European Journal of Endocrinology (2007) 157 S39S45

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 prole and not just obesity per se. The underlying mechanisms and clinical relevance of lipid deposition in the visceral compartment and in insulinsensitive 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-inammatory milieu of specic 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 S39S45

The prevalence of obesity among adults as well as children is on the rise and gaining epidemic proportions (1). There is an overall consensus based on numerous longitudinal studies that obesity poses a signicant risk factor for the development of cardiovascular disease, alterations in glucose metabolism, certain cancers, intellectual deterioration, and reduces life expectancy. Despite these observations, a signicant proportion of obese individuals can achieve longevity without developing any of the morbidities previously mentioned. One hypothesis to explain this observation is that total body fat is not the sole source of the adverse health complications of obesity; rather the fat distribution or the relative proportion of lipids in various potential lipid deposition compartments is what determines the metabolic risk of the individual. Lipid deposition is an evolutionary advantageous process that allows efcient storage of maximal calories 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 the face of cold temperatures. The capacity to store lipid within the s.c. tissue is the key to facing famine and limited caloric supply on the one hand and to handling excess calories on the other. In cases where s.c. fat reaches a threshold beyond which it can store no more, lipids may be shunted to other depots. In that scenario, lipids may be stored in less advantageous
This paper was presented at the Ipsen symposium, The evolving biology of growth and metabolism, Lisbon, Portugal, 1618 March 2007. Ipsen has supported the publication of these proceedings.

compartments such as the intra-abdominal (visceral) compartment, and in insulin-sensitive tissues that are prone to deposition of lipid in specic clinical scenarios. This may cause deposition of lipid within skeletal muscle and the liver, affecting their normal metabolic pathways. This review focuses on the metabolic impact of overall adiposity and specically lipid partitioning in the s.c. tissue, visceral compartment, muscle and liver on metabolic complications of obesity. The importance and clinical relevance of each compartment are highlighted with regards to the metabolic manifestations associated with each partitioning prole. Insights into the dynamics of the morphology of lipid storage within muscle are described. The sub-clinical inammation characteristic of increased body fat is discussed. The majority of examples are from studies performed in obese children and adolescents.

Relation of obesity, lipid partitioning, and metabolic risk

The close association of type 2 diabetes mellitus with cardiovascular disease led to the hypothesis that the two may arise from a common antecedent (2, 3). It was Reaven et al. (4) who noticed that common risk factors of cardiovascular disease and altered glucose metabolism tend to cluster in specic individuals and thus named this constellation of risk factors the insulin resistance syndrome, highlighting the critical role of peripheral insulin resistance as a driving force of the underlying pathological process. This concept has been
DOI: 10.1530/EJE-07-0125 Online version via www.eje-online.org

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dened by the World Health Organization as the metabolic syndrome (MS). According to the National Cholesterol Education Program and Adult Treatment Panel III, individuals meeting at least three of the following ve criteria qualify as having the MS: elevated blood pressure, a high triglyceride level, low HDLcholesterol level, high fasting glucose, and central obesity (5). Because of its wide prevalence, the MS has enormous clinical and public health importance, even at its earliest stages, as it promotes atherosclerosis and sets the stage for the development of diabetes (6). According to the paradigm presented herein, the impact of obesity is determined by the pattern of lipid partitioning, i.e. the specic depots in which excess fat is stored. The pattern of lipid storage has an impact on the adipocytokine secretion prole, on circulating concentrations of inammatory cytokines and on the free fatty acid (FFA) ux. The combined effect of these factors determines the sensitivity of insulin target organs (such as muscle and liver) to insulin and impacts the vascular system by affecting endothelial function. Peripheral insulin resistance and endothelial dysfunction are the early promoters of future pathology, mainly of cardiovascular disease and altered glucose metabolism, eventually manifesting as type 2 diabetes (Fig. 1).

Degree of obesity and metabolic risk

Classication of the degree of obesity in adults denes a BMIO30 kg/m2 as class 1 obesity, BMI 3539.9 kg/m2
Obesity

as class 2 obesity, and BMIR40 kg/m2 as class 3 obesity (7). No similar classications for the degree of obesity exist for children and adolescents, except for the denition of those whose BMI is between the 85th and 95th percentiles as at risk for overweight and those at greater than the 95th percentile as overweight. Several studies have shown that the degree of obesity has an adverse impact on the metabolic prole of obese youth, although no sub-categorization of the degrees of obesity within the upper 5 percentiles, as described in adults, exists for children. When obese children were divided to moderately (BMI z score of 22.5, corresponding to the 9799.5 percentiles) and severely (BMI z scoreO2.5, corresponding to the 99.5 percentile) obese and compared with overweight and non-obese children in regards to components of the MS (8), the impact of the degree of obesity was demonstrated. In that study, increasing obesity categories in children and adolescents were associated with worsening of all components of the MS, specically with an increase in fasting glucose, fasting insulin, triglycerides and systolic blood pressure, and the prevalence of impaired glucose tolerance (IGT) and a decrease of HDL cholesterol were observed with increasing adiposity. The prevalence of the MS, using a modied conservative denition adjusted for the pediatric age group, was w30% in the moderately obese and nearly 50% in severely obese participants. When the Bogalusa cohort participants (9) were stratied according to discrete percentiles above the 90th for BMI, those in the 99th percentile for age and gender had a signicantly greater prevalence of biochemical

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 prole of circulating adipocytokines, inammatory 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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components of the MS and being above the 99th percentile for age and gender during childhood had a very high predictive value for adult BMI of O35 kg/m2. The implication of these studies is that among obese children and adolescents, those at the 99th percentile and above in other words, the severely obese are an extremely high-risk group for the presence of components of the MS and for future class 23 obesity in adulthood. Importantly, the prevalence of the MS, regardless of the denition used, is signicant even among overweight and mildly obese children and adolescents (10, 11), and not limited to those with severe obesity.

Impact of lipid partitioning

Obesity does not necessarily implicate pathology in childhood or adulthood. Although obesity is the most common cause of insulin resistance in children and adolescents, some obese youth may be very insulin sensitive and thus be at reduced risk of the development of the adverse cardiovascular and metabolic outcomes driven by insulin resistance. In a study aimed at discovering the underlying pathophysiology of altered glucose metabolism in obese children and adolescents, it was clearly demonstrated that those with IGT are signicantly more insulin resistant than those with normal glucose tolerance, despite having an overall equal degree of adiposity (12). The difference in insulin sensitivity was attributed to different patterns of lipid partitioning, where those with severe insulin resistance were characterized by increased deposition of lipid in the visceral and intramyocellular compartments.

Intramyocellular lipid deposition

Increased intramyocellular lipid (IMCL) deposition has been shown to occur early in childhood obesity and be directly associated with peripheral insulin sensitivity (13). Importantly, not all obese children have increased IMCL levels and those who do not are much more insulin sensitive (14). Why intramyocellular lipid deposition differs between individuals who are seemingly equally obese and share common lifestyle and dietary habits is a matter of intensive research. An excellent model to study this issue is lean offspring of patients with type 2 diabetes, as they lack the confounding factors of obesity and hyperglycemia seen in obese patients with diabetes. These individuals have been shown to have impaired insulin-stimulated non-oxidative muscle glucose disposal, i.e. to possess signicant skeletal muscle insulin resistance earlier than the development of any clinical manifestation of altered glucose metabolism (15). The best correlate of insulin resistance in these lean individuals was indeed intramyocellular lipid content (16). A putative explanation for the tendency to

accumulate lipids in skeletal muscle may be differences in quantity and functionality of the mitochondria within the myocyte. Indeed, when elderly lean insulin-resistant individuals were compared with younger body habitus and activity-matched men using 13C and 31P magnetic resonance spectroscopy, they were found to have a w40% reduction in oxidative phosphorylation (17). When offspring of diabetics were compared with age- and activity-matched insulin-sensitive controls, it was demonstrated that they had a w30% reduction rate of ATP production in mitochondria of skeletal muscle (18). Lean offspring of diabetic parents have also been shown 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 factor leading to IMCL accumulation may be fat constituents of the diet. High-fat diets of varying durations have been shown to increase IMCL content by 3690%, depending on their duration and baseline IMCL levels (20, 21). In physically inactive obese individuals, a continuous increased supply of fatty acids by way of excess energy intake alongside a reduced capacity to oxidize fat may lead overall fat storage, specically in skeletal muscle. An obvious third source of increased IMCL is an increase in circulating FFA concentration, characteristic of obese insulin-resistant individuals. These observations indicate that the tendency to accumulate intramyocellular lipid may be genetically determined as well as inuenced by diet and activity and result from reduced quantity and altered functionality of myocellular mitochondria. A tendency for increased IMCL deposition, which is partially 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 the response of the myocyte to insulin stimulation are not caused by the stored triglyceride per se. Rather, fatty acid derivates of the accumulated IMCL cause a disturbance of the insulin signal transduction pathway, eventually leading to reduced glucose uptake (22). The insulin signal transduction pathway culminates in the trafcking of glucose transporter 4 (GLUT-4) to the cellular membrane, allowing transport of glucose into the myocyte. In brief, insulin stimulation causes phosphorylation of insulin receptor substrate 1 (IRS-1) leading to its binding and activation of phosphatidylinositol-3 (PI3) kinase. Activation of PI3 kinase leads to GLUT-4 trafcking to the cell membrane, allowing glucose transport into the myocyte. Fatty acid derivates within the cell have been shown to inhibit this signal transduction pathway through activation of protein kinase Cq which in turn blunts IRS-1 tyrosine phosphorylation via a serinethreonine kinase cascade. Reduction of IRS-1 tyrosine phosphorylation leads to reduced PI3 kinase activation and reduced GLUT-4 trafcking to the cellular membrane (23).
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Abdominal lipid deposition

Upper body obesity, manifested clinically by increased waist circumference, is known to be associated with cardiovascular disease and type 2 diabetes. The adverse impact of upper body obesity is implicated on accumulation of intraabdominal (visceral) fat yet the adverse effects of abdominal s.c. tissue should not be overlooked. The major source of circulating FFAs is fat tissue and one can assume that with greater adiposity there is an increase in FFA ux. When FFA ux is expressed per units of fat mass (from where FFAs are released), thus enabling a comparison of lean and obese individuals, FFA turnover is w50% lower in obese compared to lean individuals (24). This may be attributed to greater circulating insulin concentrations that may thus prevent an overow of FFAs released from the increased lipid stores of obese persons. When FFA turnover is 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 comparison to those with lower body obesity (26). These observations suggest that there are differences in the regulation of lipolysis in adipose tissue in individuals with different obesity phenotypes. Visceral fat has been suggested to cause insulin resistance (27). Whether this relation is due to the relative resistance of visceral fat to insulin resulting in increased FFA release is unclear. Elegant studies by Jensen et al. (28) revealed that increased visceral fat is indeed associated with increased delivery of FFAs to the liver, yet that this visceral FFA ux is responsible for only about 2030% and that splanchnic bed contributes up to 15% of FFAs reaching the liver. This implies that visceral fat is probably not the source of the majority of systemic circulating FFAs and its postulated effects on insulin resistance of tissues other than the liver cannot be attributed to increased discharge of FFAs. Thus, the abdominal s.c. fat is probably the source of increased circulating FFAs of lean and obese individuals. Indeed, upper body fat (mainly from the s.c. abdominal tissue) is lipolytically more active than lower body fat and contributes the majority of circulating FFAs in the postabsorptive state (29, 30). This observation may explain the adverse metabolic implications of male pattern obesity, characterized by greater upper body fat, in comparison with female pattern obesity which typically involves greater lower body fat. Thus, the contribution of visceral fat to insulin resistance may be related to elements other than FFA discharge and its presence may be only a surrogate of relatively increased upper body fat depots. A proposed mechanism by which visceral fat may cause its adverse effects is related to secretion of inammatory cytokines. When examined in vitro, visceral fat has been shown to secrete increased amounts of inammatory mediators, including CRP, IL-6, TNF-a, and PAI-1, compared to s.c. fat (31, 32). Similarly, obese individuals with increased visceral adiposity have increased markers of systemic inammation compared to equally obese subjects with
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increased s.c. fat (33). The contribution of visceral fat to the typical sub-clinical chronic inammation seen in some obese individuals may thus be the causal link between visceral adiposity and the MS and its related morbidity. Indeed, adults with visceral adiposity tend to manifest insulin resistance, hypertension, a hypercoagulable state and dyslipidemia in comparison with those who are equally obese with lower levels of visceral fat (34, 35). Increased visceral adiposity has also been shown to be related to a greater atherogenic metabolic prole in childhood (36). Visceral fat has been shown to be related to greater insulin resistance and lower insulin secretory response in obese children and adolescents (37), thus potentially promoting deteriorating glucose metabolism. Adiponectin levels are lower in obese children with increased visceral fat deposition (38), even when the comparison is made between those with similar overall adipositiy (10).

Hepatic lipid deposition

Non-alcoholic fatty liver disease (NAFLD) represents fatty inltration of the liver without excessive alcohol consumption (39). The spectrum of NAFLD ranges from isolated fatty inltration (steatosis) to inammation (steatohepatitis, also known as NASH), to brosis and even cirrhosis (40). Lipid accumulation in the liver is characterized as macrovesicular hepatic steatosis and is the result of an imbalance between production and utilization of triglycerides. There are three sources that may increase the hepatic fatty acid pool: circulating FFAs from various adipose compartments discussed earlier, de novo lipogenesis within the liver, and dietary factors that promote lipogenesis. De novo lipogenesis, shown to be increased in NAFLD (41), is dependent on acetyl Coenzyme A, an intermediate that enables proteins and carbohydrates to be driven towards lipogenic pathways. The two main effectors that drive hepatic de novo lipogenesis are acetyl-CoA carboxylase and fatty acid synthase. Dietary factors that may promote hepatic lipogenesis include exogenous fatty acids as well as carbohydrates which can drive triglyceride formation by way of triose phosphate as a basis for glycerol formation and by way of fatty acid formation by acetyl-CoA. A specic dietary factor that promotes hepatic lipogenesis is fructose which is an unregulated substrate for liver triglyceride synthesis. Factors that decrease the hepatic fatty acid pool are either synthesis of triglycerides and phospholipids or fatty acid oxidation. Very low density lipoprotein and chylomicron remnants have also been shown to contribute to hepatic triglyceride synthesis and storage (42). The rate-limiting step of mitochondrial b-oxidation is the transfer of fatty acids into the mitochondria, regulated by carnitine palmitoyl acyltranferase-1 which is inhibited by insulin. The balance between lipogenesis and lipolysis in the liver is mainly affected by the ratio of insulin and glucagon. In the case of insulin resistance, fatty acid ux to the liver is increased

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from increased lipolysis in adipose tissue leading to increased fatty acid uptake. This in turn increases hepatic glucose output and triggers increased insulin secretion in order to maintain euglycemia. Increased concentrations of insulin in the liver induce de novo lipogenesis thus creating a vicious cycle. The dietary factors such as increased consumption of carbohydrates (specically fructose) and saturated fats, typically seen in obese subjects, may further contribute to hepatic lipogenesis. NAFLD is not conned to adults and is now the most common liver disease among obese children and adolescents in North America (43, 44) with similar reports coming from other countries (45, 46). The NHANES III survey found NAFLD to be more prevalent in obese African American and Hispanic males, with T2DM, hypertension and hyperlipidemia (47). These associations have led to the hypothesis that NAFLD may precede the onset of type 2 diabetes in some individuals. The natural history of NAFLD in children is unknown yet it may progress to cirrhosis and related complications (48). The gold standard for the assessment of fatty liver is a liver biopsy yet recently several non-invasive quantitative methods, such as specic magnetic resonance imaging protocols and NMR spectroscopy, 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 and adolescents (49), elevated ALT (O35 U/l) was found in 14% of participants, with a predominance of male gender and white/Hispanic race/ethnicity. After adjusting for potential confounders, rising ALT was associated with reduced insulin sensitivity and glucose tolerance, as well as increasing concentrations of FFAs and triglycerides. Worsening of glucose and lipid metabolism was already evident as ALT levels rose into the upper half of the normal range (1835 U/l). When hepatic fat fraction was assessed using fast magnetic resonance imaging, 32% of subjects had an increased hepatic fat fraction, which was associated with decreased insulin sensitivity and adiponectin, and with increased triglycerides and visceral fat. The prevalence of the MS was signicantly greater in those with fatty liver. These results implicate that fatty inltration of the liver is a common nding among obese children and adolescents and is associated with the adverse components of the MS, namely insulin resistance, dyslipidemia, and altered glucose metabolism.

pattern that is advantageous and that enables efcient fatty acid utilization at times of exertion. Another observation that supports the importance of patterns of lipid storage and not only lipid quantity comes from weight loss studies performed by Kelley et al. (51). A 4-month diet and exercise weight loss program in obese adults resulted in a weight loss of w10% body weight and a w45% increase in insulin sensitivity. Intramyocellular lipid content did not signicantly change, however lipid droplet size decreased signicantly alongside an increase in mitochondrial labeling and oxidative capacity. These observations suggest that muscle lipid content per se is not the major factor that determines insulin sensitivity, rather the way lipid is stored and packaged within the cell. An increase in insulin sensitivity, in this case caused by lifestyle modications, induces storage of fat in smaller droplets without affecting overall fat content and this probably is coupled to the increased oxidative capacity that is related to greater insulin sensitivity. Further studies are needed to investigate what determines storage patterns of lipid droplets within cells and the effects of their proximity to cellular structures such as mitochondria as determinants of their potential lipotoxic effect.

Lipid deposition and sub-clinical inammation

Recent accumulating evidence indicates that obesity and insulin resistance are associated with sub-clinical chronic inammation (52). The immune and metabolic responses are tightly linked as both evolved from common structures, still present in primitive organisms such as the Drosophila fat body which shares the functions of the liver and the hemetopoietic/immune system (53). It is thus reasonable to assume that regulatory signal transduction pathways are shared by the metabolic and immunological systems and respond to similar stimuli (54). The adipose tissue is not merely a simple reservoir of energy stored as triglycerides, but serves as an active secretory organ releasing many peptides and cytokines into the circulation (55). In the presence of obesity, the balance between these numerous molecules is altered, such that enlarged adipocytes produce more pro-inammatory cytokines (i.e. TNF-a, IL-6) and fewer anti-inammatory peptides such as adiponectin (56). The relation of elevated circulating pro-inammatory molecules and peripheral insulin resistance is mediated by the common interface of these signals and the insulin signal transduction pathway at the level of insulin receptor substrates through activation of several serine kinases (57). The dysregulated production of adipocytokines has been found to participate in the development of metabolic and vascular diseases related to obesity (58). Evidence indicates that as the degree of obesity increases, the adipose tissue is inltrated by macrophages (59). Such macrophages may be the major source of
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Patterns of intracellular lipid storage

IMCL accumulation, as shown previously in this review, is associated with peripheral insulin resistance. This observation is generally true yet has a paradoxical exception trained athletes have similar IMCL levels to obese diabetic insulin-resistant patients yet possess a much greater oxidative capacity (50). As trained athletes are very insulin sensitive and have low percent of body fat, they must therefore store the lipid within the myocyte in a

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pro-inammatory cytokines initiating a pro-inammatory status that predates the development of insulin resistance and endothelial dysfunction (60). Indeed, inammation may be the missing link between obesity and insulin resistance. In obese children and adolescents, C-reactive protein, a marker of systemic inammation (61), and interleukin-6 levels are related to the degree and severity of obesity (8, 62). In contrast, levels of adiponectin, an anti-inammatory biomarker, decreased with increasing levels of obesity and insulin resistance.

Conclusion
Obesity is the major cause of insulin resistance in childhood and insulin resistance probably drives the majority of obesity-related comorbidity. In general, as the degree of obesity increases, so does the risk for disease, yet among equally obese individuals the pattern of lipid partitioning is what determines the metabolic prole. Increased deposition of fat in the visceral compartment, in muscle, and in liver, is associated with reduced insulin sensitivity and an adverse metabolic prole. The tendency to accumulate fat in less favorable depots is genetically as well as environmentally determined. Lipotoxic effects of intracellular lipids may be related to their pattern of storage. Insights into patterns of lipid storage within insulin-sensitive tissues may shed new light on the sophistication of fatty acid utilization in conditions of excess and of need.

Disclosure
This paper forms part of a European Journal of Endocrinology supplement, supported by Ipsen. The author discloses: Ram Weiss: no relation and no conict of interest. This article was subject to rigorous peer review before acceptance and publication.

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Received 28 February 2007 Accepted 2 May 2007

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