Local androgen inactivation in abdominal visceral adipose tissue

We examined the expression and activity of two enzymes from the aldoketoreductase (AKR) family 1C, namely type 5 17beta-hydroxysteroid dehydrogenase (17beta-HSD-5, AKR1C3) and type 3 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD-3, AKR1C2) in female sc and omental adipose tissue and in preadipocyte primary cultures. 17beta-HSD-5 preferentially synthesizes testosterone from the inactive adrenal precursor androstenedione, whereas 3alpha-HSD-3 inactivates dihydrotestosterone. mRNAs of both enzymes were detected in adipose tissue from the omental and sc compartments. Real-time PCR quantification indicated a 3-fold higher 3alpha-HSD-3 expression compared with 17beta-HSD-5, and the expression of both enzymes tended to be higher in the sc vs. the omental depot. Accordingly, dose-response and time-course experiments performed in preadipocyte primary cultures indicated that 3alpha-HSD activity was higher than 17beta-HSD activity (13-fold maximum velocity difference). We measured 3alpha-HSD activity in omental and sc adipose tissue samples of 32 women for whom body composition and body fat distribution were evaluated by dual-energy x-ray absorptiometry and CT, respectively. We found that androgen inactivation in omental adipose tissue through 3alpha-HSD activity was significantly higher in women with elevated vs. low visceral adipose tissue accumulation (1.7-fold difference; P < 0.05). Moreover, omental adipose tissue 3alpha-HSD activity was positively and significantly associated with CT-measured visceral adipose tissue (r = 0.43; P < 0.02) and omental adipocyte diameter (r = 0.42; P < 0.02). These results indicate that local androgen inactivation is a predominant reaction in female abdominal adipose tissue, with the greatest conversion rates observed in the presence of abdominal visceral obesity. Increased androgen inactivation in omental adipose tissue of abdominally obese women may impact locally on the regulation of adipocyte metabolism.     

Cardiovascular-related proteins and the abdominal visceral to subcutaneous adipose tissue ratio

Background and aimsAn increased amount of visceral adipose tissues has been related to atherosclerosis and future cardiovascular events. The present study aims to investigate how the abdominal fat distribution links to plasma levels of cardiovascular-related proteins.Method and resultsIn the Prospective investigation of Obesity, Energy and Metabolism (POEM) study (n = 326, all aged 50 years), abdominal visceral (VAT) and subcutaneous (SAT) adipose tissue volumes were quantified by MRI. Eighty-six cardiovascular-related proteins were measured by the proximity extension assay (PEA). Similar investigations were carried out in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 400, all aged 75 years).In the discovery dataset (POEM), 10 proteins were related to the VAT/SAT-ratio using false discovery rate <.05. Of those, Cathepsin D (CTSD), Interleukin-1 receptor antagonist protein (IL-1RA) and Growth hormone (GH) (inversely) were related to the VAT/SAT-ratio in the validation in PIVUS following adjustment for sex, BMI, smoking, education level and exercise habits (p < 0.05). In a secondary analysis, a meta-analysis of the two samples suggested that 15 proteins could be linked to the VAT/SAT-ratio following adjustment as above and Bonferroni-correction of the p-value.ConclusionThree cardiovascular-related proteins, cathepsin D, IL-1RA and growth hormone, were being associated with the distribution of abdominal adipose tissue using a discovery/validation approach. A meta-analysis of the two samples suggested that also a number of other cardiovascular-related proteins could be associated with an unfavorable abdominal fat distribution.     

Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part II: Visceral adipose tissue production and liver metabolism

Excess visceral adipose tissue is associated with anomalies of blood glucose homoeostasis, elevation of plasma triglycerides and low levels of high-density lipoprotein cholesterol that contribute to the development of type-2 diabetes and cardiovascular syndromes. Visceral adipose tissue releases a large amount of free fatty acids and hormones/cytokines in the portal vein that are delivered to the liver. The secreted products interact with hepatocytes and various immune cells in the liver. Altered liver metabolism and determinants of insulin resistance associated with visceral adipose tissue distribution are discussed, as well as, determinants of an insulin-resistant state promoted by the increased free fatty acids and cytokines delivered by visceral adipose tissue to the liver.     

Ceramide changes in abdominal subcutaneous and visceral adipose tissue among diabetic and nondiabetic patients

BackgroundThis study profiles ceramides extracted from visceral and subcutaneous adipose tissue of human subjects by liquid chromatography‐mass spectrometry to determine a correlation with status of diabetes and gender.MethodsSamples of visceral and abdominal wall subcutaneous adipose tissue (n = 36 and n = 31, respectively) were taken during laparoscopic surgery from 36 patients (14 nondiabetic, 22 diabetic and prediabetic) undergoing bariatric surgery with a body mass index (BMI) >35 kg/m² with ≥1 existing comorbidity or BMI ≥40 kg/m². Sphingolipids were extracted and analyzed using liquid chromatography‐mass spectrometry.ResultsAfter logarithm 2 conversion, paired analysis of visceral to subcutaneous tissue showed differential accumulation of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) in visceral tissue of prediabetic/diabetic female subjects, but not in males. Within‐tissue analysis showed higher mean levels of ceramide species linked to insulin resistance, such as Cer(d18:1/18:0) and Cer(d18:1/16:0), in visceral tissue of prediabetic/diabetic patients compared with nondiabetic subjects and higher content of Cer(d18:1/14:0) in subcutaneous tissue of insulin‐resistant female patients compared with prediabetic/diabetic males. Statistically significant differences in mean levels of ceramide species between insulin‐resistant African American and insulin‐resistant Caucasian patients were not evident in visceral or subcutaneous tissue.ConclusionsAnalysis of ceramides is important for developing a better understanding of biological processes underlying type 2 diabetes, metabolic syndrome, and obesity. Knowledge of the accumulated ceramides/dihydroceramides may reflect on the prelipolytic state that leads the lipotoxic phase of insulin resistance and may shed light on the predisposition to insulin resistance by gender.     

Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans

The purpose of this study was to examine the source of adipokines released by the visceral and sc adipose tissues of obese humans. Human adipose tissue incubated in primary culture for 48 h released more prostaglandin E(2), IL-8, and IL-6 than adiponectin, whereas the release of plasminogen activator inhibitor 1 and hepatocyte growth factor was less than that of adiponectin but greater than that of leptin. IL-10 and TNFalpha were released in amounts less than those of leptin, whereas vascular endothelial growth factor and IL1-beta were released in much lower amounts. The accumulation of adipokines was also examined in the three fractions (adipose tissue matrix, isolated stromovascular cells, and adipocytes) obtained by collagenase digestion of adipose tissue. Over 90% of the adipokine release by adipose tissue, except for adiponectin and leptin, could be attributed to nonfat cells. Visceral adipose tissue released greater amounts of vascular endothelial growth factor, IL-6, and plasminogen activator inhibitor 1 compared with abdominal sc tissue. The greatly enhanced total release of TNFalpha, IL-8, and IL-10 by adipose tissue from individuals with a body mass index of 45 compared with 32 was due to nonfat cells. Furthermore, most of the adipokine release by the nonfat cells of adipose tissue was due to cells retained in the tissue matrix after collagenase digestion.     

Contributions of total body fat, abdominal subcutaneous adipose tissue compartments, and visceral adipose tissue to the metabolic complications of obesity

Obesity is related to the risk for developing non-insulin-dependent diabetes mellitus (NIDDM), hypertension, and cardiovascular disease. Visceral adipose tissue (VAT) has been proposed to mediate these relationships. Abdominal subcutaneous adipose tissue (SAT) is divided into 2 layers by a fascia, the fascia superficialis. Little is known about the radiologic anatomy or metabolic correlates of these depots. The objective of this study was to relate the amounts of VAT, SAT, deep subcutaneous abdominal adipose tissue (DSAT), and superficial subcutaneous abdominal adipose tissue (SSAT) to gender and the metabolic complications of obesity after adjusting for total body fat and to discuss the implications of these findings on the measurement of adipose tissue mass and adipose tissue function. The design was a cross-sectional database study set in a nutrition research center. Subjects included 199 volunteers participating in nutrition research protocols who also had computed tomography (CT) and dual energy x-ray absorptiometry (DEXA) measurement of body fat. The amount of DSAT was sexually dimorphic, with women having 51% of the subcutaneous abdominal fat in the deep layer versus 66% for men (P <.05). Abdominal fat compartments were compared with metabolic variables before and after adjusting for body fat measured by DEXA using 2 separate methods. The unadjusted correlation coefficients between the body fat measures, R(2), were largest for fasting insulin and triglyceride and smaller for high-density lipoprotein (HDL) cholesterol and blood pressure. A large portion of the variance of fasting insulin levels in both men and women was explained by total body fat. In both men and women, the addition of VAT and subcutaneous abdominal adipose tissue depots only slightly increased the R(2). In men, when body fat compartments were considered independently, DSAT explained a greater portion of the variance (R(2) =.528) in fasting insulin than VAT (R(2) =.374) or non-VAT, non-DSAT subcutaneous adipose tissue (R(2) =.375). These data suggest that total body fat is a major contributor to the metabolic sequelae of obesity, with specific fat depots, VAT, and DSAT also making significant contributions.     

Fully automated large-scale assessment of visceral and subcutaneous abdominal adipose tissue by magnetic resonance imaging

OBJECTIVE: To describe and evaluate a fully automated method for characterizing abdominal adipose tissue from magnetic resonance (MR) transverse body scans. METHODS: Four MR pulse sequences were applied: SE, FLAIR, STIR, and FRFSE. On 39 subjects, each abdomen was traversed by 15 contiguous transaxial images. The total abdominal adipose tissue (TAAT) was calculated from thresholds obtained by slice histogram analysis. The same thresholds were also used in the manual volume calculation of TAAT, subcutaneous abdominal adipose tissue (SAAT) and visceral abdominal adipose tissue (VAAT). Image segmentation methods, including edge detection, mathematical morphology, and knowledge-based curve fitting, were used to automatically separate SAAT from VAAT in various 'nonstandard' cases such as those with heterogeneous magnetic fields and movement artefacts. RESULTS: The percentage root mean squared errors of the method for SAAT and VAAT ranged from 1.0 to 2.7% for the four sequences. It took approximately 7 and 15 min to complete the 15-slice volume estimation of the three adipose tissue classes using automated and manual methods, respectively. CONCLUSION: The results demonstrate that the proposed method is robust and accurate. Although the separation of SAAT and VAAT is not always perfect, this method could be especially helpful in dealing with large amounts of data such as in epidemiological studies.     

Intermuscular adipose tissue rivals visceral adipose tissue in independent associations with cardiovascular risk

BACKGROUND: The metabolic implications of intermuscular adipose tissue (IMAT) are poorly understood compared to those of visceral adipose tissue (VAT) even though the absolute quantities of both depots are similar in many individuals. OBJECTIVE: The aim was to determine the independent relationship between whole-body IMAT and cardiovascular risk factor parameters. DESIGN: Whole body magnetic resonance imaging (MRI) was used to quantify total skeletal muscle (SM), total adipose tissue (TAT) of which IMAT, defined as the AT visible by MRI within the boundary of the muscle fascia, is a sub-component. Fasting serum measures (n=262) of glucose, total cholesterol (T-Chol), high-density lipoprotein cholesterol (HDL-Chol), triglycerides (TG), protein bound glucose (PBG, n=206) and insulin (n=119) were acquired in healthy African-American (AA, n=78) and Caucasian (Ca, n=109) women (body mass index (BMI) 26.5+/-5.7 kg/m(2); 44.4+/-16.4 years) and men (39 AA, 62 Ca; BMI 25.6+/-3.5 kg/m(2); 45.6+/-17.4 years). General linear models identified the independent effects of IMAT after covarying for SM, VAT, TAT, race, sex and two-way interactions. RESULTS: Significant independent associations were observed for IMAT with glucose (P<0.001), PBG (P<0.001) and T-Chol (P<0.05). The association of IMAT with cholesterol differed by race in such a manner that for a unit increase in IMAT, T-Chol increased more rapidly in Ca compared to AA (P<0.05). TG, HDL-Chol and insulin had no independent association with IMAT. CONCLUSION: The strong independent associations of IMAT with fasting glucose and PBG suggest that IMAT may be related to glucose metabolism; however, IMAT is also associated with T-Chol in Ca.     

甲状腺激素通过交感神经系统对脂肪组织代谢的影响

脂肪组织在能量储存和代谢方面扮演着重要角色,与肥胖、高脂血症、动脉粥样硬化等疾病的发生密切相关。脂肪组织的代谢受交感神经系统的调节。甲状腺激素对交感神经系统具有调控作用,同时也影响脂肪组织的代谢。经典观点认为甲状腺激素对脂肪组织的影响多为外周水平,而近年来研究表明甲状腺激素也可以在中枢水平影响脂肪组织的代谢。本文就甲状腺激素通过交感神经对脂肪组织代谢的影响进行综述,探讨甲状腺激素通过交感神经对脂肪组织代谢的调节及其机制。     

Angiotensin II: a hormone that affects lipid metabolism in adipose tissue

BACKGROUND: Alterations in adipose tissue lipolysis may contribute to the pathophysiology of obesity and insulin resistance. We examined the effects of angiotensin II (Ang II) on abdominal subcutaneous adipose tissue lipolysis in humans. METHODS AND RESULTS: First, adipocytes obtained from nine normal weight and seven obese subjects were stimulated with Ang II (10(-14)-10(-6) M). Glycerol concentration in the medium, used as an indicator of adipocyte lipolysis, was significantly reduced (approximately 20%) after Ang II stimulation in adipocytes from normal weight (P=0.04) and obese subjects (P<0.001). Based on these observations, adipocytes of seven additional obese subjects were stimulated with lower doses of Ang II (10(-17)-10(-6) M) in the presence and absence of Ang II type 1 (AT(1)) receptor blockade. Lipolysis was dose dependently inhibited by approximately 20 to 25% after Ang II stimulation (P=0.001). AT(1) receptor blockade completely abolished the Ang II-induced effects (P=0.35). CONCLUSION: Ang II directly inhibits abdominal subcutaneous adipocyte lipolysis in normal weight and obese subjects via the AT(1) receptor.     

内脏脂肪组织与心肌纤维化研究进展

肥胖与心肌纤维化关系密切,尤其是内脏脂肪组织与心肌纤维化的相关性,引起了医学界的重视。既往有众多研究证实内脏脂肪组织通过分泌瘦素、脂联素等多种脂肪细胞因子参与心肌纤维化,其作用机制较为复杂。而最近研究表明内脏脂肪组织还能通过产生骨桥蛋白促进心肌纤维化。新兴起的测定内脏脂肪组织的生物电阻抗分析法亦将为其进一步的临床应用及研究奠定基础。文章就内脏脂肪组织参与心肌纤维化机制及其测定方法作一综述。     

Exercise, visceral adipose tissue, and metabolic risk

Regular exercise is associated with a substantial reduction in risk across a broad range of health outcomes. The principal mechanisms by which exercise is associated with diminished health risks are unclear, but corresponding reduction in abdominal obesity, particularly visceral adipose tissue (AT), is a likely candidate. Visceral AT is a strong independent predictor of metabolic risk, morbidity, and mortality, and this depot is markedly reduced with regular exercise. This review focuses on the relationship between exercise and corresponding reductions in visceral adiposity and metabolic risk factors.     

In vivo effects of corticotropin-releasing hormone on femoral adipose tissue metabolism in women

OBJECTIVE: To investigate whether i.v. injected corticotropin-releasing hormone (CRH) (1 microg/kg) has a direct effect on adipose tissue metabolism in humans. DESIGN: Double-blinded, placebo-controlled, crossover study. SUBJECTS: Twelve healthy normal weight female volunteers (age 20-37 years, body mass index: 22.75+/-1.33 kg/m(2)) MEASUREMENTS: Assessment of local generation of glycerol, and glucose in adipose tissue by microdialysis. Measurement of adipose tissue and skin blood flow by laser Doppler flowmetry. RESULTS: Injection of CRH acutely increases interstitial concentrations of glycerol (19.0+/-5.4%, P<0.05) and glucose (13.5+/-5.8%, P<0.05) reaching peak levels after 15 min. Plasma glycerol increases in parallel (Delta=16.7+/-5.9% after 15 min (P<0.05)), whereas plasma glucose remains unaffected. Changes in tissue blood flow do not explain interstitial metabolite alterations. Initial CRH effects on adipose tissue metabolism are short lasting and disappear after 15 min. CONCLUSIONS: The importance of CRH on human energy metabolism is underlined by the present in vivo study demonstrating peptidergic effects on lipolysis and glucose homeostasis in human subcutaneous adipose tissue.     

Subcutaneous and visceral adipose tissue: structural and functional differences

Obesity is a heterogeneous disorder. Obese individuals vary in their body fat distribution, their metabolic profile and degree of associated cardiovascular and metabolic risk. Abdominal obesity carries greater risk of developing diabetes and future cardiovascular events than peripheral or gluteofemoral obesity. There are differences between adipose tissue present in subcutaneous areas (SCAT) and visceral adipose tissue (VAT) present in the abdominal cavity. These include anatomical, cellular, molecular, physiological, clinical and prognostic differences. Anatomically, VAT is present mainly in the mesentery and omentum, and drains directly through the portal circulaion to the liver. VAT compared with SCAT is more cellular, vascular, innervated and contains a larger number of inflammatory and immune cells, lesser preadipocyte differentiating capacity and a greater percentage of large adipocytes. There are more glucocorticoid and androgen receptors in VAT than in SCAT. VAT adipocytes are more metabolically active, more sensitive to lipolysis and more insulin-resistant than SCAT adipocytes. VAT has a greater capacity to generate free fatty acids and to uptake glucose than SCAT and is more sensitive to adrenergic stimulation, while SCAT is more avid in absorption of circulating free fatty acids and triglycerides. VAT carries a greater prediction of mortality than SCAT.     

Androgens modulate osteocalcin release by human visceral adipose tissue

Objective Androgens inhibit adipogenic differentiation through an androgen receptor (AR)‐mediated pathway, increase lipolysis and reduce lipid accumulation in adipocytes. Undercarboxylated osteocalcin (ucOCN) regulates insulin and adiponectin secretion and is released by adipose tissue (AT). Our objective was to investigate, ex vivo and in vivo, the role of androgens on osteocalcin (OCN) modulation in human AT. Design, Patients, Setting Omental AT (OAT) for in vitro study and blood samples from 91 male patients of Padova University Hospital were used. Measurements Omental AT was treated with dihydrotestosterone (DHT) in presence and in absence of flutamide. cOCN and ucOCN release by AT in a simple growth medium was evaluated by ELISA. OCN, both undercarboxylated (ucOCN) and carboxylated (cOCN) forms, was measured in serum by ELISA. Results After 24‐h DHT stimulation, the release of both cOCN and ucOCN by OAT was statistically increased (P < 0·05). Co‐incubation with flutamide blunted OCN production. Overweight and obese patients had lower total and free testosterone (T), associated with lower ucOCN and ucOCN/OCN ratio. Free T was negatively correlated to BMI (ρ = ?0·706, P < 0·05) and positively correlated to ucOCN/OCN ratio (ρ = 0·223, P < 0·05). Conclusions Our data suggest that androgens modulate OCN release by OAT in vitro. In addition to the anti‐adipogenic role of androgens, they support a novel mechanism by which androgens could exert a protective effect in energy metabolism. This hypothesis appears even more significant considering that sexual hormones’ levels are greatly altered in obesity and that AT is both highly involved in their clearance and able to produce OCN.     

Divergent regulation of adipose tissue metabolism by calorie restriction and inhibition of growth hormone signaling

Calorie restriction (CR) and a reduced growth hormone (GH) signal affect insulin sensitivity and lifespan in mammals in a similar manner. We investigated the effects of CR and moderate inhibition of GH on glucose-stimulated activation of insulin signaling and the expression of genes related to fat metabolism in white adipose tissue (WAT) in rats. We used 10-month-old male, wild-type (W) Wistar rats, fed ad libitum (AL) or a 30% CR diet from 6 weeks of age, and transgenic (Tg) rats with moderately suppressed GH signaling. Rats were killed 15 min after an intraperitoneal injection of glucose or saline. In control W–AL rats, the levels of serum insulin, phosphorylated (p) insulin receptor (pY-IR), p-Akt, and the expression of glucose transporter (Glut) 4 in the membrane fraction were greater in the glucose-injected group than in the saline-injected group, indicating significant activation of insulin signaling in response to glucose loading. In the W–CR and Tg–AL rats, the serum insulin and pY-IR levels were lower than those in the W–AL rats. The Akt–Glut pathway was up-regulated even after saline-injection. Expression levels of adipogenic and lipogenic genes including PPARγ, adiponectin, and its receptors, were higher in the W–CR rats than in the W–AL and Tg–AL rats. The present findings indicate adipose tissue metabolic profiles specific to CR.     

Comparison of the delayed actions of growth hormone and somatomedin on adipose tissue metabolism.

Although acute insulin-like effects of growth hormone (GH) on adipose tissue are readily demonstrable in vitro, it has not been possible to reproduce in vitro the delayed (3 h) inhibition of glucose utilization seen after the administration of GH in vivo. To examine the possibility that somatomedin (Sm), the postulated mediator of GH action, might, like GH, have biphasic effects on adipose tissue metabolism and mediate the delayed inhibition of glucose utilization, Sm was prepared by gel filtration from an acid-ethanol extract of normal rat plasma. The partially purified material increased 35SO4 incorporation into costal cartilage of hypophysectomized rats and produced in adipose tissue an acute stimulation of glucose oxidation that was not suppressed by insulin anti-serum. Unlike GH, whose insulin-like effects disappear in 3--4 hours, Sm-stimulated glucose oxidation remained linear for the entire 4 hour incubation period. Although acute stimulation of tissues with GH rendered them refractory to renewed insulin-like stimulation by GH, no such refractoriness to the action of Sm was seen. Furthermore, acute stimulation with Sm failed to render tissues refractory either to itself or to GH. Finally, Sm failed to reproduce the delayed lipolytic effects produced by GH in conjunction with glucocorticoids. These results make it highly unlikely that Sm alone accounts for the delayed metabolic effects of GH.