Ectopic Depots Research Articles

Association Between Alcohol Consumption and Ectopic Fat in the Multi-Ethnic Study of Atherosclerosis.

Background The relationship between alcohol consumption and ectopic fat distribution, both known factors for cardiovascular disease, remains understudied. Therefore, we aimed to examine the association between alcohol consumption and ectopic adiposity in adults at risk for cardiovascular disease. Methods and Results In this cross-sectional analysis, we categorized alcohol intake among participants in MESA (Multi-Ethnic Study of Atherosclerosis) as follows (drinks/day): <1 (light drinking), 1 to 2 (moderate drinking), >2 (heavy drinking), former drinking, and lifetime abstention. Binge drinking was defined as consuming ≥5 drinks on 1 occasion in the past month. Visceral, subcutaneous, and intermuscular fat area, pericardial fat volume, and hepatic fat attenuation were measured using noncontrast computed tomography. Using multivariable linear regression, we examined the associations between categories ofalcohol consumption and natural log-transformed fat in ectopic depots. We included 6756 MESA participants (62.1±10.2 years; 47.2% women), of whom 6734 and 1934 had chest computed tomography (pericardial and hepatic fat) and abdominal computed tomography (subcutaneous, intermuscular, and visceral fat), respectively. In adjusted analysis, heavy drinking, relative to lifetime abstention, was associated with a higher (relative percent difference) pericardial 15.1 [95% CI, 7.1-27.7], hepatic 3.4 [95% CI, 0.1-6.8], visceral 2.5 [95% CI, -10.4 to 17.2], and intermuscular 5.2 [95% CI, -6.6 to 18.4] fat but lower subcutaneous fat -3.5 [95% CI, -15.5 to 10.2]). The associations between alcohol consumption and ectopic adiposity exhibited a J-shaped pattern. Binge drinking, relative to light-to-moderate drinking, was also associated with higher ectopic fat. Conclusions Alcohol consumption had a J-shaped association with ectopic adiposity. Both heavy alcohol intake and binge alcohol drinking were associated with higher ectopic fat.

Relationship of Subcutaneous Adipose Tissue Inflammation-Related Gene Expression With Ectopic Lipid Deposition in Persons With HIV.

Fat redistribution from subcutaneous adipose tissue (SAT) to the abdominal viscera, pericardium, liver, and skeletal muscle contributes to the rising burden of cardiometabolic disease among persons with HIV (PWH). Previous studies found SAT inflammation in PWH impairs lipid storage and persists despite plasma viral suppression on antiretroviral therapy (ART). In this study, we identified SAT immune-related genes associated with ectopic fat deposition in PWH on long-term ART. A total of 92 PWH with well-controlled viremia underwent computed tomography imaging and abdominal SAT biopsy for gene expression analysis. SAT gene expression was measured using a NanoString panel of 255 immune-related genes. Associations between gene expression and computed tomography measurements of the volume and attenuation (radiodensity) of metabolically relevant ectopic fat depots were assessed using multivariable linear regression and network analysis. Greater SAT volume was associated with higher visceral and pericardial adipose tissue volume, but lower skeletal muscle attenuation. Lower SAT attenuation, a measure of lipid content, was associated with lower visceral adipose tissue attenuation. Hierarchical clustering identified a subset of macrophage-related genes in SAT, including CCL2, CCL22, CCL13, CCR1, CD86, CD163, IL-6, IL-10, MRC1, and TREM2, which were associated with an increased lipid deposition in multiple ectopic depots. Altered expression of macrophage-related genes in SAT is associated with differences in ectopic fat depot morphometrics among PWH on long-term ART, including in the pericardial and visceral compartments. These findings provide basis for future studies to assess host, virus, and treatment factors shaping the SAT immune environment and its effects on morphometric changes and metabolic comorbidities in PWH.

Ectopic fat depots as a factor of cardiovascular risk in patients with nonalcoholic fatty liver disease

The review represents evaluation of the ectopic fatty depots effect on the development of cardiovascular diseases (CVD) in patients with nonalcoholic fatty liver disease (NAFLD). Nowadays, NAFLD is the most common cause of chronic liver disease in most countries of the world. A number of studies have confirmed the important role of NAFLD in the formation and progression of CVD, which is manifested by an increased risk of cardiovascular events in patients with NAFLD according to Framingham Risk Score. The statement that NAFLD should be recognized as an independent risk factor for CVD, in addition to other metabolic disorders, is often confirmed. One of the possible mechanisms of interrelation between NAFLD and CVD is the paracrine activity of visceral adipose tissue; the possibility of local effects of various ectopic depots of visceral fat is being discussed. There is no doubt that epicardial adipose tissue plays an important role in the formation of the hepato-cardiac continuum. Тhere are more and more studies evaluating the effect of other ectopic depots on the development of CVD in patients with NAFLD. The article provides an analysis of publications devoted to the interrelation between fatty ectopic depots and CVD risks in patients with NAFLD. MedLine and PubMed databases in English and Russian languages were used for the search. The review includes articles published from 2000 to 2020.

Polycystic ovary syndrome in adolescent girls.

PCOS is already a prevalent endocrinopathy in adolescent girls, and its prevalence is rising further since, in essence, it is the result of a mismatch between an energy-sparing (epi)genetic background and a (relatively) obesogenic environment. This mismatch results in an excess of fat storage in ectopic depots, notably in the liver and viscera (= hepato-visceral, or central fat). There is still no FDA-approved treatment for adolescent PCOS. The prime aim should be a preferential loss of central fat, through lifestyle measures. Failure to sustain these measures is frequent, and the standard approach is to add an estroprogestagen contraceptive, even for girls who do not need contraception. Treatment with SPIOMET, a low-dose combination of spironolactone (to antagonize androgen and mineralocorticoid effects, and to activate BAT thereby raising energy expenditure), pioglitazone (to raise circulating HMW adiponectin concentrations) and metformin, is an alternative approach that holds the potential to revert the PCOS phenotype.

Metabolic syndrome: what changed during last 30 years?

Metabolic syndrome (MS) is a cluster of cardiometabolic factors that are strongly associated with the risk of serious chronic diseases. The prevalence of MS continues to grow, including among children, adolescents and people of active reproductive age. For the sphere of reproductive medicine, the problem of MS is of particular importance not only because of its negative impact on fertility, the frequency of complications of pregnancy and childbirth, but also because of its transgenerative effect on the health of offspring: it is proved that each of the components of the metabolic syndrome is a powerful epigenetic factor. Recent studies have revealed many new facets of the pathogenesis of MS and expanded the range of its etiologic factors beyond the alimentary factors, which determines the possibility of finding new approaches to prevention and treatment of this pathology. The review presents: evolution of diagnostic criteria for MS and reflection of this process in epidemiology and clinical approaches to the disease; epidemiological data on the prevalence of MS in young adults. A brief overview of a large array of scientific research of the last decade on etiology and pathogenesis of MS, in particular the role of adipose tissue dysfunction of visceral, ileofemoral and ectopic depots, causes of the tendency to prevail in one or another adipose tissue depot, new obesity classification, as well as the role of perinatal and epigenetic, ecological (environmental obesogenes, artificial light contamination), composition of intestinal microbiota, state of the sympathetic nervous system, nutritional deficiencies in the development of obesity and MS is provided. The gender differences of pathogenesis and clinical features of MS, as well as the association of MS with dyshormonal and other pathologies (PCOS, hyperprolactinemia, uterine myoma, endometriosis) of female reproductive health are considered.

The epidemiology of obesity

Obesity is a complex multifactorial disease. The worldwide prevalence of overweight and obesity has doubled since 1980 to an extent that nearly a third of the world's population is now classified as overweight or obese. Obesity rates have increased in all ages and both sexes irrespective of geographical locality, ethnicity or socioeconomic status, although the prevalence of obesity is generally greater in older persons and women. This trend was similar across regions and countries, although absolute prevalence rates of overweight and obesity varied widely. For some developed countries, the prevalence rates of obesity seem to have levelled off during the past few years. Body mass index (BMI) is typically used to define overweight and obesity in epidemiological studies. However, BMI has low sensitivity and there is a large inter-individual variability in the percent body fat for any given BMI value, partly attributed to age, sex, and ethnicity. For instance, Asians have greater percent body fat than Caucasians for the same BMI. Greater cardiometabolic risk has also been associated with the localization of excess fat in the visceral adipose tissue and ectopic depots (such as muscle and liver), as well as in cases of increased fat to lean mass ratio (e.g. metabolically-obese normal-weight). These data suggest that obesity may be far more common and requires more urgent attention than what large epidemiological studies suggest. Simply relying on BMI to assess its prevalence could hinder future interventions aimed at obesity prevention and control.

Neck adipose tissue - tying ties in metabolic disorders.

Upper body adipose tissue accumulation has been associated with clustering of metabolic disorders and increased cardiovascular risk. Neck circumference (NC) indicated that subcutaneous adipose tissue (SAT) in that region is an independent pathogenic depot that might account for the additional risk missed by visceral adipose tissue (VAT). Neck adipose tissue (NAT) is not only one more ectopic depot but has several particular features that might modulate its metabolic role. Besides a controversial impact on obstructive apnea syndrome, neck fat encompasses carotid arteries as an important perivascular adipose tissue (PVAT) depot. With dysfunctional changes in obesity, physiologic vascular regulation is lost and inflammatory signals accelerate atherogenesis. Unexpected was the discovery of brown and beige adipocytes in the neck of human adults. When stimulated, brown adipose tissue (BAT) dissipates energy through thermogenesis and it is associated with other favorable metabolic effects. Moreover, the neck is the region where the browning mechanism was disclosed. With this unique plastic nature, NAT revealed multiple ties, challenging dynamics and potential new therapeutic targets that might have significant implications on metabolic outcomes and vascular risk.

What have human experimental overfeeding studies taught us about adipose tissue expansion and susceptibility to obesity and metabolic complications?

Overfeeding experiments, in which we impose short-term positive energy balance, help unravel the cellular, physiological and behavioural adaptations to nutrient excess. These studies mimic longer-term mismatched energy expenditure and intake. There is considerable inter-individual heterogeneity in the magnitude of weight gain when exposed to similar relative caloric excess reflecting variable activation of compensatory adaptive mechanisms. Significantly, given similar relative weight gain, individuals may be protected from/predisposed to metabolic complications (insulin resistance, dyslipidaemia, hypertension), non-alcoholic fatty liver disease and cardiovascular disease. Similar mechanistic considerations underpinning the heterogeneity of overfeeding responses are pertinent in understanding emerging metabolic phenotypes, for example, metabolically unhealthy normal weight and metabolically healthy obesity. Intrinsic and extrinsic factors modulate individuals' overfeeding response: intrinsic factors include gender/hormonal status, genetic/ethnic background, baseline metabolic health and cardiorespiratory fitness; extrinsic factors include macronutrient (fat vs carbohydrate) content, fat/carbohydrate composition and overfeeding pattern. Subcutaneous adipose tissue (SAT) analysis, coupled with metabolic assessment, with overfeeding have revealed how SAT remodels to accommodate excess nutrients. SAT remodelling occurs either by hyperplasia (increased adipocyte number) or by hypertrophy (increased adipocyte size). Biological responses of SAT also govern the extent of ectopic (visceral/liver) triglyceride deposition. Body composition analysis by DEXA/MRI (dual energy X-ray absorptiometry/magnetic resonance imaging) have determined the relative expansion of SAT (including abdominal/gluteofemoral SAT) vs ectopic fat with overfeeding. Such studies have contributed to the adipose expandability hypothesis whereby SAT has a finite capacity to expand (governed by intrinsic biological characteristics), and once capacity is exceeded ectopic triglyceride deposition occurs. The potential for SAT expandability confers protection from/predisposes to the adverse metabolic responses to overfeeding. The concept of a personal fat threshold suggests a large inter-individual variation in SAT capacity with ectopic depot expansion/metabolic decompensation once one's own threshold is exceeded. This review summarises insight gained from overfeeding studies regarding susceptibility to obesity and related complications with nutrient excess.

Adipose tissue regulates insulin sensitivity: role of adipogenesis, de novo lipogenesis and novel lipids.

Obesity, the major cause of the current global epidemic of type 2 diabetes (T2D), induces insulin resistance in peripheral insulin target tissues. Several mechanisms have been identified related to cross-talk between adipose tissue, skeletal muscle and liver. These mechanisms involve both increased free fatty acid release and altered secretion of adipokines from adipose tissue. A major determinant of metabolic health is the ability of subcutaneous adipose tissue (SAT) to store excess fat rather than allowing it to accumulate in ectopic depots including liver (i.e. in nonalcoholic fatty liver disease), muscle and heart, or in epicardial/pericardial and visceral fat depots which promote the metabolic complications of obesity. The ability to recruit and differentiate precursor cells into adipose cells (adipogenesis) in SAT is under genetic regulation and is reduced in high-risk individuals who have first-degree relatives with T2D. Early recruitment of new adipose cells is dependent on the cross-talk between canonical WNT and BMP4 signalling; WNT enhances their undifferentiated and proliferative state whereas BMP4 induces their commitment to the adipogenic lineage. Dysregulation of these signalling pathways is associated with impaired adipogenesis and impaired ability to respond to the need to store excess lipids in SAT. This leads to hypertrophic, dysfunctional and insulin-resistant adipose cells with a reduced content of GLUT4, the major insulin-regulated glucose transporter, which in turn reduces adipose tissue glucose uptake and de novo lipogenesis. We recently identified that reduced GLUT4 and lipogenesis in adipocytes impairs the synthesis of a novel family of lipids secreted by adipose tissue (and potentially other tissues), branched fatty acid esters of hydroxy fatty acids (FAHFAs). FAHFAs have beneficial metabolic effects, including enhancing insulin-stimulated glucose transport and glucose-stimulated GLP1 and insulin secretion, as well as powerful anti-inflammatory effects. FAHFA levels are reduced in subcutaneous adipose tissue in insulin-resistant individuals, and this novel family of lipids may become of future therapeutic use.

Type 2 Diabetes is a Delayed Late Effect of Whole-Body Irradiation in Nonhuman Primates.

One newly recognized consequence of radiation exposure may be the delayed development of diabetes and metabolic disease. We document the development of type 2 diabetes in a unique nonhuman primate cohort of monkeys that were whole-body irradiated with high doses (6.5-8.4 Gy) 5-9 years earlier. We report here a higher prevalence of type 2 diabetes in irradiated monkeys compared to age-matched nonirradiated monkeys. These irradiated diabetic primates demonstrate insulin resistance and hypertriglyceridemia, however, they lack the typical obese presentation of primate midlife diabetogenesis. Surprisingly, body composition analyses by computed tomography indicated that prior irradiation led to a specific loss of visceral fat mass. Prior irradiation led to reductions in insulin signaling effectiveness in skeletal muscle and higher monocyte chemoattractant protein 1 levels, indicative of increased inflammation. However, there was an absence of large defects in pancreatic function with radiation exposure, which has been documented previously in animal and human studies. Monkeys that remained healthy and did not become diabetic in the years after irradiation were significantly leaner and smaller, and were generally smaller and younger at the time of exposure. Irradiation also resulted in smaller stature in both diabetic and nondiabetic monkeys, compared to nonirradiated age-matched controls. Our study demonstrates that diabetogenesis postirradiation is not a consequence of disrupted adipose accumulation (generalized or in ectopic depots), nor generalized pancreatic failure, but suggests that peripheral tissues such as the musculature are impaired in their response to insulin exposure. Ongoing inflammation in these animals appears to be a consequence of radiation exposure and can interfere with insulin signaling. The reasons that some animals remain protected from diabetes as a late effect of irradiation are not clear, but may be related to body size. The translational relevance for these results suggest that muscle may be an important and underappreciated target organ for the delayed late effect of whole-body irradiation, leading to increased risk of insulin resistance and diabetes development.

Age-related different relationships between ectopic adipose tissues and measures of central obesity in sedentary subjects.

Accumulation of fat at ectopic sites has been gaining attention as pivotal contributor of insulin resistance, metabolic syndrome and related cardiovascular complications. Intermuscular adipose tissue (IMAT), located between skeletal muscle bundles and beneath muscle fascia, has been linked to physical inactivity, ageing and body mass index, but little is known about its relationship with the other AT compartments, in particular with increasing age. To address this issue, erector spinae IMAT, epicardial (EAT), intraabdominal (IAAT) and abdominal subcutaneous adipose tissue (SAT) were simultaneously measured by Magnetic Resonance Imaging (MRI) and related to waist circumference measurements and age in 32 sedentary subjects without cardiovascular disease (18 men; 14 women; mean age 48.5±14 years). Fasting glucose, triglycerides and HDL-cholesterol were also assessed. We observed that, after dividing individuals according to age (≤ or >50 years), IMAT and EAT depots were significantly more expanded in older subjects (63.2±8.3 years) than in the younger ones (38.4±5.2 years) (p<0.001). Overall, both IMAT and EAT showed stronger positive associations with increasing age (β = 0.63 and 0.67, respectively, p<0.001 for both) than with waist circumference (β = 0.55 and 0.49, respectively, p<0.01 for both) after adjusting for gender. In addition, the gender-adjusted associations of IMAT and EAT with waist circumference and IAAT were significant in individuals ≤50 years only (p<0.05 for all) and not in the older ones. In contrast, no age-related differences were seen in the relationships of IAAT and SAT with waist circumference. Finally, serum triglycerides levels turned out not to be independently related with ectopic IMAT and EAT. In conclusion, the expansion of IMAT and EAT in sedentary subjects is more strongly related to age than waist circumference, and a positive association of these ectopic depots with waist circumference and IAAT amount can be postulated in younger individuals only.

Relationships between total and regional adiposity and epicardial fat in obese women: how can dual-energy X-ray absorptiometry be associated with echocardiographic epicardial fat measurements?

Obesity is an increasingly prevalent metabolic disorder and it is associated with a large number of comorbidities, including cardiovascular diseases. Adipose tissue is an active endocrine organ and its ectopic depots and distribution have different metabolic meanings on risks for health; as a matter of fact, epicardial fat seems to play a specific role in cardiovascular diseases. The use of dual-energy X-ray absorptiometry (DXA) to evaluate and follow-up patients affected by obesity is becoming a very important point in the management of the disease. An investigation of the association between epicardial fat and regional adiposity by DXA in female obese patients. The total amount of central (trunk) fat mass is more strongly correlated than android visceral fat mass to epicardial thickness in obese women. In the interpretation of whole-body DXA data, physician should consider trunk fat mass for good and independent predictivity on epicardial fat depots. Our aim was to analyse in a population of obese women the relationship between the amount of epicardial fat as measured by transthoracic echocardiography (US) and the parameters of regional adiposity by dual-energy X-ray absorptiometry (DXA), with particular reference to a new software for visceral fat assessment and to a new 'heart-suited' regions of interests (ROIs). Sixty patients who satisfied technical inclusion criteria underwent whole-body DXA scan and US on the same day. Total and android fat mass (FM) and FM percentage (FM%) were considered as well as visceral fat (VAT) subcompartment in the android region; moreover, six new ROIs were designed on whole-body DXA images for the investigation of adiposity parameters at heart level. US provided epicardial fat thickness (EPI-thickness) and area (EPI-area), as measured following previously validated methods. Body mass index (BMI), gynoid and lower limbs (FM and FM%) were found not statistically correlated with EPI-thickness. The highest correlation was achieved by trunk FM (and FM%, with r = 0.544 and 0.480 respectively, P < 0.001), followed by ROI-1 FM (ROI-1 was drawn following thoroughly the cardiac profile), and android FM. Multivariate analysis including age, weight, BMI, trunk FM and the new ROIs (added one by one), retained in the final model trunk FM. Correlations of DXA with EPI-area were superimposable. In obese women, VAT or other new-designed ROIs are not better correlated than traditional ROIs (i.e. trunk) with epicardial fat amount.

Ectopic Lipid Accumulation and Reduced Glucose Tolerance in Elderly Adults Are Accompanied by Altered Skeletal Muscle Mitochondrial Activity

Aging is associated with insulin resistance and unfavorable changes in body composition including increased fat accumulation, particularly in visceral and ectopic depots. Recent studies suggest that skeletal muscle mitochondrial activity may underlie some age-associated metabolic abnormalities. Our objective was to measure mitochondrial capacity and coupling of the vastus lateralis muscle in elderly and young adults using novel in vivo approaches and relate mitochondrial activity to metabolic characteristics. This was a cross-sectional study. Fourteen sedentary young (seven males and seven females, 20-34 yr of age) and 15 sedentary elderly (seven males and eight females, 70-84 yr of age) nonobese subjects selected for similar body weight underwent measures of body composition by magnetic resonance imaging and dual-energy x-ray absorptiometry, oral glucose tolerance, and in vivo mitochondrial activity by (31)P magnetic resonance and optical spectroscopy. Muscle biopsy was carried out in the same muscle to measure mitochondrial content, antioxidant activity, fiber type, and markers of mitochondrial biogenesis. Elderly volunteers had reduced mitochondrial capacity (P = 0.05) and a trend for decreased coupling efficiency (P = 0.08) despite similar mitochondrial content and fiber type distribution. This was accompanied by greater whole-body oxidative stress (P = 0.007), less skeletal muscle mass (P < 0.001), more adipose tissue in all depots (P ≤ 0.002) except intramyocellular (P = 0.72), and lower glucose tolerance (P = 0.07). Elderly adults show evidence of altered mitochondrial activity along with increased adiposity, oxidative stress, and reduced glucose tolerance, independent of obesity. We propose that mild uncoupling may be induced secondary to age-associated oxidative stress as a mechanism to dissipate the proton-motive force and protect against further reactive oxygen species production and damage.

Effects of PNPLA3 on Liver Fat and Metabolic Profile in Hispanic Children and Adolescents

OBJECTIVEA genome-wide study of adults identified a variant of PNPLA3 (rs738409) associated with ∼twofold higher liver fat. The purpose of this study was to examine the influence of PNPLA3 genotype on liver fat and other related metabolic outcomes in obese Hispanic children and adolescents.RESEARCH DESIGN AND METHODSThree hundred and twenty-seven Hispanics aged 8–18 years were genotyped for rs738409. One hundred and eighty-eight subjects had measures of visceral (VAT) and subcutaneous (SAT) adipose tissue volume and hepatic (HFF) and pancreatic (PFF) fat fraction by magnetic resonance imaging. One hundred and thirty-nine subjects did not have HFF measures but had extensive measures of insulin sensitivity and fasting lipids.RESULTSLiver fat in GG subjects was 1.7 and 2.4 times higher than GC and CC (11.1 ± 0.8% in GG vs. 6.6 ± 0.7% in GC and 4.7 ± 0.9% in CC; P < 0.0001), and this effect was observed even in the youngest children (8–10 years of age). The variant was not associated with VAT, SAT, PFF, or insulin sensitivity or other glucose/insulin indexes. However, Hispanic children carrying the GG genotype had significantly lower HDL cholesterol (40.9 ± 10.9 in CC vs. 37.0 ± 8.3 in CG vs. 35.7 ± 7.4 in GG; P = 0.03) and a tendency toward lower free fatty acid levels (P = 0.06).CONCLUSIONSThese results provide new evidence that the effect of the PNPLA3 variant is apparent in Hispanic children and adolescents, is unique to fat deposition in liver as compared with other ectopic depots examined, and is associated with lower HDL cholesterol.

The Relationship of Ectopic Lipid Accumulation to Cardiac and Vascular Function in Obesity and Metabolic Syndrome

Storage of lipid in ectopic depots outside of abdominal visceral and subcutaneous stores, including within the pericardium and liver, has been associated with obesity, insulin resistance, and cardiovascular risk. We sought to determine whether anatomically distinct ectopic depots were physiologically correlated and site-specific effects upon cardiovascular function could be identified. Obese subjects (n = 28) with metabolic syndrome but without known atherosclerotic disease and healthy controls (n = 18) underwent magnetic resonance imaging (MRI) and proton MR spectroscopy (MRS) to quantify pericardial and periaortic lipid volumes, cardiac function, aortic compliance, and intrahepatic lipid content. Fasting plasma lipoproteins, glucose, insulin, and free-fatty acids were measured. Pericardial and intrahepatic (P < 0.01) and periaortic (P < 0.05) lipid volumes were increased in obese subjects vs. controls and were strongly and positively correlated (P <or= 0.01) but independent of BMI (P = NS) among obese subjects. Intrahepatic lipid was associated with insulin resistance (P < 0.01) and triglycerides (P < 0.05), whereas pericardial and periaortic lipid were not (P = NS). Periaortic and pericardial lipid positively correlated to free-fatty acids (P <or= 0.01) and negatively correlated to high-density lipoprotein (HDL) cholesterol (P < 0.05). Pericardial lipid negatively correlated to cardiac output (P = 0.03) and stroke volume (P = 0.01) but not to left ventricular ejection fraction (P = 0.46). None of the ectopic depots correlated to aortic compliance. In conclusion, ectopic storage of lipid in anatomically distinct depots appeared tightly correlated but independent of body size. Site-specific functional abnormalities were observed for pericardial but not periaortic lipid. These findings underscore the utility of MRI to assess individual differences in ectopic lipid that are not predictable from BMI.

High Circulating Retinol-Binding Protein 4 Is Associated With Elevated Liver Fat but Not With Total, Subcutaneous, Visceral, or Intramyocellular Fat in Humans

Retinol-binding protein 4 (RBP4) is an adipokine that induced insulin resistance in mice, and high plasma RBP4 levels were associated with insulin-resistant states in humans. To determine which fat compartments are associated with elevated RBP4 levels in humans, we measured circulating RBP4 in 75 healthy subjects and used state-of-the-art measurements of body fat distribution. Total body, visceral, and subcutaneous abdominal fat were determined by magnetic resonance tomography and liver fat and intramyocellular fat by localized proton magnetic resonance spectroscopy. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp and, together with insulin clearance, estimated from the oral glucose tolerance test (OGTT). Adjusted circulating RBP4 correlated negatively with insulin sensitivity (clamp: r = -0.33, P = 0.005; OGTT: r = -0.36, P = 0.002) and positively with parameters in the fasting state as insulin levels (r = 0.35, P = 0.003) and homeostasis model assessment of insulin resistance (r = 0.34, P = 0.004). In addition, circulating RBP4 correlated negatively with hepatic insulin clearance (r = -0.25, P = 0.04). Circulating RBP4 was not associated with total body, visceral, or subcutaneous abdominal fat (all P > or = 0.29). Plasma RBP4 levels were also not associated with intramyocellular fat or circulating adiponectin or leptin. In contrast, plasma RBP4 levels correlated positively with liver fat in cross-sectional (r = 0.27, P = 0.03) and longitudinal (r = 0.37, P = 0.04) analyses. Circulating RBP4 is not associated with the amount of fat in the classical depots or in the ectopic depots in muscle. However, it correlates positively with liver fat. Furthermore, metabolic parameters support the close relationship between circulating RBP4 with liver fat and, presumably, hepatic insulin resistance.