Activity In Subcutaneous Adipose Tissue Research Articles

Sex differences in abdominal visceral fat composition and metabolism as predictors of DLBCL prognosis: A retrospective cohort study

PurposeWe aimed to determine if sex differences in abdominal visceral fat composition and metabolism can help predict the prognosis of diffuse large B-cell lymphoma (DLBCL) patients. MethodsThis retrospective cohort study included 117 DLBCL patients. The area and metabolic activity of subcutaneous adipose tissue and visceral adipose tissue were measured using CT and PET imaging. Kaplan–Meier survival analysis was employed to evaluate the effect of these parameters on progression-free survival. Multivariate Cox proportional hazard regression models were used to determine the effects of relative visceral fat area (rVFA) on sex-specific survival. ResultsFemales with an rVFA greater than the optimal threshold of 35 % and a visceral-to-subcutaneous adipose tissue ratio (V/S) >3.24 had worse progression-free survival (p = 0.01, 0.001, respectively). No rVFA or V/S were identified in significantly stratified males with DLBCL (p = 0.249 and 0.895, respectively). Combining the changes in rVFA and V/S identified a subgroup of females with high rVFA and V/S values and exceptionally poor outcomes. The rVFA was a significant predictor of DLBCL progression in females alone. ConclusionOnce female DLBCL patients accumulate fat over the tolerable range in the visceral area, they might be at an increased risk of progression (hazard ratio, 3.87; 95 % CI, 1.81–12.69, p = 0.02).Sex differences in visceral fat composition and metabolism may provide a new risk stratification system for patients with DLBCL.

ODP001 AKR1C2 Activity in Abdominal Adipose Tissue of Women with or without Excess Visceral Adiposity

Abstract Background Adipose tissue is known to play an active role in androgen turnover, as illustrated by the presence of enzymes of the aldo-keto reductase 1C family such as AKR1C2 and AKR1C3, respectively coding for 3α-hydroxysteroid dehydrogenase type 3 and 17β-hydroxysteroid dehydrogenase type 5. Our group demonstrated that these enzymes are mainly expressed in mature adipocytes and that in women, trunk fat percentage is positively associated with adipose tissue mRNA abundance of both AKR1C2 and AKR1C3. In this context, our aim was to assess whether abdominal adipose tissue activity of AKR1C2 relates to excess visceral adiposity index (VAI) in women. Methods AKR1C2 activity was measured in visceral (VAT) and subcutaneous adipose tissue (SAT) of 31 women (age: 39 ± 7; BMI: 51 ± 6) undergoing bariatric surgery. Adipose tissue homogenate activity was measured by fluorimetry in a 12-hour kinetic experiment using the chemical compound cumberone, a competitive substrate in the inactivation of 5a-dihydrotestosterone to 3α-androstanediol by AKR1C2. Visceral adipose tissue excess was quantified using the previously published VAI equation and using the age-specific cut-offs for women, who were categorized into either high VAI or low VAI. Other markers of adipose tissue dysfunction included diacylglycerol acyltransferase 2 (DGAT2) and glutathione peroxidase 3 (GPX3) mRNA abundance, adipocyte size and pericellular fibrosis. Results Our technique allowed us to detect significant AKR1C2 activity in SAT (13.5±5.7 fluorescence units (FU)/min) and VAT (8.3±4.8 FU/min). Using the VAI equation, we identified 18 women with high VAI and 13 with low VAI. Women with high VAI were characterized by significantly higher VAT AKR1C2 activity when compared to women with low VAI (9.5 ± 4.4 vs. 6.4± 3.6 FU/min, p<0. 05). AKR1C2 mRNA abundance in either VAT or SAT was not significantly different as a function of VAI. Women with high VAI also had larger VAT adipocyte diameter and lower mRNA abundance of GPX3 in both adipose tissue depots compared to women with low VAI (p<0. 05 for all). No differences were seen in DGAT2 mRNA abundance, pericellular fibrosis or SAT adipocyte diameter as a function of VAI. Conclusion In women with severe obesity, excess visceral adiposity as indicated by a high VAI, is associated with higher AKR1C2 activity in VAT only. Similarly, adipose tissues of women with high VAI displayed features of adipose tissue dysfunction such as increased VAT adipocyte diameter and decreased GPX3expression in comparison to women with low VAI. Taken together our results confirm the link between adipose AKR1C2 and excess visceral adiposity. Presentation: No date and time listed

Beneficial Effects of High Intensity Interval Training and/or Linseed Oil Supplementation to Limit Obesity-Induced Oxidative Stress in High Fat Diet-Fed Rats.

High-intensity interval training (HIIT) and linseed oil (LO) supplementation are effective strategies to reduce obesity-induced oxidative stress. Our aim was to determine whether the HIIT + LO combination prevents obesity-induced oxidative stress in high fat diet (HFD)-fed rats. HFD-fed 8-week-old, male, Wistar rats were subdivided in four groups: HFD, LO (2% of sunflower oil replaced with 2% of LO in the HFD), HIIT (4 days/week for 12 weeks), and HIIT + LO. Wistar rats fed a low-fat diet (LFD) were used as controls. Epididymal and subcutaneous adipose tissue, gastrocnemius muscle, liver, and plasma samples were collected to measure oxidative stress markers (AOPP, oxLDL), antioxidant (SOD, CAT, and GPx activities) and pro-oxidant (NOx and XO) enzyme activities. Compared with the LFD, the HFD altered the pro/antioxidant status in different tissues (increase of AOPP, oxLDL, SOD and catalase activities in plasma, and SOD activity increase in liver and decrease in adipose tissues) but not in gastrocnemius. LO upregulated CAT activity and decreased NOx in liver. HIIT alleviated HFD negative effects in liver by reducing SOD and NOx activities. Moreover, the HIIT + LO combination potentiated SOD activity upregulation in subcutaneous tissue. HIIT and LO supplementation have independent beneficial effects on the pro/antioxidant balance. Their association promotes SOD activity in subcutaneous adipose tissue.

A Non-Synonymous Single Nucleotide Polymorphism in FASN Gene Alters FASN Enzyme Activity in Subcutaneous and Intramuscular Adipose Tissue in Holstein Friesian Steers

Abstract The FASN enzyme plays a key role in fatty acids synthesis as the main long-chain fatty acid synthesizer. A non-synonymous SNP (single nucleotide polymorphism) (g.17925A>G) located in the thioesterase domain of this enzyme and an effect in fat deposition has been observed, but has not been evaluated in this breed and, moreover, the reason whereby this occurs remains unclear. The objective of this study was to evaluate the effect of this SNP on the activity of FASN enzyme in subcutaneous and intramuscular adipose tissue from Holstein Friesian steers. To achieve this, 196 animals were sampled in a local abattoir, genotyped for the FASN g.17924A>G SNP and characterized for fatty acid profile. Then a sub-sample of 20 animals per genotype were selected to extract the total protein from subcutaneous and intramuscular adipose tissue to estimate the FASN enzyme activity. The FASN activity for each genotyped animal was assessed indirectly by measuring the decrease in the absorbance of NADPH at 340 nm by spectrophotometry in a 24 well plate in the presence of Acetyl-CoA, Malonyl-CoA, and NADPH. To assess the impact of SNP induced amino acid changes in FASN protein structure, in-silico simulations were performed. Our results indicated that FASN g.17924A>G SNP induces a change in the enzyme activity in subcutaneous adipose tissue, which is higher when the AA genotype is present and lower in the presence of the AG genotype. The in-silico analysis of the amino acid substitution shows that there was a structural change in the dimeric form of the protein between genotypes. Moreover, the global energy between subunits is lower and more favorable when the AA genotype is present and higher and less favorable for the AG genotype. It was also found that the fatty acid profile of subcutaneous adipose tissue was affected when the AG genotype was present, decreasing the C16:0 fatty acid levels and increasing the C18:0 fatty acid levels. The FASN g.17924A>G SNP alters the FASN enzyme structure and activity, leading to a variation in the fatty acid composition of subcutaneous adipose tissue in Holstein Friesian steers. Implications: This SNP could be considered as a tool to improve the fat deposition or marbling and the fatty acid profile in cattle.

Molecular networks of insulin signaling and amino acid metabolism in subcutaneous adipose tissue are altered by body condition in periparturient Holstein cows

Peripartal cows mobilize not only body fat but also body protein to satisfy their energy requirements. The objective of this study was to determine the effect of prepartum BCS on blood biomarkers related to energy and nitrogen metabolism, and mRNA and protein abundance associated with AA metabolism and insulin signaling in subcutaneous adipose tissue (SAT) in peripartal cows. Twenty-two multiparous Holstein cows were retrospectively classified into a high BCS (HBCS; n = 11, BCS ≥ 3.5) or normal BCS (NBCS; n = 11, BCS ≤ 3.17) group at d 28 before expected parturition. Cows were fed the same diet as a total mixed ration before parturition and were fed the same lactation diet postpartum. Blood samples collected at -10, 7, 15, and 30 d relative to parturition were used for analyses of biomarkers associated with energy and nitrogen metabolism. Biopsies of SAT harvested at -15, 7, and 30 d relative to parturition were used for mRNA (real time-PCR) and protein abundance (Western blotting) assays. Data were subjected to ANOVA using the MIXED procedure of SAS (v. 9.4; SAS Institute Inc., Cary, NC), with P ≤ 0.05 being the threshold for significance. Cows in HBCS had greater overall plasma nonesterified fatty acid concentrations, due to marked increases at 7 and 15 d postpartum. This response was similar (BCS × Day effect) to protein abundance of phosphorylated (p) protein kinase B (p-AKT), the insulin-induced glucose transporter (SLC2A4), and the sodium-coupled neutral AA transporter (SLC38A1). Abundance of these proteins was lower at -15 d compared with NBCS cows, and either increased (SLC2A4, SLC38A1) or did not change (p-AKT) at 7 d postpartum in HBCS. Unlike protein abundance, however, overall mRNA abundances of the high-affinity cationic (SLC7A1), proton-coupled (SLC36A1), and sodium-coupled amino acid transporters (SLC38A2) were greater in HBCS than NBCS cows, due to upregulation in the postpartum phase. Those responses were similar to protein abundance of p-mTOR, which increased (BCS × Day effect) at 7 d in HBCS compared with NBCS cows. mRNA abundance of argininosuccinate lyase (ASL) and arginase 1 (ARG1) also was greater overall in HBCS cows. Together, these responses suggested impaired insulin signaling, coupled with greater postpartum AA transport rate and urea cycle activity in SAT of HBCS cows. An in vitro study using adipocyte and macrophage cocultures stimulated with various concentrations of fatty acids could provide some insights into the role of immune cells in modulating adipose tissue immunometabolic status, including insulin resistance and AA metabolism.

Increased inflammasome activity in subcutaneous adipose tissue of patients with metabolic syndrome.

The metabolic syndrome (MetS) is an inflammatory disorder associated with an increased risk for diabetes and atherosclerotic cardiovascular disease (ASCVD). Studies in patients and animal models of obesity and diabetes have shown increased NOD-like receptor family pyrin domain containing 3 (NLPR3) inflammasome activity. However, there is scanty data on the activity of the NLRP3 inflammasome in patients with nascent MetS. The aim of this study was to determine the status of the inflammasome in subcutaneous adipose tissue (SAT) of patients with nascent MetS without concomitant diabetes, ASCVD and smoking. Patients with nascent MetS and controls were recruited from Sacramento County. Fasting blood samples were collected for biomediators of inflammation and SAT was obtained by biopsy for immunohistochemical (IHC) staining for caspase 1, IL-1β and IL-18. Caspase1, a marker of inflammasome activity and its downstream mediators IL-1β and IL-18 were significantly increased in SAT of patients with MetS compared to controls. Significant positive correlations of caspase 1 were obtained with certain cardio-metabolic features, biomediators of inflammation and markers of angiogenesis and fibrosis in SAT. Both mast cell and eosinophil abundance but not macrophage density correlated with caspase1. We make the novel observation that the SAT of patients with nascent MetS displays increased NLRP3 inflammasome activity manifest by increased caspase 1 in SAT and this may contribute to increased insulin resistance, inflammation and SAT fibrosis in these patients.

Prognostic significance of adipose tissue distribution and metabolic activity in PET-CT images of patients with metastatic colorectal cancer.

e16038 Background: The metabolic activity in visceral and subcutaneous adipose tissue have different metabolic risk profiles for colorectal cancer. The aim of this study was to investigate the prognostic significance of adipose tıssue distribution and metabolic activity in PET-CT and predict the overall survival in patients with metastatic colorectal cancer (mCRC). Methods: A total of 83 patients diagnosed with mCRC between 2010-2018 were evaluated retrospectively. Pretreatment PET-CT images were reevaluated to determine adipose tissue distribution and metabolic activity. Volume and metabolic activity of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on FDG PET-CT images were measured. SAT volume, SAT density (HU), SAT ratio (SAT volume/ SAT density) were calculated. The maximum standardized uptake (SUV) of tumor tissue was measured. The relationship between adipose tissue and overall survival was examined. Results: 53 patients died during follow-up and the median overall survival was 33.76 months (95% CI: 28.185-39.349). According to univariate analysis results, tumor location (HR:2.5; 95% CI 1.27-4.98, p = 0.008) and SAT ratio (HR:0.5; 95% CI 0.34-1.00, p = 0.053) were the significant parameters for the OAS. VAT volume (p = 0.774), VAT density (p = 0.899), VAT suv mean (p = 0.831) and SAT volume (p = 0.423), SAT density (p = 0.353), SAT suv mean (p = 0.575), tumor suv max (p = 0.589) values were not correlated with OAS. In the multivariate analysis, SAT ratio (p = 0.011) and tumor location (p = 0.001) were correlated significantly with OAS. The median OAS for the patients with SAT ratio value < -1.1 and -1.1 were 38.5 (95% CI 31.54-45.58) and 24.5 (95% CI 14.13-34.93) months, respectively (p = 0.05). Conclusions: This study showed that SAT ratio was an independent prognostic factor for OAS in patients with mCRC. We need prospective studies for to observe the relationship between adipose tissue distribution and response to treatment in mCRC.

Usefulness of metabolic activity of adipose tissue in FDG PET/CT of colorectal cancer.

To determine the relationship between metabolic activity of adipose tissue on FDG PET/CT and prognosis in colorectal cancer. A total of 176 colorectal cancer patients with curative surgical resection were retrospectively enrolled. Volume and metabolic activity of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on FDG PET/CT images were measured. The maximum standardized uptake value (SUV) of primary tumor (SUVtumor) was also obtained. Univariate analysis with log-rank test and multivariate Cox regression analyses were used to evaluate prognostic values of volume and metabolic activity of SAT and VAT as well as SUVtumor and clinicopathologic factors. Of 176 patients, 26 experienced recurrence during follow-up. SUVtumor showed significant correlation with serum C-reactive protein level (r=0.242, p=0.001), SUV of VAT (r=0.167, p=0.026), and size of primary tumor (r=0.341, p<0.001). In univariate analysis with log-rank test, SUV of VAT (p=0.009) and SAT (p=0.006), volume of VAT (p=0.015), N stage (p<0.001), M stage (p<0.001), tumor involvement of resection margin (p=0.001), and lymphatic invasion (p=0.024) were significantly associated with recurrence-free survival (RFS). However, SUVtumor showed no significant association with RFS. In multivariate Cox regression analysis, SUV of VAT (p=0.016), presence of lymph node metastasis (p<0.001), and tumor involvement of resection margin (p=0.011) were independent prognostic factors for RFS. The SUV of VAT in patients with colorectal cancer is significantly associated with FDG uptake of primary tumor. It is an independent predictor for RFS.

The effect of growth hormone replacement on the thyroid axis in patients with hypopituitarism: in vivo and ex vivo studies.

Alterations in the hypothalamic-pituitary-thyroid axis have been reported following growth hormone (GH) replacement. The aim was to examine the relationship between changes in serum concentration of thyroid hormones and deiodinase activity in subcutaneous adipose tissue, before and after GH replacement. A prospective, observational study of patients receiving GH replacement as part of routine clinical care. Twenty adult hypopituitary men. Serum TSH, thyroid hormones - free and total thyroxine (T4) and triiodothyronine (T3) and reverse T3, thyroglobulin and thyroid-binding globulin (TBG) levels were measured before and after GH substitution. Changes in serum hormone levels were compared to the activity of deiodinase isoenzymes (DIO1, DIO2 and DIO3) in subcutaneous adipose tissue. The mean daily dose of growth hormone (GH) was 0·34 ± 0·11 mg (range 0·15-0·5 mg). Following GH replacement, mean free T4 levels declined (-1·09 ± 1·99 pmol/l, P = 0·02). Reverse T3 levels also fell (-3·44 ± 1·42 ng/dl, P = 0·03) and free T3 levels increased significantly (+0·34 ± 0·15 pmol/l, P = 0·03). In subcutaneous fat, DIO2 enzyme activity declined; DIO1 and DIO3 activities remained unchanged following GH substitution. Serum TSH, thyroglobulin and TBG levels were unaltered by GH therapy. In vitro analysis of subcutaneous adipose tissue from hypopituitary human subjects demonstrates that GH replacement is associated with significant changes in deiodinase isoenzyme activity. However, the observed variation in enzyme activity does not explain the changes in the circulating concentration of thyroid hormones induced by GH replacement. It is possible that deiodinase isoenzymes are differentially regulated by GH in other tissues including liver and muscle.

Increased NOD1, but not NOD2, activity in subcutaneous adipose tissue from patients with metabolic syndrome.

Nucleotide-binding oligomerization domain (NOD) protein, as cytoplasmic receptor of the innate immune response, plays an important role in adipose inflammation and insulin resistance in obesity. Our objective was to examine adipose tissue (AT) NOD in nascent metabolic syndrome (MetS) patients and to investigate its association with MetS features. Thirty-four MetS subjects and 31 controls were recruited. Fasting blood was collected, and abdominal subcutaneous AT was obtained by biopsy for NOD1/NOD2 expression and activity. MetS subjects showed significantly increased expression for NOD1 on adipose depots as compared to controls. In addition to increased expression of downstream signaling mediators RIPK2 and NF-κB p65 nuclear translocation, there was remarkably higher release of monocyte chemotactic protein1 (MCP-1), interleukin (IL)-6, and IL-8 in MetS versus controls following priming of the isolated adipocytes with NOD1 ligand iE-DAP. With regard to NOD2, the differences between the two groups were not significant in either basal state or after activation. Increased NOD1 positively correlated with waist circumference. NOD1 was also correlated with HbA1c and HOMA-IR. NOD1 positively correlated with serum levels of IL-6, MCP-1, and NF-κB activity. Activation of the innate immune pathway via NOD1 may be partially responsible for the increased systemic inflammation and insulin resistance in MetS.

Reduced Slc2a4/GLUT4 expression in subcutaneous adipose tissue of monosodium glutamate obese mice is recovered after atorvastatin treatment.

BackgroundDecreased expression of glucose transporter protein GLUT4, encoded by the solute carrier 2A4 (Slc2a4) gene, is involved in obesity-induced insulin resistance. Local tissue inflammation, by nuclear factor-κB (NFκB)-mediated pathway, has been related to Slc2a4 repression; a mechanism that could be modulated by statins. Using a model of obesity with insulin resistance, this study investigated whether (1) inflammatory markers and Slc2a4 expression are altered; (2) atorvastatin has beneficial effects on inflammation and Slc2a4 expression; and (3) inhibitor of NFκB (IKK)/NFκB pathway is involved in subcutaneous adipose tissue (SAT).FindingsObese mice showed insulin resistance, decreased expression of Slc2a4 mRNA (66%, P < 0.01) and GLUT4 protein (30%, P < 0.05), and increased expression of interleukin 6 (Il6) mRNA (44%, P < 0.05) in SAT. Obese mice treated with atorvastatin had enhanced in vivo insulin sensitivity, besides increased Slc2a4/GLUT4 expression and reduced Il6 expression in SAT. No alterations of tumor necrosis factor-α, interleukin 1β and adiponectin expression or IKKα/β activity in SAT of obese mice or obese mice treated with atorvastatin were observed.ConclusionsAtorvastatin has beneficial effect upon glycemic homeostasis, which may be related to its positive impact on Il6 and Slc2a4/GLUT4 expression in SAT.

11β-hydroxysteroid dehydrogenase types 1 and 2 activity in subcutaneous adipose tissue in humans: implications in obesity and diabetes.

The role of 11β-hydroxysteroid dehydrogenase types 1 (11β-HSD-1) and 2 (11β-HSD-2) enzymes in sc adipose tissue is controversial. The objective of the study was to determine the activity of 11β-HSD-1 and -2 enzymes in the abdominal and leg sc adipose tissue in obesity and diabetes. 11β-HSD-1 and -2 enzyme activities in abdominal and leg sc adipose tissue were measured by infusing [2,2,4,6,6,12,12-(2)H7] cortisone (D7 cortisone) and [9,12,12-(2)H3] cortisol (D3 cortisol) via microdialysis catheters placed in sc fat depots. The study was conducted at the Mayo Clinic Clinical Research Unit. Lean nondiabetic (n = 13), overweight/obese nondiabetic (n = 15), and overweight/obese participants with type 2 diabetes mellitus (n = 15) participated in the study. The conversion of infused D7 cortisone to D7 cortisol (via 11β-HSD reductase activity) and D3 cortisol to D3 cortisone (via 11β-HSD dehydrogenase activity) in sc adipose tissue. Enrichment of D7 cortisone and D3 cortisol were similar in the effluents from both sites in all groups. D3 cortisone enrichment did not differ in the three cohorts, indicating that 11β-HSD-2 enzyme activity (conversion of cortisol to cortisone) occurs equally in all groups. However, D7 cortisol enrichment was detectable in abdominal sc fat of overweight/obese participants with type 2 diabetes mellitus only, implying 11β-HSD-1 reductase activity (conversion of cortisone to cortisol) occurs in obese subjects with type 2 diabetes. There is conversion of cortisone to cortisol via the 11β-HSD-1 enzyme pathway in abdominal sc fat depots in overweight/obese participants with type 2 diabetes mellitus. This observation has significant implications for developing tissue-specific 11β-HSD-1 inhibitors in type 2 diabetes mellitus.

Abstract 632: Lipoprotein Lipase Activators: A New Potent Drug Class for Treatment of Dyslipidemia

Aim: Elevated plasma TG and low HDL-cholesterol are part of CVD residual risk. Lipoprotein lipase (LPL) is the central enzyme controlling plasma TG hydrolysis and affecting de novo HDL formation. Thus LPL is an attractive target for correcting dyslipidemia and reduction of CVD residual risk. We have identified a novel first-in-class small molecule LPL activator - LP071. The objective with this study was to characterize the plasma lipid metabolism in LPL activator treated mice. Methods: ApoE3L:CETP mice were treated week with LP071. Plasma lipid profiles were analyzed using FPLC fractioning. LPL activity was investigated systemically and in specific tissue. Using triton WR1339 blockade chylomicron and VLDL secretion were assessed. Functional lipid clearance test were performed by oral fat tolerance tests. Results: Fasting plasma TG levels decreased with 97 % in apoE3L:CETP mice treated with LP071; HDL-c were increased by 116 % and (V)LDL-c were decreased with 91 %. Plasma free glycerol and NEFA were significantly lowered, 26 % and 22 % respectively. After an oral lipid load the plasma lipid response was significantly blunted in LP071 treated mice compared to controls. LPL activity in subcutaneous adipose tissue was increased 1500 % and in BAT LPL was increased by 100% at 3 h after a lipid gavage in WT mice treated with LP071. Conclusions: LP071 is a potent compound that can improve plasma lipid levels to a less atherogenic profile. The LP-class LPL activators can potentially help battle CVD residual risk in the future.

Adipose tissue stearoyl-CoA desaturase 1 index is increased and linoleic acid is decreased in obesity-prone rats fed a high-fat diet

BackgroundFatty acid (FA) composition and desaturase indices are associated with obesity and related metabolic conditions. However, it is unclear to what extent desaturase activity in different lipid fractions contribute to obesity susceptibility. Our aim was to test whether desaturase activity and FA composition are linked to an obese phenotype in rats that are either obesity prone (OP) or resistant (OR) on a high-fat diet (HFD).MethodsTwo groups of Sprague–Dawley rats were given ad libitum (AL-HFD) or calorically restricted (HFD-paired; pair fed to calories consumed by chow-fed rats) access to a HFD. The AL-HFD group was categorized into OP and OR sub-groups based on weight gain over 5 weeks. Five different lipid fractions were examined in OP and OR rats with regard to proportions of essential and very long-chain polyunsaturated FAs: linoleic acid (LA), alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid and the stearoyl-CoA desaturase 1 (SCD-1) product 16:1n-7. FA ratios were used to estimate activities of the delta-5-desaturase (20:4n-6/20:3n-6), delta-6-desaturase (18:3n-6/18:2n-6), stearoyl-CoA desaturase 1 (SCD-1; 16:1n-7/16:0, SCD-16 and 18:1n-9/18:0, SCD-18), de novo lipogenesis (16:0/18:2n-6) and FA elongation (18:0/16:0). Fasting insulin, glucose, adiponectin and leptin concentrations were measured in plasma.ResultsAfter AL-HFD access, OP rats had a significantly higher SCD-16 index and 16:1n-7 proportion, but a significantly lower LA proportion, in subcutaneous adipose tissue (SAT) triacylglycerols, as well as significantly higher insulin and leptin concentrations, compared with OR rats. No differences were found between the two phenotypes in liver (phospholipids; triacylglycerols) or plasma (cholesterol esters; phospholipids) lipid fractions or for plasma glucose or adiponectin concentrations. For the desaturase indices of the HFD-paired rats, the only significant differences compared with the OP or OR rats were higher SCD-16 and SCD-18 indices in SAT triacylglycerols in OP compared with HFD-paired rats.ConclusionThe higher SCD-16 may reflect higher SCD-1 activity in SAT, which in combination with lower LA proportions may reflect higher insulin resistance and changes in SAT independent of other lipid fractions. Whether a lower SCD-16 index protects against diet-induced obesity is an interesting possibility that warrants further investigation.

A novel genetically-obese rat model with elevated 11beta-hydroxysteroid dehydrogenase type 1 activity in subcutaneous adipose tissue

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive glucocorticoids to active glucocorticoids and plays an important role in the development of obesity and metabolic syndrome. 11β-HSD1 activity is lower in liver and higher in omental adipose tissue of obese rodent models like obese zucker rats, Ob/Ob and db/db mice. Here, we report the 11β-HSD1 activity in liver and adipose tissue of lean and obese rats of WNIN/Ob strain, a new genetic rat model of obesity. 11β-HSD1 activity in liver, omental and subcutaneous adipose tissues of 3 month-old male WNIN/Ob lean and obese rats was assayed. As observed in other rodent models, 11β-HSD1 activity was lower in liver and higher in omental adipose tissue. In contrast to other rodent obese models, WNIN/Ob obese rats had elevated 11β-HSD1 activity in subcutaneous adipose tissue, which is in line with the observation in human obesity. Here, we conclude that dysregulation of 11β-HSD1 in WNIN/Ob obese rat model is identical to human obesity, which makes it an excellent model for studying the effect of 11β-HSD1 inhibitors in ameliorating obesity and metabolic syndrome.

Repeated Measurements of 11β-HSD-1 Activity in Subcutaneous Adipose Tissue from Lean, Abdominally Obese, and Type 2 Diabetes Subjects – No Change Following a Mixed Meal

The aim of this study was to measure 11β-HSD-1 activity in subcutaneous adipose tissue by an ex vivo method in three subgroups; lean, obese, and type 2 diabetes subjects, both in the fasting state and after a mixed meal and to determine the variability and reproducibility of this method. Eighteen subjects were investigated; 6 lean, 6 abdominally obese, and 6 type 2 diabetes subjects (BMI 22 ± 1, 30 ± 3 and 31 ± 3 kg/m², respectively). Needle biopsies were taken repeatedly and an index of 11β-HSD-1 activity was measured as percent conversion of (3)H-cortisone to (3)H-cortisol/100 mg tissue. For two separate biopsies taken in the fasting state on the same day, the within subjects CV was 16% and the between CV was 36% for 11β-HSD-1 activity for all subjects. For two biopsies taken in the fasting state at two different days, the total within subjects CV was 38% and the between subjects CV was 46%. Lean subjects had lower 11β-HSD-1 activity (4.8 ± 1.5% conversion of ³H-cortisone to ³H-cortisol/100 mg tissue) than both obese (14.4 ± 1.6% conversion, p<0.01) and type 2 diabetes subjects (11.7 ± 1.9% conversion, p<0.05) in the fasting state. There was no effect of a meal on 11β-HSD-1 activity in any of the three groups. The conclusions from this study are: 1) the variation coefficient for the ex vivo adipose tissue 11β-HSD-1 activity method was ∼25% for repeat measures within subjects; 2) food intake had no major impact on enzyme activity; and 3) 11β-HSD-1 activity in subcutaneous adipose tissue was significantly increased in obese subjects with or without T2DM compared to lean subjects without diabetes.

Regional Decrease of Subcutaneous Adipose Tissue in Patients with Type 2 Familial Partial Lipodystrophy Is Associated with Changes in Thyroid Hormone Metabolism

Familial partial lipodystrophy of the Dunnigan type (FPLD2) presents with a decrease of subcutaneous adipose tissue (SAT) in the limbs and trunk. As thyroid hormones (TH) play an important role in adipogenesis, we studied if SAT from subjects with FPLD2 have changes in the gene expression levels of monocarboxylate transporter 8 (MCT8), a TH transporter, and TH nuclear receptors and in iodothyronine deiodinases (DIOs) expression and activities that could affect TH bioavailability and action in white adipose tissue. Seven subjects with FPLD2 and 10 healthy controls were studied. Two biopsies of SAT were obtained from each subject, one near the umbilicus and the other from the thigh. Expression of MCT8, DIO2, DIO3, THRA1, THRB1, and RXRG mRNAs were quantified by real-time polymerase chain reaction. DIO1 and DIO2 activities in adipose tissue homogenates were determined. Serum thyroid-stimulating hormone and TH levels were measured by chemiluminescence. Subjects with FPLD2 had lower levels of MCT8 mRNA expression in the thigh than in the abdomen SAT, and lower than in the abdomen and thigh SAT from control subjects. FPLD2 subjects also had higher DIO2 expression and activity in the thigh than in the abdomen SAT and higher than in controls. Thigh SAT from subjects with FPLD2 has lower expression of MCT8 and higher DIO2 expression and activity than abdominal SAT, suggesting that changes in local TH metabolism may occur in areas with lipoatrophy. DIO2 expression and activity in SAT suggest that DIO2 can regulate the metabolism and action of TH in human white adipose tissue.

Effects of Chromium on Energy Metabolism in Lambs Fed with Different Dietary Protein Levels

The effects of chromium (Cr), dietary crude protein (CP) level, and potential interactions of these two factors were investigated in term of energy metabolism in lambs. Forty-eight 9-week-old weaned lambs (DorperxSmall-tail Han sheep, male, mean initial body weight = 22.96 kg±2.60 kg) were used in a 2x3 factorial arrangement of supplemental Cr (0 μg/kg, 400 μg/kg or 800 μg/kg from chromium yeast) and protein levels (low protein: 157 g/d to 171 g/d for each animal, or high protein: 189 g/d to 209 g/d for each animal). Blood samples were collected at the beginning and end of the feeding trial. The lambs were then sacrificed and tissue samples were frozen for further analysis. Chromium at 400 μg/kg decreased fasting insulin level and the ratio of plasma insulin to glucagon, but these differences were not statistically significant; in contrast, chromium at 800 μg/kg increased the ratio significantly (p<0.05). Protein at the high level increased plasma tumor necrosis factor α (TNF-α) level (p = 0.060). Liver glycogen content was increased significantly by Cr (p<0.05), which also increased liver glucose-6-phosphatase (G-6-Pase) and adipose hormone-sensitive lipase (HSL) activity. At 400 μg/kg, Cr increased muscle hexokinase (HK) activity. High protein significantly increased G-6-Pase activities in both the liver (p< 0.05) and the kidney (p<0.05), but significantly decreased fatty acid synthase (FAS) activity in subcutaneous adipose tissue (p<0.05). For HSL activity in adipose tissue, a Cr×CP interaction (p<0.05) was observed. Overall, Cr improved energy metabolism, primarily by promoting the glycolytic rate and lipolytic processes, and these regulations were implemented mainly through the modulation by Cr of the insulin signal transduction system. High protein improved gluconeogenesis in both liver and kidney. The interaction of Cr×CP indicated that 400 μg/kg Cr could reduce energy consumption in situations where energy was being conserved, but could improve energy utilization when metabolic rate was increased.

C-Jun NH2-Terminal Kinase Activity in Subcutaneous Adipose Tissue but Not Nuclear Factor-κB Activity in Peripheral Blood Mononuclear Cells Is an Independent Determinant of Insulin Resistance in Healthy Individuals

OBJECTIVEChronic low-grade activation of the immune system (CLAIS) predicts type 2 diabetes via a decrease in insulin sensitivity. Our study investigated potential relationships between nuclear factor-κB (NF-κB) and c-Jun NH2-terminal kinase (JNK) pathways—two pathways proposed as the link between CLAIS and insulin resistance.RESEARCH DESIGN AND METHODSAdiposity (dual-energy X-ray absorptiometry), waist-to-hip ratio (WHR), and insulin sensitivity (M, hyperinsulinemic-euglycemic clamp) were measured in 22 healthy nondiabetic volunteers (aged 29 ± 11 years, body fat 28 ± 11%). NF-κB activity (DNA-binding assay) and JNK1/2 activity (phosphorylated JNK) were assessed in biopsies of the vastus lateralis muscle and subcutaneous adipose tissue and in peripheral blood mononuclear cell (PBMC) lysates.RESULTSNF-κB activities in PBMCs and muscle were positively associated with WHR after adjustment for age, sex, and percent body fat (both P < 0.05). NF-κB activity in PBMCs was inversely associated with M after adjustment for age, sex, percent body fat, and WHR (P = 0.02) and explained 16% of the variance of M. There were no significant relationships between NF-κB activity and M in muscle or adipose tissue (both NS). Adipose-derived JNK1/2 activity was not associated with obesity (all P> 0.1), although it was inversely related to M (r = −0.54, P < 0.05) and explained 29% of its variance. When both NF-κB and JNK1/2 were examined statistically, only JNK1/2 activity in adipose tissue was a significant determinant of insulin resistance (P = 0.02).CONCLUSIONSJNK1/2 activity in adipose tissue but not NF-κB activity in PBMCs is an independent determinant of insulin resistance in healthy individuals.

Effects of Chromium Yeast on Performance, Insulin Activity, and Lipid Metabolism in Lambs Fed Different Dietary Protein Levels

This experiment was conducted to study the effects of chromium (Cr), dietary crude protein (CP) level and potential interactions between these two factors on growth rate and carcass response, insulin activity and lipid metabolism in lambs. Forty-eight, 9-week-old weaned lambs (DorperxSmall-tail Han sheep, mean initial body weight = 22.96 kg±2.60 kg) were used in a 2x3 factorial arrangement of supplemental Cr (0 ppb, Cr0; 400 ppb, Cr1; or 800 ppb, Cr2 from chromium yeast) and CP levels (157 g/d to 171 g/d for each animal, LP; or 189 g/d to 209 g/d for each animal, HP). Growth data and blood samples were collected at the beginning and end of the feed trial, after which the lambs were killed. Both Cr additive groups and the HP group increased final weight and average daily gain, especially the Cr1 and HP group (p<0.01). HP increased pelvic fat weight (p<0.05), fat thickness of the 10th rib (p<0.05), longissimus muscle area (p<0.01) and rate of deposition of intramuscular fat (p<0.01). Supplemental Cr decreased the rate of deposition of intramuscular fat (p<0.05). Fasting insulin level and the ratio of insulin to glucose were lower with Cr1 than other groups, but with no significant difference. Glucose concentration was not affected by any treatment. Nonesterified fatty acids increased in the Cr1 (p<0.05) and HP (p<0.05) conditions and there was a significant CrxCP interaction (p<0.05). Cr1 decreased triglycerides (p<0.05) and total cholesterol (p = 0.151) and HP increased high-density lipoprotein cholesterol (p<0.05). Cr1 decreased lipoprotein lipase activity in subcutaneous adipose tissue (aLPL, p<0.05) and the ratio of aLPL to lipoprotein lipase activity in skeletal muscle (mLPL, p = 0.079). mLPL and hepatic lipase (hHL) were not affected by any treatment. In the present study, Cr had limited effects on growth rate and carcass response, whereas Cr and CP had some notable effects on plasma metabolites and enzyme activities. Cr has a potential effect on energy modulation between lipid and muscle tissue. In addition, few CrxCP interactions were observed.