dynamics of the morphology of lipid storage within
deposition compartments is what determines the                            muscle are described. The ‘sub-clinical’ inflammation
metabolic risk of the individual.                                         characteristic of increased body fat is discussed. The
   Lipid deposition is an evolutionary advantageous                       majority of examples are from studies performed in
process that allows efficient storage of maximal calories                 obese children and adolescents.
per unit volume of tissue. The classic compartment
intended for storage of excess calories is subcutaneous
fat tissue that potentially also serves as insulation in
                                                                          Relation of obesity, lipid partitioning, and
the face of cold temperatures. The capacity to store
                                                                          metabolic risk
lipid within the s.c. tissue is the key to facing famine                  The close association of type 2 diabetes mellitus with
and limited caloric supply on the one hand and to                         cardiovascular disease led to the hypothesis that the two
handling excess calories on the other. In cases where                     may arise from a common antecedent (2, 3). It was
s.c. fat reaches a threshold beyond which it can store                    Reaven et al. (4) who noticed that common risk factors
no more, lipids may be shunted to other depots. In that                   of cardiovascular disease and altered glucose metab-
scenario, lipids may be stored in less advantageous                       olism tend to cluster in specific individuals and thus
                                                                          named this constellation of risk factors ‘the insulin
This paper was presented at the Ipsen symposium, ‘The evolving            resistance syndrome’, highlighting the critical role of
biology of growth and metabolism’, Lisbon, Portugal, 16–18 March          peripheral insulin resistance as a driving force of the
2007. Ipsen has supported the publication of these proceedings.           underlying pathological process. This concept has been

q 2007 Society of the European Journal of Endocrinology                                                               DOI: 10.1530/EJE-07-0125
                                                                                                            Online version via www.eje-online.org
S40    R Weiss                                                                                  EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157

defined by the World Health Organization as the                             as class 2 obesity, and BMIR40 kg/m2 as class 3 obesity
‘metabolic syndrome’ (MS). According to the National                        (7). No similar classifications for the degree of obesity
Cholesterol Education Program and Adult Treatment                           exist for children and adolescents, except for the
Panel III, individuals meeting at least three of the                        definition of those whose BMI is between the 85th and
following five criteria qualify as having the MS: elevated                  95th percentiles as ‘at risk for overweight’ and those at
blood pressure, a high triglyceride level, low HDL-                         greater than the 95th percentile as ‘overweight’. Several
cholesterol level, high fasting glucose, and central                        studies have shown that the degree of obesity has an
obesity (5). Because of its wide prevalence, the MS has                     adverse impact on the metabolic profile of obese youth,
enormous clinical and public health importance, even                        although no sub-categorization of the degrees of obesity
at its earliest stages, as it promotes atherosclerosis and                  within the upper 5 percentiles, as described in adults,
sets the stage for the development of diabetes (6).                         exists for children. When obese children were divided to
According to the paradigm presented herein, the impact                      moderately (BMI z score of 2–2.5, corresponding to the
of obesity is determined by the pattern of lipid                            97–99.5 percentiles) and severely (BMI z scoreO2.5,
partitioning, i.e. the specific depots in which excess fat                  corresponding to the 99.5 percentile) obese and
is stored. The pattern of lipid storage has an impact on                    compared with overweight and non-obese children in
the adipocytokine secretion profile, on circulating                         regards to components of the MS (8), the impact of the
concentrations of inflammatory cytokines and on the                         degree of obesity was demonstrated. In that study,
free fatty acid (FFA) flux. The combined effect of these                    increasing obesity categories in children and adolescents
factors determines the sensitivity of insulin target                        were associated with worsening of all components of the
organs (such as muscle and liver) to insulin and impacts                    MS, specifically with an increase in fasting glucose,
the vascular system by affecting endothelial function.                      fasting insulin, triglycerides and systolic blood pressure,
Peripheral insulin resistance and endothelial dysfunc-                      and the prevalence of impaired glucose tolerance (IGT)
tion are the early promoters of future pathology, mainly                    and a decrease of HDL cholesterol were observed with
of cardiovascular disease and altered glucose metab-                        increasing adiposity. The prevalence of the MS, using a
olism, eventually manifesting as type 2 diabetes (Fig. 1).                  modified conservative definition adjusted for the pedi-
                                                                            atric age group, was w30% in the moderately obese and
                                                                            nearly 50% in severely obese participants. When the
Degree of obesity and metabolic risk                                        Bogalusa cohort participants (9) were stratified accor-
                                                                            ding to discrete percentiles above the 90th for BMI, those
Classification of the degree of obesity in adults defines a                 in the 99th percentile for age and gender had a
BMIO30 kg/m2 as class 1 obesity, BMI 35–39.9 kg/m2                          significantly greater prevalence of biochemical

                                                                  Obesity

                                                          Altered lipid partitioning

                                      Adipocytokines               Cytokines                     FFAs

                                   Insulin resistance                                  Endothelial dysfunction

                                                           Metabolic syndrome

                                                        T2DM                     CVD

Figure 1 The metabolic effects of obesity are determined by patterns of lipid partitioning. A less favorable lipid partitioning pattern induces a
typical profile of circulating adipocytokines, inflammatory cytokines and free fatty acids (FFAs) that promotes peripheral insulin resistance
and endothelial dysfunction. The latter two are the mechanistic elements that drive the development of type 2 diabetes and accelerated
atherosclerosis.

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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157                                                  Fat distribution and storage   S41

components of the MS and being above the 99th                    accumulate lipids in skeletal muscle may be differences
percentile for age and gender during childhood had a             in quantity and functionality of the mitochondria within
very high predictive value for adult BMI of O35 kg/m2.           the myocyte. Indeed, when elderly lean insulin-resistant
The implication of these studies is that among obese             individuals were compared with younger body habitus
children and adolescents, those at the 99th percentile           and activity-matched men using 13C and 31P magnetic
and above – in other words, the ‘severely obese’ – are an        resonance spectroscopy, they were found to have a
extremely high-risk group for the presence of com-               w40% reduction in oxidative phosphorylation (17).
ponents of the MS and for future class 2–3 obesity in            When offspring of diabetics were compared with age- and
adulthood. Importantly, the prevalence of the MS,                activity-matched insulin-sensitive controls, it was
regardless of the definition used, is significant even           demonstrated that they had a w30% reduction rate of
among overweight and mildly obese children and                   ATP production in mitochondria of skeletal muscle (18).
adolescents (10, 11), and not limited to those with              Lean offspring of diabetic parents have also been shown
severe obesity.                                                  to have lower mitochondrial content in skeletal muscle
                                                                 and this is postulated to predispose them to increased
                                                                 lipid accumulation within the myocyte (19). A second
Impact of lipid partitioning                                     factor leading to IMCL accumulation may be fat
                                                                 constituents of the diet. High-fat diets of varying
Obesity does not necessarily implicate pathology in              durations have been shown to increase IMCL content
childhood or adulthood. Although obesity is the most             by 36–90%, depending on their duration and baseline
common cause of insulin resistance in children and               IMCL levels (20, 21). In physically inactive obese
adolescents, some obese youth may be very insulin                individuals, a continuous increased supply of fatty
sensitive and thus be at reduced risk of the development         acids by way of excess energy intake alongside a reduced
of the adverse cardiovascular and metabolic outcomes             capacity to oxidize fat may lead overall fat storage,
driven by insulin resistance. In a study aimed at                specifically in skeletal muscle. An obvious third source of
discovering the underlying pathophysiology of altered            increased IMCL is an increase in circulating FFA
glucose metabolism in obese children and adolescents, it         concentration, characteristic of obese insulin-resistant
was clearly demonstrated that those with IGT are                 individuals. These observations indicate that the
significantly more insulin resistant than those with
                                                                 tendency to accumulate intramyocellular lipid may be
normal glucose tolerance, despite having an overall
                                                                 genetically determined as well as influenced by diet and
equal degree of adiposity (12). The difference in insulin
                                                                 activity and result from reduced quantity and altered
sensitivity was attributed to different patterns of lipid
                                                                 functionality of myocellular mitochondria. A tendency
partitioning, where those with severe insulin resistance
were characterized by increased deposition of lipid in           for increased IMCL deposition, which is partially
the visceral and intramyocellular compartments.                  genetically determined, predisposes individuals to
                                                                 greater insulin resistance while obesity with low IMCL
                                                                 deposition seems to be more ‘metabolically benign’.
                                                                    The effects of intramyocellular lipid accumulation on
Intramyocellular lipid deposition                                the response of the myocyte to insulin stimulation are
                                                                 not caused by the stored triglyceride per se. Rather, fatty
Increased intramyocellular lipid (IMCL) deposition has
                                                                 acid derivates of the accumulated IMCL cause a
been shown to occur early in childhood obesity and be
directly associated with peripheral insulin sensitivity          disturbance of the insulin signal transduction pathway,
(13). Importantly, not all obese children have increased         eventually leading to reduced glucose uptake (22).
IMCL levels and those who do not are much more insulin           The insulin signal transduction pathway culminates in
sensitive (14). Why intramyocellular lipid deposition            the trafficking of glucose transporter 4 (GLUT-4) to the
differs between individuals who are seemingly equally            cellular membrane, allowing transport of glucose into
obese and share common lifestyle and dietary habits is a         the myocyte. In brief, insulin stimulation causes
matter of intensive research. An excellent model to study        phosphorylation of insulin receptor substrate 1 (IRS-1)
this issue is lean offspring of patients with type 2 diabetes,   leading to its binding and activation of phosphatidyl-
as they lack the confounding factors of obesity and              inositol-3 (PI3) kinase. Activation of PI3 kinase leads to
hyperglycemia seen in obese patients with diabetes.              GLUT-4 trafficking to the cell membrane, allowing
These individuals have been shown to have impaired               glucose transport into the myocyte. Fatty acid derivates
insulin-stimulated non-oxidative muscle glucose dispo-           within the cell have been shown to inhibit this signal
sal, i.e. to possess significant skeletal muscle insulin         transduction pathway through activation of protein
resistance earlier than the development of any clinical          kinase C–q which in turn blunts IRS-1 tyrosine
manifestation of altered glucose metabolism (15). The            phosphorylation via a serine–threonine kinase cascade.
best correlate of insulin resistance in these lean               Reduction of IRS-1 tyrosine phosphorylation leads to
individuals was indeed intramyocellular lipid content            reduced PI3 kinase activation and reduced GLUT-4
(16). A putative explanation for the tendency to                 trafficking to the cellular membrane (23).

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S42    R Weiss                                                                     EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157

Abdominal lipid deposition                                         increased s.c. fat (33). The contribution of visceral fat to the
                                                                   typical sub-clinical chronic inflammation seen in some
Upper body obesity, manifested clinically by increased waist       obese individuals may thus be the causal link between
circumference, is known to be associated with cardiovas-           visceral adiposity and the MS and its related morbidity.
cular disease and type 2 diabetes. The adverse impact of              Indeed, adults with visceral adiposity tend to manifest
upper body obesity is implicated on accumulation of intra-         insulin resistance, hypertension, a hypercoagulable state
abdominal (visceral) fat yet the adverse effects of abdominal      and dyslipidemia in comparison with those who are equally
s.c. tissue should not be overlooked. The major source of          obese with lower levels of visceral fat (34, 35). Increased
circulating FFAs is fat tissue and one can assume that with        visceral adiposity has also been shown to be related to a
greater adiposity there is an increase in FFA flux. When FFA       greater atherogenic metabolic profile in childhood (36).
flux is expressed per units of fat mass (from where FFAs are       Visceral fat has been shown to be related to greater insulin
released), thus enabling a comparison of lean and obese            resistance and lower insulin secretory response in obese
individuals, FFA turnover is w50% lower in obese                   children and adolescents (37), thus potentially promoting
compared to lean individuals (24). This may be attributed          deteriorating glucose metabolism. Adiponectin levels are
to greater circulating insulin concentrations that may thus        lower in obese children with increased visceral fat
prevent an overflow of FFAs released from the increased            deposition (38), even when the comparison is made
lipid stores of obese persons. When FFA turnover is                between those with similar overall adipositiy (10).
expressed per lean body (fat free) mass (where FFAs are
mainly consumed), FFA lipolysis is greater in obese
compared to lean individuals by w50% (25) and those
with upper body obesity have greater FFA lipolysis rates in
                                                                   Hepatic lipid deposition
comparison to those with lower body obesity (26). These            Non-alcoholic fatty liver disease (NAFLD) represents fatty
observations suggest that there are differences in the             infiltration of the liver without excessive alcohol con-
regulation of lipolysis in adipose tissue in individuals with      sumption (39). The spectrum of NAFLD ranges from
different obesity phenotypes.                                      isolated fatty infiltration (steatosis) to inflammation
   Visceral fat has been suggested to cause insulin                (steatohepatitis, also known as NASH), to fibrosis and
resistance (27). Whether this relation is due to the relative      even cirrhosis (40). Lipid accumulation in the liver is
resistance of visceral fat to insulin resulting in increased       characterized as macrovesicular hepatic steatosis and is
FFA release is unclear. Elegant studies by Jensen et al. (28)      the result of an imbalance between production and
revealed that increased visceral fat is indeed associated with     utilization of triglycerides. There are three sources that
increased delivery of FFAs to the liver, yet that this visceral    may increase the hepatic fatty acid pool: circulating FFAs
FFA flux is responsible for only about 20–30% and that             from various adipose compartments discussed earlier,
splanchnic bed contributes up to 15% of FFAs reaching the          de novo lipogenesis within the liver, and dietary factors that
liver. This implies that visceral fat is probably not the source   promote lipogenesis. De novo lipogenesis, shown to be
of the majority of systemic circulating FFAs and its               increased in NAFLD (41), is dependent on acetyl Co-
postulated effects on insulin resistance of tissues other          enzyme A, an intermediate that enables proteins and
than the liver cannot be attributed to increased discharge of      carbohydrates to be driven towards lipogenic pathways.
FFAs. Thus, the abdominal s.c. fat is probably the source of       The two main effectors that drive hepatic de novo
increased circulating FFAs of lean and obese individuals.          lipogenesis are acetyl-CoA carboxylase and fatty acid
Indeed, upper body fat (mainly from the s.c. abdominal             synthase. Dietary factors that may promote hepatic
tissue) is lipolytically more active than lower body fat and       lipogenesis include exogenous fatty acids as well as
contributes the majority of circulating FFAs in the post-          carbohydrates which can drive triglyceride formation by
absorptive state (29, 30). This observation may explain the        way of triose phosphate as a basis for glycerol formation
adverse metabolic implications of ‘male pattern obesity’,          and by way of fatty acid formation by acetyl-CoA. A
characterized by greater upper body fat, in comparison             specific dietary factor that promotes hepatic lipogenesis is
with ‘female pattern obesity’ which typically involves             fructose which is an unregulated substrate for liver
greater lower body fat. Thus, the contribution of visceral fat     triglyceride synthesis. Factors that decrease the hepatic
to insulin resistance may be related to elements other than        fatty acid pool are either synthesis of triglycerides and
FFA discharge and its presence may be only a surrogate of          phospholipids or fatty acid oxidation. Very low density
relatively increased upper body fat depots. A proposed             lipoprotein and chylomicron remnants have also been
mechanism by which visceral fat may cause its adverse              shown to contribute to hepatic triglyceride synthesis and
effects is related to secretion of inflammatory cytokines.         storage (42). The rate-limiting step of mitochondrial
When examined in vitro, visceral fat has been shown to             b-oxidation is the transfer of fatty acids into the
secrete increased amounts of inflammatory mediators,               mitochondria, regulated by carnitine palmitoyl acyltran-
including CRP, IL-6, TNF-a, and PAI-1, compared to s.c. fat        ferase-1 which is inhibited by insulin. The balance
(31, 32). Similarly, obese individuals with increased              between lipogenesis and lipolysis in the liver is mainly
visceral adiposity have increased markers of systemic              affected by the ratio of insulin and glucagon. In the case of
inflammation compared to equally obese subjects with               insulin resistance, fatty acid flux to the liver is increased

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EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157                                                      Fat distribution and storage   S43

from increased lipolysis in adipose tissue leading to              pattern that is advantageous and that enables efficient
increased fatty acid uptake. This in turn increases hepatic        fatty acid utilization at times of exertion. Another
glucose output and triggers increased insulin secretion in         observation that supports the importance of patterns of
order to maintain euglycemia. Increased concentrations             lipid storage and not only lipid quantity comes from weight
of insulin in the liver induce de novo lipogenesis thus            loss studies performed by Kelley et al. (51). A 4-month diet
creating a vicious cycle. The dietary factors such as              and exercise weight loss program in obese adults resulted
increased consumption of carbohydrates (specifically               in a weight loss of w10% body weight and a w45%
fructose) and saturated fats, typically seen in obese              increase in insulin sensitivity. Intramyocellular lipid
subjects, may further contribute to hepatic lipogenesis.           content did not significantly change, however lipid droplet
   NAFLD is not confined to adults and is now the most             size decreased significantly alongside an increase in
common liver disease among obese children and adoles-              mitochondrial labeling and oxidative capacity. These
cents in North America (43, 44) with similar reports               observations suggest that muscle lipid content per se is
coming from other countries (45, 46). The NHANES III               not the major factor that determines insulin sensitivity,
survey found NAFLD to be more prevalent in obese African           rather the way lipid is stored and packaged within the cell.
American and Hispanic males, with T2DM, hypertension               An increase in insulin sensitivity, in this case caused by
and hyperlipidemia (47). These associations have led to the        lifestyle modifications, induces storage of fat in smaller
hypothesis that NAFLD may precede the onset of type 2              droplets without affecting overall fat content and this
diabetes in some individuals. The natural history of NAFLD         probably is coupled to the increased oxidative capacity that
in children is unknown yet it may progress to cirrhosis and        is related to greater insulin sensitivity. Further studies are
related complications (48). The gold standard for the              needed to investigate what determines storage patterns of
assessment of fatty liver is a liver biopsy yet recently several   lipid droplets within cells and the effects of their proximity
non-invasive quantitative methods, such as specific                to cellular structures such as mitochondria as
magnetic resonance imaging protocols and NMR spec-                 determinants of their potential ‘lipotoxic’ effect.
troscopy, have been developed to evaluate patients
suspected to have NAFLD. A surrogate typically used in
the clinical setting is screening of alanine amino
transferase (ALT) levels. In a study of 392 obese children
                                                                   Lipid deposition and ‘sub-clinical
and adolescents (49), elevated ALT (O35 U/l) was found             inflammation’
in 14% of participants, with a predominance of male                Recent accumulating evidence indicates that obesity and
gender and white/Hispanic race/ethnicity. After adjusting          insulin resistance are associated with sub-clinical
for potential confounders, rising ALT was associated with          chronic inflammation (52). The immune and metabolic
reduced insulin sensitivity and glucose tolerance, as well as      responses are tightly linked as both evolved from
increasing concentrations of FFAs and triglycerides.               common structures, still present in primitive organisms
Worsening of glucose and lipid metabolism was already              such as the Drosophila fat body which shares the
evident as ALT levels rose into the upper half of the normal       functions of the liver and the hemetopoietic/immune
range (18–35 U/l). When hepatic fat fraction was assessed          system (53). It is thus reasonable to assume that
using fast magnetic resonance imaging, 32% of subjects             regulatory signal transduction pathways are shared by
had an increased hepatic fat fraction, which was                   the metabolic and immunological systems and respond
associated with decreased insulin sensitivity and adipo-           to similar stimuli (54). The adipose tissue is not merely a
nectin, and with increased triglycerides and visceral fat.         simple reservoir of energy stored as triglycerides, but
The prevalence of the MS was significantly greater in those        serves as an active secretory organ releasing many
with fatty liver. These results implicate that fatty               peptides and cytokines into the circulation (55). In the
infiltration of the liver is a common finding among obese          presence of obesity, the balance between these numerous
children and adolescents and is associated with the                molecules is altered, such that enlarged adipocytes
adverse components of the MS, namely insulin resistance,           produce more pro-inflammatory cytokines (i.e. TNF-a,
dyslipidemia, and altered glucose metabolism.                      IL-6) and fewer anti-inflammatory peptides such as
                                                                   adiponectin (56). The relation of elevated circulating
                                                                   pro-inflammatory molecules and peripheral insulin
Patterns of intracellular lipid storage                            resistance is mediated by the common interface of
                                                                   these signals and the insulin signal transduction
IMCL accumulation, as shown previously in this review, is          pathway at the level of insulin receptor substrates
associated with peripheral insulin resistance. This obser-         through activation of several serine kinases (57).
vation is generally true yet has a paradoxical exception –         The dysregulated production of adipocytokines has
trained athletes have similar IMCL levels to obese diabetic        been found to participate in the development of
insulin-resistant patients yet possess a much greater              metabolic and vascular diseases related to obesity (58).
oxidative capacity (50). As trained athletes are very              Evidence indicates that as the degree of obesity increases,
insulin sensitive and have low percent of body fat, they           the adipose tissue is infiltrated by macrophages (59).
must therefore store the lipid within the myocyte in a             Such macrophages may be the major source of

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S44    R Weiss                                                                              EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 157

pro-inflammatory cytokines initiating a pro-inflam-                        7 Kuczmarski RJ & Flegal KM. Criteria for definition of overweight in
matory status that predates the development of insulin                       transition: background and recommendations for the United
                                                                             States. American Journal of Clinical Nutrition 2000 72 1074–1081.
resistance and endothelial dysfunction (60). Indeed,                       8 Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE,
inflammation may be the missing link between obesity                         Yeckel CW, Allen K, Lopes M, Savoye M, Morrison J, Sherwin RS &
and insulin resistance. In obese children and adoles-                        Caprio S. Obesity and the metabolic syndrome in children
cents, C-reactive protein, a marker of systemic inflam-                      and adolescents. New England Journal of Medicine 2004 350
                                                                             2362–2374.
mation (61), and interleukin-6 levels are related to the                   9 Freedman DS, Mei Z, Srinivasan SR, Berenson GS & Dietz WH.
degree and severity of obesity (8, 62). In contrast, levels                  Cardiovascular risk factors and excess adiposity among overweight
of adiponectin, an anti-inflammatory biomarker,                              children and adolescents: the Bogalusa Heart Study. Journal of
decreased with increasing levels of obesity and insulin                      Pediatrics 2007 150 12–17.
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                                                                             Chevenne D, Ricour C, Tauber M, Polak M, Alberti C & Levy-
                                                                             Marchal C. Insulin resistance and the metabolic syndrome in
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Conclusion                                                                11 de Ferranti SD, Gauvreau K, Ludwig DS, Neufeld EJ, Newburger JW &
                                                                             Rifai N. Prevalence of the metabolic syndrome in American
Obesity is the major cause of insulin resistance in                          adolescents: findings from the Third National Health and Nutrition
childhood and insulin resistance probably drives the                         Examination Survey. Circulation 2004 110 2494–2497.
                                                                          12 Weiss R, Dufour S, Taksali SE, Tamborlane WV, Petersen KF,
majority of obesity-related comorbidity. In general, as the                  Bonadonna RC, Boselli L, Barbetta G, Allen K, Rife F, Savoye M,
degree of obesity increases, so does the risk for disease, yet               Dziura J, Sherwin R, Shulman GI & Caprio S. Prediabetes in obese
among equally obese individuals the pattern of lipid                         youth: a syndrome of impaired glucose tolerance, severe insulin
partitioning is what determines the metabolic profile.                       resistance, and altered myocellular and abdominal fat partition-
Increased deposition of fat in the visceral compartment,                     ing. Lancet 2003 362 951–957.
                                                                          13 Sinha R, Dufour S, Petersen KF, LeBon V, Enoksson S, Ma YZ,
in muscle, and in liver, is associated with reduced insulin                  Savoye M, Rothman DL, Shulman GI & Caprio S. Assessment of
sensitivity and an adverse metabolic profile. The                            skeletal muscle triglyceride content by (1)H nuclear magnetic
tendency to accumulate fat in less favorable depots is                       resonance spectroscopy in lean and obese adolescents: relation-
genetically as well as environmentally determined.                           ships to insulin sensitivity, total body fat, and central adiposity.
‘Lipotoxic’ effects of intracellular lipids may be related                   Diabetes 2002 51 1022–1027.
                                                                          14 Weiss R, Taksali SE, Dufour S, Yeckel CW, Papademetris X, Cline G,
to their pattern of storage. Insights into patterns of lipid                 Tamborlane WV, Dziura J, Shulman GI & Caprio S. The ‘obese
storage within insulin-sensitive tissues may shed new                        insulin-sensitive’ adolescent: importance of adiponectin and lipid
light on the sophistication of fatty acid utilization in                     partitioning. Journal of Clinical Endocrinology and Metabolism 2005
conditions of excess and of need.                                            90 3731–3737.
                                                                          15 Rothman DL, Magnusson I, Cline G, Gerard D, Kahn CR,
                                                                             Shulman RG & Shulman GI. Decreased muscle glucose trans-
                                                                             port/phosphorylation is an early defect in the pathogenesis of
Disclosure                                                                   non-insulin-dependent diabetes mellitus. PNAS 1995 92
                                                                             983–987.
This paper forms part of a European Journal of                            16 Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM,
Endocrinology supplement, supported by Ipsen. The                            Rothman DL, Roden M & Shulman GI. Intramyocellular lipid
author discloses:                                                            concentrations are correlated with insulin sensitivity in humans:
                                                                             a 1H NMR spectroscopy study. Diabetologia 1999 42 113–116.
Ram Weiss: no relation and no conflict of interest.                       17 Petersen KF, Befroy D, Dufour S, Dziura J, Ariyan C, Rothman DL,
This article was subject to rigorous peer review before                      DiPietro L, Cline GW & Shulman GI. Mitochondrial dysfunction in
acceptance and publication.                                                  the elderly: possible role in insulin resistance. Science 2003 300
                                                                             1140–1142.
                                                                          18 Petersen KF, Dufour S, Befroy D, Garcia R & Shulman GI. Impaired
                                                                             mitochondrial activity in the insulin-resistant offspring of patients
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