Insulin signaling in human visceral and subcutaneous adipose tissue in vivo

In this study, we evaluated the activation of various insulin signaling molecules in human fat in vivo and compared signaling reactions in visceral and subcutaneous fat depots. Paired abdominal omental and subcutaneous fat biopsies were obtained from nonobese subjects with normal insulin sensitivity under basal conditions and 6 and 30 min following administration of intravenous insulin. Insulin receptor phosphorylation was more intense and rapid and insulin receptor protein content was greater in omental than in subcutaneous adipose tissue (P < 0.05). Insulin-induced phosphorylation of Akt also occurred to a greater extent and earlier in omental than in subcutaneous fat (P < 0.05) in the absence of significant changes in Akt protein content. Accordingly, phosphorylation of the Akt substrate glycogen synthase kinase-3 was more responsive to insulin stimulation in omental fat. Protein content of extracellular signal-regulated kinase (ERK)-1/2 was threefold higher in omental than in subcutaneous fat (P < 0.05), and ERK phosphorylation showed an early 6-min peak in omental fat, in contrast with a more gradual increase observed in subcutaneous fat. In conclusion, the adipocyte insulin signaling system of omental fat shows greater and earlier responses to insulin than that of subcutaneous fat. These findings may contribute to explain the biological diversity of the two fat depots.     

Oscillations of fatty acid and glycerol release from human subcutaneous adipose tissue in vivo

We sought evidence for pulsatility of lipolysis in human subcutaneous adipose tissue in vivo. Arterialized and adipose tissue venous blood samples were drawn at 2-min intervals from nine healthy subjects. This procedure was repeated during hyperinsulinemic-euglycemic clamp to remove insulin pulsatility. We found evidence for pulsatile release of both nonesterified fatty acids (NEFAs) (seven of nine subjects) and glycerol (five of six subjects) with a period of approximately 12-14 min. This pulsatility was maintained even during the hyperinsulinemic clamp. Checks were made for spurious pulse detection, including the creation of "mock" venoarterialized differences by subtracting one subject's arterialized concentrations from another's venous; the peaks detected were less consistent in character than with real data (peak width, P = 0.006; peak interval, P < 0.004). Significant cross-correlations between NEFA and glycerol release also provided evidence of a real effect. Arterialized norepinephrine concentrations were also pulsatile, but the period did not match that of NEFA and glycerol release. Insulin concentrations were pulsatile with a typical period of 12 min, but this was not significantly cross-correlated with lipolysis. We conclude that release from adipose tissue of the products of lipolysis is pulsatile in humans.     

Angiogenesis associated with visceral and subcutaneous adipose tissue in severe human obesity

OBJECTIVE—The expansion of adipose tissue is linked to the development of its vasculature. However, the regulation of adipose tissue angiogenesis in humans has not been extensively studied. Our aim was to compare the angiogenesis associated with subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from the same obese patients in an in vivo model.RESEARCH DESIGN AND METHODS—Adipose tissue samples from visceral (VAT) and subcutaneous (SAT) sites, obtained from 36 obese patients (mean BMI 46.5 kg/m²) during bariatric surgery, were layered on chick chorioallantoïc membrane (CAM).RESULTS—Both SAT and VAT expressed angiogenic factors without significant difference for vascular endothelial growth factor (VEGF) expression. Adipose tissue layered on CAM stimulated angiogenesis. Angiogenic stimulation was macroscopically detectable, with engulfment of the samples, in 39% and was evidenced by angiography in 59% of the samples. A connection between CAM and adipose tissue vessels was evidenced by immunohistochemistry, with recruitment of both avian and human endothelial cells. The angiogenic potency of adipose tissue was not related to its localization (with an angiogenic stimulation in 60% of SAT samples and 61% of VAT samples) or to adipocyte size or inflammatory infiltrate assessed in adipose samples before the graft on CAM. Stimulation of angiogenesis by adipose tissue was nearly abolished by bevacizumab, which specifically targets human VEGF.CONCLUSIONS—We have established a model to study the regulation of angiogenesis by human adipose tissue. This model highlighted the role of VEGF in angiogenesis in both SAT and VAT.Adipose tissue retains substantial plasticity in adulthood. Its mass can increase or decrease up to 10-fold throughout life. The prevalence of obesity has doubled over the last 20 years, and current pharmacotherapy is relatively ineffective in maintaining long-term weight loss (1). A better understanding of the development of adipose tissue is required to identify new therapeutic approaches to obesity.Angiogenesis and adipogenesis are linked functionally (2). During embryogenesis, the development of adipose tissue and its vascularization are temporally and spatially related (3). In animal models of genetic and induced obesity, the expansion of adipose tissue is associated with active angiogenesis, whereas inhibition of angiogenesis prevents adipose tissue development (4–6). Angiogenesis induced by adipose cells in animal models increases along with adipocyte differentiation (7–9), and conversely, angiogenic factors, such as vascular endothelial growth factor (VEGF), can modulate adipocyte differentiation (8). The cross-talk between adipocytes and endothelial cells involves numerous paracrine factors associated with angiogenesis and/or adipose tissue differentiation. It also involves direct cell-to-cell interactions, and it should be noted that human adipose tissue–derived stem cells can differentiate into either adipocyte or endothelial cells (10–12).Numerous studies have shown that adipose tissue can stimulate angiogenesis in physiological models, such as the chick chorioallantoïc membrane (CAM) and the rabbit cornea (7,13,14), or in pathophysiological models, such as wound healing and revascularization of ischemic tissues (2,11,12,15–17). Adipose tissue produces several factors involved in angiogenesis, and local or circulating levels of tumor necrosis factor-α (TNF-α), VEGF, plasminogen activator inhibitor-1 (PAI-1), and angiopoïetin-2 are increased in animal and human obesity (2,18–20). Conversely, factors involved in adipocyte regulation, such as leptin, adiponectin, visfatin, or peroxisome proliferator–activated receptor γ (PPARγ), for example (2,3,8,21–24), also regulate angiogenesis.However, there have been few studies of the mechanisms of stimulation of adipose tissue angiogenesis in obesity. The characteristics of adipose tissue that could influence angiogenesis in humans, such as whether the tissue is of subcutaneous or visceral origin, the presence of infiltrating macrophages, and the profile of expression of angiogenic factors are still unknown. Very few studies (8,24,25) have tried to inhibit angiogenic factors to identify their role in adipose tissue angiogenesis.Our main objectives were to compare the angiogenic potency of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from obese patients and to assess whether the characteristics of adipose tissue and the phenotype of the patients influence angiogenesis associated with adipose tissue.     

Regulation of dietary fatty acid entrapment in subcutaneous adipose tissue and skeletal muscle

Using stable isotopic labeling of dietary fatty acids in conjunction with arteriovenous difference measurements, we have assessed the regulation of lipoprotein lipase-derived fatty acid entrapment in subcutaneous adipose tissue and forearm muscle in healthy subjects in the postprandial state. Eight volunteers fasted overnight and were then given a mixed meal containing [ 1-(13)C]palmitic acid and [1-(13)C]oleic acid. At baseline and for 6 h after the meal, blood samples were obtained from an arterialized hand vein and veins draining subcutaneous abdominal adipose tissue and forearm muscle, and arteriovenous differences were calculated. Entrapment of labeled fatty acids released by circulating triacylglycerol hydrolysis was close to 100% at 60 min, decreasing to 10-30% by 360 min. Entrapment of labeled fatty acids in forearm muscle was >100% and did not change with time. This study shows that entrapment of dietary fatty acids in adipose tissue in the postprandial period is a highly regulated process (varying with time) and that this can be studied in humans using stable isotope- labeled fatty acids in combination with measurement of appropriate arteriovenous differences. Also, fatty acid trapping in skeletal muscle is fundamentally different from that in adipose tissue, in that all the fatty acids released by lipoprotein lipase in skeletal muscle are taken up by the tissue.     

Attenuated adiposopathy in perivascular adipose tissue compared with subcutaneous human adipose tissue

Background

We hypothesized that human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. We also evaluated the impact of clinical parameters on the adipose phenotype. Our overall goal is to understand the determinants of adipose biology so that this tissue can be manipulated therapeutically to lessen peripheral vascular disease.

Methods

Perivascular and subcutaneous adipose tissues were collected from patients undergoing lower-extremity amputation (n = 27) and protein assayed for proinflammatory mediators (ie, interleukin 6, interleukin 8, leptin, tumor necrosis factor α, monocyte chemoattractant protein-1, and resistin), atheroprotective adiponectin, and the fibrinolysis inhibitor plasminogen activator inhibitor-1.

Results

Leptin (2.7-fold, P = .015), TNF-α (2.2-fold, P = .013), MCP-1 (1.5-fold, P = .047), and adiponectin (1.8-fold, P = .004) were more abundant in subcutaneous vs perivascular adipose tissue. Age positively correlated with perivascular adipose tissue PAI-1 expression (β = .64, P = .042), and hyperlipidemia negatively correlated with perivascular adiponectin (β = −1.18, P = .039).

Conclusions

Human perivascular and subcutaneous adipose tissues hold distinct phenotypic signatures. In amputation patients, the subcutaneous adipose tissue proinflammatory phenotype was relatively attenuated in perivascular adipose tissue.     

Site differences in human subcutaneous adipose tissue metabolism in obesity

The results of several recent studies indicate that there are regional differences in the metabolism of subcutaneous fatty depots in obesity. Fat cells are larger in the femoral than in the abdominal region. Lipids are mobilized at a slower rate but synthesized at a higher rate in the former than the latter region. Fasting is accompanied by an increased rate of fat mobilization and a decreased rate of fat synthesis in all fat depots. These changes are, however, more pronounced in abdominal than in femoral fat. There are also regional differences in the hormonal regulation of fat metabolism in obesity. The action of insulin is most pronounced in the femoral region whereas that of catecholamines is most marked in the abdominal area. The regional differences in hormone action are further enhanced during therapeutic fasting. These differences may partly explain why adiposity is more catching in some fatty regions than in others and also why some obese areas are resistant to slimming.     

Relationship of abdominal visceral and subcutaneous adipose tissue with lipoprotein particle number and size in type 2 diabetes

OBJECTIVE—Insulin resistance and type 2 diabetes are associated with an atherogenic lipoprotein profile. We examined the role of visceral and subcutaneous fat depots, independent of BMI, on the dyslipidemia associated with type 2 diabetes.RESEARCH DESIGN AND METHODS— A total of 382 subjects with type 2 diabetes underwent abdominal computed tomography to evaluate subcutaneous (SAT) and visceral adipose tissue (VAT) distribution and had anthropometric measurements to determine BMI and waist and hip circumference. Fasting blood was obtained for lipoprotein particle number and size using nuclear magnetic resonance spectroscopy. The relationship of lipoprotein particle number and size with BMI, SAT, and VAT was examined using multivariable regression models adjusted for age, sex, diabetes therapy, duration of diabetes, smoking, statin use, and A1C levels. The relation of VAT to lipoprotein particle number and size was further evaluated after the addition of BMI, BMI plus SAT, or BMI plus homeostatis is model assessment of insulin resistance (HOMA-IR) to the model.RESULTS—VAT was positively related to VLDL particle number (P < 0.0001), LDL particle number (P < 0.01), and VLDL size (P < 0.0001) and negatively related to LDL size (P < 0.0001) and HDL size (P < 0.0001). These relationships remained unchanged after addition of BMI and SAT to the model. After addition of HOMA-IR, VAT remained positively related to VLDL particle number (P < 0.0001) and size (P < 0.01) and negatively related to LDL and HDL particle size (P < 0.0001 for both comparisons). Neither BMI nor SAT was independently related to lipoprotein parameters.CONCLUSIONS—In patients with type 2 diabetes, higher VAT independent of BMI was associated with higher VLDL and LDL particle number, larger VLDL particles, and smaller LDL and HDL particles. This lipoprotein pattern has been associated with increased risk for atherosclerosis and cardiovascular disease.Dyslipidemia and increased adiposity, especially of abdominal type, are common metabolic features of type 2 diabetes. The dyslipidemia associated with type 2 diabetes is characterized by changes in lipoprotein particle number and size and has been attributed to insulin resistance (1,2). Studies using nuclear magnetic resonance (NMR) spectroscopy to analyze lipoprotein subclass profile along with euglycemic-hyperinsulinemic clamps (1) or frequently sampled intravenous glucose tolerance tests (2) to assess insulin sensitivity have clearly demonstrated that all three major human lipoproteins are affected by insulin resistance. The alterations in lipoprotein particle number and size in type 2 diabetes and insulin resistance have been linked to increased risk for cardiovascular disease (CVD) in both cross-sectional (3–9) and prospective studies (10,11).Obesity has been clearly demonstrated to be associated with insulin resistance and its metabolic consequences, including type 2 diabetes, dyslipidemia, and CVD (12–14). Recently, studies have suggested that fat tissue distribution may be more important than overall fat mass for these associations (15–17). Epidemiologic and physiologic studies have suggested that abdominal fat is more strongly associated with metabolic risk factors and CVD than total amount of body fat (15,16,18). Whether specific abdominal fat compartments—for example, visceral abdominal fat (VAT) compared with subcutaneous abdominal fat (SAT)—carry greater metabolic and cardiovascular risks remains more controversial (16,17), especially in subjects with type 2 diabetes (17). Even though many studies have pointed to a greater cardiovascular and metabolic risk associated with VAT (18–27), SAT has also been associated with insulin resistance and metabolic disorders in other studies (27–30). For this report, we examined the association between abdominal fat compartments measured by computed tomography (CT) and lipoprotein particle number and size using NMR spectroscopy in 382 subjects with type 2 diabetes who participated in the CHICAGO study (31). We further analyzed how the relationship of abdominal fat depots to lipoprotein parameters was impacted by BMI as a measure of overall adiposity or by hip circumference as an index of peripheral subcutaneous fat mass.     

Thiazolidinediones upregulate fatty acid uptake and oxidation in adipose tissue of diabetic patients

Thiazolidinediones (TZDs) are a new class of insulin-sensitizing drugs. To explore how and in which tissues they improve insulin action, we obtained fat and muscle biopsies from eight patients with type 2 diabetes before and 2 months after treatment with rosiglitazone (n = 5) or troglitazone (n = 3). TZD treatment was associated with a coordinated upregulation in the expression of genes and synthesis of proteins involved in fatty acid uptake, binding, beta-oxidation and electron transport, and oxidative phosphorylation in subcutaneous fat but not in skeletal muscle. These changes were accompanied by a 13% increase in total body fat oxidation, a 20% decrease in plasma free fatty acid levels, and a 46% increase in insulin-stimulated glucose uptake. We conclude that TZDs induced a coordinated stimulation of fatty acid uptake, oxidation, and oxidative phosphorylation in fat of diabetic patients and thus may have corrected, at least partially, a recently recognized defect in patients with type 2 diabetes consisting of reduced expression of genes related to oxidative metabolism and mitochondrial function.     

Expression of peroxisome proliferator-activated receptor-gamma1 and peroxisome proliferator-activated receptor-gamma2 in visceral and subcutaneous adipose tissue of obese women

Data regarding the expression of peroxisome proliferator-activated receptor (PPAR)-gamma(1) and PPAR-gamma(2) in human visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are conflicting. To clarify this issue, we studied 50 women who had a BMI >35 kg/m(2) were undergoing gastric reduction surgery. Phenotyping included recording of anthropometric parameters and of a biological profile. Quantification of the expression of PPAR-gamma(1) and PPAR-gamma(2) in samples of VAT and SAT was performed by real-time RT-PCR. In both SAT and VAT, the level of expression of PPAR-gamma(2) were >20-fold that of PPAR-gamma(1) (P < 0.001 for both). However, only PPAR-gamma(1) was differentially expressed, its levels in SAT being 216 +/- 34% those in VAT (P < 0.001). In a stepwise, multivariate regression analysis, the levels of PPAR-gamma(1) in both SAT and VAT were the major determinants of waist circumference (R(2) = 21% for both; P < 0.01). Finally, leptin but not PPARs appeared as the single parameter explaining the largest part of the variability of BMI in our cohort of patients (R(2) = 22%, P < 0.001). These results are consistent with the putative roles of PPAR-gamma(1) and PPAR-gamma(2) in carbohydrate metabolism and energy homeostasis, respectively. As such, they constitute an important step toward the identification of potential targets for novel therapeutic strategies in the fields of obesity.     

Influence of motor complete spinal cord injury on visceral and subcutaneous adipose tissue measured by multi-axial magnetic resonance imaging

Objective

Abdominal obesity conveys substantial health risks, in association with high levels of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and an increased proportion of VAT to SAT. The purposes were to determine the influence of spinal cord injury (SCI) on the associations between single axial cross-sectional area (CSA) slices and the average CSA or volumes of VAT and SAT across multi-axial slices of magnetic resonance imaging (MRI); and the relationships relative to the whole body composition and anthropometrics.

Methods

Thirteen healthy male participants with traumatic motor complete SCI underwent fast spin-echo MRI to measure VAT and SAT across multi-axial slices, followed by dual-energy X-ray absorptiometry to measure whole body fat-free mass (FFM) and fat mass (FM). Waist circumference (WC) was also measured in the seated position.

Results

The trunk CSAs of VAT and SAT were 99 ± 51 and 164 ± 69 cm², respectively, and the ratio of VAT to SAT was 0.68 ± 0.33. The CSAs of VAT and SAT at a single slice strongly predicted the average CSA and modestly predicted the volumes across multi-axial slices. VAT and SAT represented 5.7 ± 1.8% and 9.7 ± 3.2% of the total body FM, respectively. Percent body FFM was negatively related to VAT and SAT volumes, but not to a single axial CSA.

Conclusion

A single slice CSA can modestly predict the volume of multi-axial slices in individuals with SCI, yet it is not related to any of the body composition variables. Increased percent FFM is associated with a reduction in VAT and SAT volumes measured across multi-axial slices. The ratio of VAT to SAT is greater than 0.4, suggesting that individuals with SCI are at high risk of developing metabolic sequelae.     

Similar VLDL-TG storage in visceral and subcutaneous fat in obese and lean women

OBJECTIVE

Excess visceral fat accumulation is associated with the metabolic disturbances of obesity. Differential lipid redistribution through lipoproteins may affect body fat distribution. This is the first study to investigate VLDL-triglyceride (VLDL-TG) storage in visceral fat.

RESEARCH DESIGN AND METHODS

Nine upper-body obese (UBO; waist circumference >88 cm) and six lean (waist circumference <80 cm) women scheduled for elective tubal ligation surgery were studied. VLDL-TG storage in visceral, upper-body subcutaneous (UBSQ), and lower-body subcutaneous (LBSQ) fat were measured with [9,10-³H]-triolein–labeled VLDL.

RESULTS

VLDL-TG storage in visceral fat accounted for only ∼0.8% of VLDL-TG turnover in UBO and lean women, respectively. A significantly larger proportion of VLDL-TG turnover was stored in UBSQ (∼5%) and LBSQ (∼4%) fat. The VLDL-TG fractional storage was similar in UBO and lean women for all regional depots. VLDL-TG fractional storage and VLDL-TG concentration were correlated in UBO women in UBSQ fat (r = 0.68, P = 0.04), whereas an inverse association was observed for lean women in visceral (r = −0.89, P = 0.02) and LBSQ (r = −0.87, P = 0.02) fat.

CONCLUSIONS

VLDL-TG storage efficiency is similar in all regional fat depots, and trafficking of VLDL-TG into different adipose tissue depots is similar in UBO and lean women. Postabsorptive VLDL-TG storage is unlikely to be of major importance in the development of preferential upper-body fat distribution in obese women.Upper-body obesity, especially when associated with visceral fat accumulation, is related to the development of metabolic abnormalities, such as insulin resistance, type 2 diabetes, and dyslipidemia (1,2). In contrast, lower-body obesity does not exhibit these abnormalities (3,4). The mechanism behind the development of these different obesity phenotypes remains unclear (5,6). Studies have not provided clear evidence to suggest that differences in regional lipolysis promote the development of differences in adipose tissue distribution (6–8). Moreover, studies of meal fat storage and direct plasma free fatty acid (FFA) storage have failed to demonstrate definite differences, with reports showing greater (9,10) and similar (6,11) storage in visceral compared with subcutaneous adipose tissue in lean and obese men and women.Differences between chylomicron and VLDL-triglyceride (VLDL-TG) uptake in different regional adipose tissues (12) underscore that studies of VLDL-TG storage are warranted. By using an ex vivo–labeled VLDL-TG tracer, we recently reported that VLDL-TG adipose tissue fatty acid storage was similar in upper-body subcutaneous (UBSQ) and lower-body subcutaneous (LBSQ) fat in lean and obese women (13) and in obese and type 2 diabetic men (14). Thus far, no studies have investigated VLDL-TG fatty acid storage in visceral adipose tissue.The aim of this study was to test the hypothesis that VLDL-TG fatty acid storage is greater in visceral adipose tissue compared with LBSQ and UBSQ adipose tissue. We wanted to test this hypothesis in both upper-body obese (UBO) and lean women. A secondary aim was to assess whether the storage pattern differed between UBO and lean women.     

脂肪干细胞在皮下软组织充填中的研究进展

脂肪干细胞(Adipose-Derived Stem CeLIs ADSCs)具有一般干细胞的特点,即多向分化潜能和稳定的体外多代增殖能力,其免疫相容性好,来源丰富,易于获得,可反复取材,无伦理学问题,作为组织工程的种子细胞有着非常重要的实际研究和应用价值.本文着重对脂肪干细胞在生物学特性、体外成脂诱导分化,以及与之相配的生物学载体支架方面的最新进展进行阐述.     

Subcutaneous and visceral adipose tissue in patients with primary and recurrent incisional hernia

Hernia - Visceral obesity rather than body mass index has been reported to be associated with a higher incidence of incisional hernias. The aim of this study was to examine the relationship between...