Altered Adipose Tissue Research Articles

Glucocorticoids increase adiposity and alter adipose tissue phenotype in rats, despite elevated lipolytic rates

Glucocorticoids increase adiposity and alter adipose tissue phenotype in rats, despite elevated lipolytic rates

HIV‐1 Infection and the PPARγ‐Dependent Control of Adipose Tissue Physiology

PPARγ is a ligand-dependent master transcription factor controlling adipocyte differentiation as well as multiple biological processes taking place in other cells present in adipose tissue depots such as macrophages. Recent research indicates that HIV-1 infection-related events may alter adipose tissue biology through several mechanisms involving PPARγ, ranging from direct effects of HIV-1-encoded proteins on adipocytes to the promotion of a proinflammatory environment that interferes with PPARγ actions. This effect of HIV-1 on adipose tissue cells can occur even in the absence of direct infection of adipocytes, as soluble HIV-1-encoded proteins such as Vpr may enter cells and inhibit PPARγ action. Moreover, repression of PPARγ actions may relieve inhibitory pathways of HIV-1 gene transcription, thus enhancing HIV-1 effects in infected cells. HIV-1 infection-mediated interference of PPARγ-dependent pathways in adipocytes and other cells inside adipose depots such as macrophages is likely to create an altered local environment that, after antiretroviral treatment, leads to lipodystrophy in HIV-1-infected and HAART-treated patients.

773: Stress-signaling in subcutaneous versus omental adipose tissue in normal and gestational diabetes mellitus (GDM) pregnancies: Comparison to obesity-associated adipose tissue alterations

773: Stress-signaling in subcutaneous versus omental adipose tissue in normal and gestational diabetes mellitus (GDM) pregnancies: Comparison to obesity-associated adipose tissue alterations

Obesity and the lung: 5 · Obesity and COPD

Chronic obstructive pulmonary disease (COPD) and obesity are common and disabling chronic health conditions with increasing prevalence worldwide. A relationship between COPD and obesity is increasingly recognised, although the nature...

Catalytically inactive SHIP2 inhibits proliferation by attenuating pdgf signaling in 3T3‐L1 preadipocytes

Inadequate proliferation and/or differentiation of preadipocytes may lead to adipose tissue dysfunction characterized by hypertrophied, insulin-resistant adipocytes. Platelet-derived growth factor (PDGF) may alter adipose tissue function by promoting proliferation of preadipocytes. Two principal signaling pathways that regulate proliferation are PI3K/PI(3,4,5)P3/Akt and Shc/Ras/ERK1/2. SH2 domain-containing inositol 5-phosphatase 2 (SHIP2) dephosphorylates PI(3,4,5)P3, and also binds to Shc. Our goal was to determine how SHIP2 affects these PDGF signaling routes. To assess the role of the 5-phosphatase domain, we expressed wild-type or catalytically inactive dominant-negative SHIP2 (P686A-D690A-R691A; PDR/AAA) in 3T3-L1 preadipocytes. Surprisingly, SHIP2 PDR/AAA inhibited proliferation more potently than wild-type SHIP2. After three days of proliferation, phospho-Akt, phospho-ERK1/2, and PDGF receptor (PDGFR) levels were reduced in PDR/AAA-expressing preadipocytes. SHIP2 PDR/AAA interference with PDGFR signaling was demonstrated using imatinib, an inhibitor of PDGFR tyrosine kinase. The anti-proliferative effect of imatinib observed in control preadipocytes was not significant in SHIP2 PDR/AAA-expressing preadipocytes, indicating a pre-existing impairment of PDGFR-dependent mitogenesis in these cells. The inhibition of PDGF-activated mitogenic pathways by SHIP2 PDR/AAA was consistent with a decrease in PDGFR phosphorylation caused by a drop in receptor levels in SHIP2 PDR/AAA-expressing cells. SHIP2 PDR/AAA promoted ubiquitination of the PDGFR and its degradation via the lysosomal pathway independently of the association between the E3 ubiquitin ligase c-Cbl and PDGFR. Overall, our findings indicate that SHIP2 PDR/AAA reduces preadipocyte proliferation by attenuating PDGFR signaling.

Identification of a Lipokine, a Lipid Hormone Linking Adipose Tissue to Systemic Metabolism

Dysregulation of lipid metabolism in individual tissues leads to systemic disruption of insulin action and glucose metabolism. Utilizing quantitative lipidomic analyses and mice deficient in adipose tissue lipid chaperones aP2 and mal1, we explored how metabolic alterations in adipose tissue are linked to whole-body metabolism through lipid signals. A robust increase in de novo lipogenesis rendered the adipose tissue of these mice resistant to the deleterious effects of dietary lipid exposure. Systemic lipid profiling also led to identification of C16:1n7-palmitoleate as an adipose tissue-derived lipid hormone that strongly stimulates muscle insulin action and suppresses hepatosteatosis. Our data reveal a lipid-mediated endocrine network and demonstrate that adipose tissue uses lipokines such as C16:1n7-palmitoleate to communicate with distant organs and regulate systemic metabolic homeostasis.

Sex steroid hormones induce acylation stimulating protein resistance in 3T3‐L1 adipocytes

Acylation stimulating protein (ASP) stimulates triglyceride synthesis and glucose transport via its receptor C5L2. In human studies, ASP is increased in insulin resistant states such as obesity, diabetes, polycystic ovary syndrome and late pregnancy (the latter two associated with altered sex hormones). The aims were (i) to evaluate ASP response and C5L2 expression following treatment with sex steroid hormones and (ii) to identify mechanisms of ASP resistance using 3T3-L1 adipocytes and preadipocytes. Overnight incubation with physiological progesterone (PROG) concentrations induced dose-dependent inhibition of ASP-stimulated glucose transport in adipocytes (188 +/- 11% +ASP, 100 +/- 4% control, 129 +/- 18% to 85 +/- 7% [ASP + PROG 10(-8) to 10(-6) M] and preadipocytes (263 +/- 18% +ASP, 100 +/- 3% control, 170 +/- 11% to 167 +/- 4% [ASP + PROG 10(-8) to 10(-6) M]), while estradiol and testosterone (TEST) were effective only at the highest concentration (10(-6) M). In adipocytes, dose-dependent maximal C5L2 mRNA decreases were 39-75% (P = 0.003), with decreased cell-surface C5L2 of -22% and -27% (10(-6) M PROG and TEST, respectively) with no change in preadipocytes. Adipocytes treated with PROG displayed decreases in G proteins: Gbeta (-55%), Galphaq/11 (-56%) as well as complete inhibition of ASP stimulation. PROG significantly decreased basal levels of phosphorylated PKCalpha (p-PKCalpha) while there was no change in p- PKCzeta. ASP increased p-PKCalpha and PKCzeta to 161% (P < 0.0.001) and 160% (P < 0.01), a stimulation effectively blocked by PROG (10(-8) and 10(-6) M) and TEST (10(-6) M). Sex steroid hormone-induced ASP resistance via C5L2 may contribute to altered adipose tissue function and insulin resistance phenotype in humans.

Adipose Tissue Expandability in the Maintenance of Metabolic Homeostasis

Adipose tissue expands to accommodate increased lipid through hypertrophy of existing adipocytes and by initiating differentiation of preadipocytes. The capacity of adipose tissue to expand is critical for accommodating changes in energy availability, but this capacity is not an unlimited process and likely varies between individuals. We suggest that it is not the absolute amount of adipose tissue but rather the capacity of adipose tissue to expand that affects metabolic homeostasis. Here we highlight examples of disease states and transgenic animal models with altered adipose tissue function that support this hypothesis and discuss possible mechanisms by which altered adipose tissue expandability impairs metabolic homeostasis.

Prevalence and clinical significance of sonographic evidence of mesenteric fat alterations in Crohnʼs disease

Mesenteric adipose tissue hypertrophy is a frequent sonographic finding in Crohn's disease (CD). This study assessed its sonographic prevalence, the correlation with the degree of clinical or biochemical activity of the disease, and its impact on disease outcome in CD patients. In all, 185 consecutive CD patients underwent bowel ultrasound to assess the presence of mesenteric fat tissue alteration as well as thickness and echopattern of the bowel wall, site and extent of CD, and presence of stenosis, fistulas, and abscesses. Clinical and biochemical parameters of disease activity were also assessed. Multiple logistic regression analysis was used to identify variables related to mesenteric adipose tissue alteration. Mesenteric adipose tissue alteration, detected in 88 (47.6%) patients, showed a significant correlation both with clinical and biochemical CD activity and with internal fistulas, bowel wall thickness, and length of thickened bowel wall. Logistic regression analysis showed that internal fistulas (odds ratio [OR] = 13.5), thickened bowel wall (OR = 7.6), C-reactive protein (OR = 6.1), CD Activity Index (CDAI) (OR = 3.1), and length of diseased bowel walls (OR = 2.6) were significantly associated with mesenteric adipose tissue alteration. Of the 111 patients with quiescent CD, 22 showed mesenteric adipose tissue hypertrophy. These patients did not show increased risk of relapse compared with quiescent patients without mesenteric fat alteration. Mesenteric adipose tissue alteration is correlated with biochemical and clinical activity of CD and with internal fistulas and increased bowel wall thickness. In quiescent CD, mesenteric hypertrophy does not appear to be a risk factor of relapse.

Alterations In Abdominal Adipose Tissue Distribution With Exercise During Weight Regain

Metabolic syndrome risk factors, especially abdominal obesity, are reduced with weight loss; however, many individuals regain the weight. PURPOSE: The purpose of this study was to determine whether exercise training effectively maintains beneficial alterations in abdominal adipose tissue (AT) distribution during weight regain. METHODS: Twenty-three sedentary and overweight to class II obese (body mass index = 32.5 ± 0.8 kg/m2) individuals (8 males, and15 females, age = 41 ± 2 y) with components of the metabolic syndrome, lost ∼10% of their initial body weight during a 4-7 mo diet- and exercise-induced weight loss phase (WL phase). After weight loss, each subject was randomly assigned to either an exercise or non-exercise group for the 4-6 mo weight regain phase (WR phase) to regain 50% of the lost weight. The diet consisted of modest caloric restriction (reduced by ∼600 kcal/d) during the WL phase and a slight increase in consumption (∼450-500 kcal/d compared to WL) during the WR phase. All subjects during the WL phase and those assigned to the exercise group during the WR phase performed 45 minutes of aerobic exercise 5 d/wk at 60% of VO2max (∼ 375 kcal/session). Abdominal AT depots were measured using computed tomography (CT). Anthropometric and cardiovascular fitness measurements and CT scans were completed at baseline (BL), post weight loss (post WL), and post weight regain (post WR). RESULTS: Following weight loss (9.2 ± 0.8%), body weight, body mass index (BMI), % body fat, waist circumference (WC), and waist-to-hip ratio (WHR) were significantly reduced. All abdominal adipose tissue (AT) depots [total AT (TAT), total subcutaneous AT (TSAT), superficial SAT (sSAT), deep SAT (dSAT), and visceral AT (VAT)] also were significantly reduced. During weight regain, anthropometric variables (with the exception of WHR) and abdominal AT depots (with the exception of sSAT) increased significantly in both groups, with no differences between the groups. Improvements in cardiovascular fitness were maintained during weight regain in the exercise group only. CONCLUSIONS: Exercise training was not able to preserve the beneficial reduction in abdominal adiposity during weight regain; however, it was sufficient to maintain cardiovascular fitness. Supported by NIH ROI DK67036

THE EFFECT OF NANDROLONE DECANOATE THERAPY ON LIPOPROTEIN(A) AND HOMOCYSTEINE LEVELS IN HEMODIALYSIS PATIENTS

An important sex difference in body fat distribution is generally observed. Men are usually characterized by the android type of obesity, with accumulation of fat in the abdominal region, whereas women often display the gynoid type of obesity, with a greater proportion of their body fat in the gluteal-femoral region. Accordingly, the amount of fat located inside the abdominal cavity (intra-abdominal or visceral adipose tissue) is twice as high in men compared to women. This sex difference has been shown to explain a major portion of the differing metabolic profiles and cardiovascular disease risk in men and women. Association studies have shown that circulating androgens are negatively associated with intra-abdominal fat accumulation in men, which explains an important portion of the link between low androgens and features of the metabolic syndrome. In women, the low circulating sex hormone-binding globulin (SHBG) levels found in abdominal obesity may indirectly indicate that elevated free androgens are related to increased visceral fat accumulation. However, data on non SHBG-bound and total androgens are not unanimous and difficult to interpret for total androgens. These studies focusing on plasma levels of sex hormones indirectly suggest that androgens may alter adipose tissue mass in a depot-specific manner. This could occur through site-specific modulation of preadipocyte proliferation and/or differentiation as well as lipid synthesis and/or lipolysis in mature adipocytes. Recent results on the effects of androgens in cultured adipocytes and adipose tissue have been inconsistent, but may indicate decreased adipogenesis and increased lipolysis upon androgen treatment. Finally, adipose tissue has been shown to express several steroidogenic and steroid-inactivating enzymes. Their mere presence in fat indirectly supports the notion of a highly complex enzymatic system modulating steroid action on a local basis. Recent data obtained in both men and women suggest that enzymes from the aldoketoreductase 1C family are very active and may be important modulators of androgen action in adipose tissue.

Lower Visceral and Subcutaneous but Higher Intermuscular Adipose Tissue Depots in Patients with Growth Hormone and Insulin-Like Growth Factor I Excess Due to Acromegaly

GH and IGF-I are important regulators of metabolism and body composition. In acromegaly, a state of GH and IGF-I excess, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) distribution. Our objective was to test the hypothesis that in acromegaly whole-body AT mass is less and to examine for the first time the relationship between GH/IGF-I excess and intermuscular AT (IMAT), an AT depot associated with insulin resistance in other populations. We conducted a cross-sectional study in 24 adults with active acromegaly compared with predicted models developed in 315 healthy non-acromegaly subjects. Mass of AT in the visceral AT (VAT), sc AT (SAT), and IMAT compartments from whole-body magnetic resonance imaging and serum levels of GH, IGF-I, insulin, and glucose were measured. VAT and SAT were less in active acromegaly (P < 0.0001); these were 68.2 +/- 27% and 79.5 +/- 15% of predicted values, respectively. By contrast, IMAT was greater (P = 0.0052) by 185.6 +/- 84% of predicted. VAT/trunk AT ratios were inversely related to IGF-I levels (r = 0.544; P = 0.0054). Acromegaly subjects were insulin resistant. VAT and SAT, most markedly VAT, are less in acromegaly. The proportion of trunk AT that is VAT is less with greater disease activity. IMAT is greater in acromegaly, a novel finding, which suggests that increased AT in muscle could be associated with GH-induced insulin resistance. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use.

Fermented Soy Product Reduces Adipose Mass, Improves Insulin Sensitivity and Alters Adipose Tissue Gene Products in Mice

Obesity is a problem affecting much of the world. Intake of soy may decrease tissue lipid accumulation and adipose tissue mass. We aimed to determine the effect of fermented soy product on weight gain and adiposity in growing male C57Bl/6 mice. Eight week old mice were put in a Casein Diet (C), Soy Diet (S), or Fermented Soy Diet (F) group for 17 weeks. Half of the mice fed C were switched to F at 8 weeks (CtoF). F reduced weight gain and adiposity compared to S and C. At 16 weeks, fasting glucose from the F was significantly lower from the C or S. In an insulin tolerance test (ITT), glucose lowering was more dramatic from F compared to S or C. Fasting insulin was significantly lower from F and S verses C, and the F group was significantly lower than the S group. Serum leptin was significantly reduced from F and S compared to C. mRNA of adiponectin and adipose triglyceride lipase (ATGL) were significantly elevated from S compared to C while F had no effect. F significantly lowered levels of peroxisome proliferator activated receptor gamma (PPARγ) compared to S. F reduced adipose mass, plasma insulin and glucose, serum leptin, and adipose tissue responses in fatty acid‐binding protein‐4 (FABP‐4), PPARγ, hormone‐sensitive lipase (HSL) and ATGL gene transcription. Protein analysis of PPAR responsive genes and histological evaluation will provide further insight to the mechanism.This work was supported by Ajinomoto Corp.

Monocytes stimulate replication of human subcutaneous preadipocytes and reduce adipocyte differentiation

HIV Lipodystrophy is a condition identified mainly by adipose tissue redistribution and metabolic abnormalities. Persons with HIV Lipodystrophy have higher numbers of leukocytes, such as monocytes and lymphocytes within their adipose tissues compared to controls, indicating that immune cells may have a role in the adipose tissue changes. However, evidence is lacking that describe interactions between immune cells and adipose cells. To determine if leukocytes can influence adipose tissue growth and morphology, human PBMC's such as lymphocytes or monocytes were co‐cultured with human subcutaneous preadipocytes for up to 6 days. Utilizing cell cycle analysis with flow cytometry, monocytes were found to increase preadipocyte replication (percentages in the S+G2/M phase) 2–3 fold compared to controls, whereas addition of lymphocytes had no effect. In addition, when preadipocytes were then induced to differentiate into adipocytes, the ability to mature into lipid‐filled adipocytes was reduced by 60% in preadipocytes incubated with monocytes as measured by Oil Red O staining for triglyceride accumulation. Although high amounts of inflammatory cytokines such as IL‐6 and IL‐8 were found in the co‐culture supernatants and despite reports showing that IL‐6 and IL‐8 can stimulate preadipocyte proliferation, the use of neutralizing abs against IL‐6 and IL‐8 during our co‐culture experiments failed to block the enhanced replication of the preadipocytes suggesting the involvement of different molecules. These findings suggest that immune cells may be involved in the adipose tissue alterations observed not only in HIV Lipodystrophy but other complications involving immune cell infiltration of adipose tissues such as Obesity and other inflammatory conditions.

Effect of altitude on leptin levels, does it go up or down?

reports of a relationship between altitude and circulating levels of leptin suggest a possible role of hypoxia in leptin regulation. However, studies on the changes in plasma leptin levels at altitude are controversial, with some showing an increase and others suggesting no change or a fall in these

Adipose tissue failure and mitochondria as a possible target for improvement by bioactive food components

Adipose tissue is an essential, highly dynamic and metabolically active tissue that vigorously communicates to support its primary function: the storage of lipids. It performs this function to secure energy supply and prevent lipotoxicity. Adipose tissue is essential for maintaining a healthy glucose and lipid homeostasis and failure results in disease. This review discusses causes of adipose tissue failure and four categories of bioactive food components that may help to prevent this. Based on recent findings, it is argued that initial adipose failure following long-term excess energy intake may be the result of reduced mitochondrial capacity associated with altered mitochondrial reactive oxygen species signaling and adipose tissue hypoxia. Current data suggest that different classes of bioactive food components, including vitamin B3, retinoids, fatty acids and polyphenols, may have the potential to modulate mitochondrial function and consequently prevent adipose dysfunction in obesity. It seems most attractive to aim nutritional intervention at the prevention of initial adipose dysfunction and hence to target dietary intervention at improvement of mitochondrial function.

A Reduction in the Amount and Anti-Contractile Effect of Periadventitial Mesenteric Adipose Tissue Precedes Hypertension Development in Spontaneously Hypertensive Rats

The aim of this study was to determine whether alterations in periadventitial adipose tissue and its anti-contractile effect precede hypertension development. We used 4-week-old male Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), which were pre-hypertensive. Vascular function was studied in the perfused mesenteric bed (MB, 1.5 mL/min). MB weight was lower in SHR (8.0 +/- 0.3 mg/g body weight) than in WKY (9.0 +/- 0.3 mg/g body weight) rats. Concentration-response curves to KCI (6 to 75 mmol/L) and to acetylcholine (10(-9) to 10(-5) mol/L) were similar between groups. Contractile responses to serotonin (10(-9) to 10(-5) mol/L) were significantly higher in SHR compared to WKY. 4-Aminopyridine (4-AP, 2 mmol/L), a blocker of Kv channels, induced a similar increase in perfusion pressure in both strains. However, 4-AP (2 mmol/L) significantly increased the contractile response to serotonin (10(-9) to 10(-5) mol/L) only in WKY. The anti-contractile effect of fat was confirmed by a comparison of (+) fat and (-) fat mesenteric arteries, which revealed that 4-AP significantly enhanced contractions only in (+) fat rings from WKY. These results show that alterations in visceral periadventitial fat mass and function in SHR precede hypertension, suggesting a constitutive mechanism independent of age and the hypertensive state.

Acylation-stimulating protein deficiency and altered adipose tissue in alternative complement pathway knockout mice

Acylation-stimulating protein (C3adesArg/ASP) is an adipokine that acts on its receptor C5L2 to stimulate triglyceride (TG) synthesis in adipose tissue. The present study investigated ASP levels in mouse models of obesity and leanness and the effect of ASP deficiency in C3 knockout (C3KO) mice on adipose tissue morphology. Plasma ASP levels in wild-type (WT) mice correlated positively with plasma nonesterified fatty acids (NEFA) (R = 0.664, P < 0.001) and total cholesterol (R = 0.515, P < 0.001). Plasma ASP was increased by 85% in obese ob/ob leptin-deficient mice and decreased in lean diacylglycerol acyltransferase 1 (DGAT1) KO mice (-54%) and C/EBPalpha(beta/beta) transgenic mice (-70%) compared with WT. Mice lacking alternative complement factor B or adipsin (FBKO or ADKO), required for ASP production, were also ASP deficient. Both FBKO and C3KO mice had delayed postprandial TG and NEFA clearance on low-fat (LF) and high-fat (HF) diets, suggesting that lack of ASP, not C3, drives the metabolic phenotype. Adipocyte size distribution in C3KO mice was polarized (increased number of both small and large cells), with decreased adipsin expression (-33% gonadal HF), DGAT1 expression (-31% to -50%) and DGAT activity (-41%). Overall, a reduction/deficiency in ASP is associated with an antiadipogenic state and ASP may provide a target for controlling fat storage.

Osteopontin Expression in Human and Murine Obesity: Extensive Local Up-Regulation in Adipose Tissue but Minimal Systemic Alterations

Obesity is associated with a chronic low-grade inflammation characterized by macrophage infiltration of adipose tissue (AT) that may underlie the development of insulin resistance and type 2 diabetes. Osteopontin (OPN) is a multifunctional protein involved in various inflammatory processes, cell migration, and tissue remodeling. Because these processes occur in the AT of obese patients, we studied in detail the regulation of OPN expression in human and murine obesity. The study included 20 morbidly obese patients and 20 age- and sex-matched control subjects, as well as two models (diet-induced and genetic) of murine obesity. In high-fat diet-induced and genetically obese mice, OPN expression was drastically up-regulated in AT (40 and 80-fold, respectively) but remained largely unaltered in liver (<2-fold). Moreover, OPN plasma concentrations remained unchanged in both murine models of obesity, suggesting a particular local but not systemic importance for OPN. OPN expression was strongly elevated also in the AT of obese patients compared with lean subjects in both omental and sc AT. In addition, we detected three OPN isoforms to be expressed in human AT and, strikingly, an obesity induced alteration of the OPN isoform expression pattern. Analysis of AT cellular fractions revealed that OPN is exceptionally highly expressed in AT macrophages in humans and mice. Moreover, OPN expression in AT macrophages was strongly up-regulated by obesity. In conclusion, our data point toward a specific local role of OPN in obese AT. Therefore, OPN could be a critical regulator in obesity induced AT inflammation and insulin resistance.

Alterations in Adipose Tissue and Hepatic Lipid Kinetics in Obese Men and Women With Nonalcoholic Fatty Liver Disease

Steatosis in patients with nonalcoholic fatty liver disease (NAFLD) is due to an imbalance between intrahepatic triglyceride (IHTG) production and export. The purpose of this study was to evaluate TG metabolism in adipose tissue and liver in NAFLD. Fatty acid, VLDL-TG, and VLDL-apolipoprotein B-100 (apoB100) kinetics were assessed by using stable isotope tracers in 14 nondiabetic obese subjects with NAFLD (IHTG, 22.7% +/- 2.0%) and 14 nondiabetic obese subjects with normal IHTG content (IHTG, 3.4% +/- 0.4%), matched on age, sex, body mass index, and percent body fat. Compared with the normal IHTG group, the NAFLD group had greater rates of palmitate release from adipose tissue into plasma (85.4 +/- 6.6 and 114.1 +/- 8.1 micromol/min, respectively; P = .01) and VLDL-TG secretion (11.4 +/- 1.1 and 24.3 +/- 3.1 micromol/min, respectively; P = .001); VLDL-apoB100 secretion rates were not different between groups. The increase in VLDL-TG secretion was primarily due to an increased contribution from "nonsystemic" fatty acids, presumably derived from lipolysis of intrahepatic and intra-abdominal fat and de novo lipogenesis. VLDL-TG secretion rate increased linearly with increasing IHTG content in subjects with normal IHTG but reached a plateau when IHTG content was >/=10% (r = 0.618, P < .001). Obese persons with NAFLD have marked alterations in both adipose tissue (increased lipolytic rates) and hepatic (increased VLDL-TG secretion) TG metabolism. Fatty acids derived from nonsystemic sources are responsible for the increase in VLDL-TG secretion. However, the increase in hepatic TG export is not adequate to normalize IHTG content.