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Aim/hypothesis: Altered adipose tissue secretory profile contributes to insulin resistance and type 2 diabetes in obesity. Preclinical studies have identified senescent cells as a cellular source of proinflammatory factors in adipose tissue of obese mice. In humans, potential links with obesity comorbidities are poorly defined. Here, we investigated adipose tissue senescent status and relationships with metabolic complications in human obesity., Methods: The study includes a prospective cohort of 227 individuals with severe obesity. A photometric method was used to quantify senescence-associated β-galactosidase (SA-β-gal) activity in paired subcutaneous and omental adipose tissue biopsies obtained during gastric surgery. Gene and secretory profiling was performed in adipose tissue biopsies and in human primary pre-adipocytes in the presence or absence of senolytic drugs targeting senescent cells. Participants were phenotyped for anthropometric and bioclinical variables, metabolic complications and gastric surgery-induced improvement to address relationships with adipose tissue SA-β-gal., Results: SA-β-gal activity was sevenfold higher in subcutaneous than in omental adipose tissue and not associated with BMI or chronological age. Several factors, including insulin-like growth factor binding protein 3 (IGFBP3), plasminogen activator inhibitor 1 (PAI1), C-C motif chemokine ligand 2 (CCL2) and IL-6, were upregulated in subcutaneous adipose tissue in relation with SA-β-gal (p for linear trend across tertiles <0.05) and in pre-adipocytes cultured with inflammatory macrophage conditioned media. Senolytic treatment reduced SA-β-gal staining and normalised these alterations. In the whole population, subcutaneous adipose tissue SA-β-gal activity was positively associated with serum leptin, markers of insulin resistance and increased trunk fat mass. Metabolic complications, including type 2 diabetes and dyslipidaemia, were more prevalent in patients with high levels of SA-β-gal, but improved with bariatric surgery whatever the initial adipose tissue senescent status., Conclusions/interpretation: This study highlights a phenotype of senescence in adipose tissue of severely obese individuals, which characterises prominently subcutaneous fat depots. Subcutaneous adipose tissue senescence is significantly linked to altered glucose metabolism and body fat distribution. Elimination of senescent cells through senolytic treatment could alleviate metabolic complications in severely obese people. Graphical abstract.

Branched-chain amino acids (BCAA) are major components of milk protein and important precursors for nonessential AA. Thus, the BCAA transport and break-down play a key role in the metabolic adaptation to the high nutrient demands in lactation. However, in monogastrics, increased BCAA levels have been linked with obesity and certain metabolic disorders such as impaired insulin sensitivity. Our objective was to study the effect of over-conditioning at calving on plasma BCAA levels as well as the tissue abundance of the most relevant BCAA transporters and degrading enzymes in dairy cows during late pregnancy and early lactation. Thirty-eight Holstein cows were allocated 15 wk antepartum to either a normal- (NBCS) or over-conditioned (HBCS) group, receiving 6.8 or 7.2 MJ of NE L /kg of DM, respectively, during late lactation to reach the targeted differences in body condition score (BCS) and back fat thickness (BFT; NBCS: BCS <3.5, BFT <1.2 cm; HBCS: BCS >3.75, BFT >1.4 cm) until dry-off. During the dry period and next lactation, cows were fed the same diets, whereby differences in BCS and BFT were maintained: prepartum means were 3.16 ± 0.06 and 1.03 ± 0.07 cm (NBCS) vs. 3.77 ± 0.08 and 1.89 ± 0.11 cm (HBCS), postpartum means were 2.89 ± 0.06 and 0.81 ± 0.05 cm (NBCS) vs. 3.30 ± 0.06 and 1.38 ± 0.08 cm (HBCS). Blood and biopsies from liver, semitendinosus muscle, and subcutaneous adipose tissue (scAT) were sampled at d 49 antepartum, 3, 21, and 84 postpartum. Free BCAA were analyzed and the mRNA abundance of solute carrier family 1 member 5 (SLC1A5), SLC7A5, and SLC38A2 as well as branched-chain aminotransferase 2 (BCAT2), branched-chain α-keto acid dehydrogenase E1α (BCKDHA), and branched-chain α-keto acid dehydrogenase E1β (BCKDHB) as well as the protein abundance of BCKDHA were assessed. Concentrations of all BCAA changed with time, most markedly in HBCS cows, with a nadir around calving. Apart from Ile, neither individual nor total BCAA differed between groups. The HBCS group had greater BCKDHA mRNA as well as higher prepartum BCKDHA protein abundance in scAT than NBCS cows, pointing to a greater oxidative capacity for the irreversible degradation of BCAA transamination products in scAT of over-conditioned cows. Prepartum hepatic BCKDHA protein abundance was lower in HBCS than in NBCS cows. In both groups, SLC1A5, SLC7A5, and BCAT2 mRNA were most abundant in scAT, whereas SLC38A2 was higher in scAT and muscle compared with liver, and BCKDHA and BCKDHB mRNA were greatest in liver and muscle, respectively. Our results indicate that scAT may be a major site of BCAA uptake and initial catabolism, with the former, however, being independent of BCS and time relative to calving in dairy cows., (Copyright © 2020 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

To evaluate the effect of overfeeding on fatty acid distribution and metabolism, especially stearoyl-CoA desaturase-1 (SCD-1) indices, 8 cats in the experimental and control groups (4 per group) were evaluated in this study. The experiments involved feeding the experimental group cats twice their daily energy requirement with a commercial diet for 4 weeks. The control group was fed the estimated daily energy requirement with the same diet. Body weight, feline body mass index, body condition score, several zoometry measurements, and plasma metabolites/hepatic injury markers were measured in all the cats before and after the experiment. In addition, the fatty acid profiles in the liver and subcutaneous adipose tissue were measured after the experiment. After 4 weeks of overfeeding, the experimental group demonstrated significant increases in hepatic C18:1, plasma triglyceride, and nonesterified fatty acid (NEFA) concentrations and in alanine aminotransferase activity. Furthermore, hepatic SCD-1 indices were positively correlated with body weight, feline body mass index, body condition score, and plasma NEFA concentration, although subcutaneous adipose tissue did not demonstrate any increase in SCD-1 indices in this study. The increase in hepatic SCD-1 indices might be enhanced by the inflow of plasma NEFA into the liver, and NEFA toxicity might stimulate C18:1 synthesis by SCD-1.

In adipose tissue, resistance to insulin's ability to increase glucose uptake can be induced by multiple factors, including obesity. Impaired insulin action may take place at different spatial loci at the cellular or subcellular level. To begin to understand the spatial response to insulin in human subcutaneous adipose tissue (hSAT), we developed a quantitative imaging method for activation of a major signaling node in the glucoregulatory insulin signaling pathway. After treatment with insulin or control media, biopsied tissues were immunostained for Akt phosphorylation at Thr-308/9 (pAkt) and then imaged by confocal fluorescence microscopy automated to collect a large grid of high resolution fields. In hSAT from 40 men and women with obesity, substantial heterogeneity of pAkt densities in adipocyte membranes were quantified in each image mosaic using a spatial unit of at least twice the size of the point spread function. Statistical analysis of the distribution of pAkt spatial units was best fit as the weighted sum of two separate distributions, corresponding to either a low or high pAkt density. A "high pAkt fraction" metric was calculated from the fraction of high pAkt distributed units over the total units. Importantly, upon insulin stimulation, tissues from the same biopsy showed either a minimal or a substantial change in the high pAkt fraction. Further supporting a two-state response to insulin stimulation, subjects with similar insulin sensitivity indices are also segregated into either of two clusters identified by the amount of membrane-localized pAkt., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Purpose: The study aimed to determine the effects of maternal low-protein (LP) diet on subcutaneous fat deposition of weaning piglets and the potential mechanism., Methods: Sows were fed either a standard protein (SP, 15 and 18% crude protein) or a LP diet (50% protein levels of SP) throughout pregnancy and lactation. Subcutaneous fat and blood were sampled from male piglets at 28 days of age. Serum biochemical metabolites and hormone concentrations were detected with the enzymatic colorimetric methods. Serum-free amino acid (FAA) levels were measured by amino acid auto-analyzer. The mRNA and protein were measured by qRT-PCR and Western blot., Results: Body weight, back fat thickness, triglycerides concentrations in subcutaneous fat tissue, and serum, as well as FFA concentrations were significantly reduced in LP piglets when compared with SP piglets. Further studies showed that mRNA and protein expression of acetyl-CoA carboxylase and fatty acid synthetase, two key enzymes of de novo lipogenesis, were significantly reduced in LP piglets, while mRNA expression and the lipolytic enzymes activities of lipolysis genes, adipose triglyceride lipase and hormone-sensitive lipase, were significantly increased. Furthermore, expression of autophagy-related gene 7 and autophagy maker gene microtubule-associated protein 1A/1B-light chain 3 (LC 3) as well as the conversion of LC3I to LC3II were significantly elevated, along with the expression of activating transcription factor-4 and eukaryotic translation initiation factor-2a., Conclusion: These results indicate that amino acid starvation-induced autophagy is involved in reduced subcutaneous fat deposition in maternal LP weaning piglets, demonstrating links between maternal protein restriction and offspring fat deposition.

BackgroundFacial infiltrating lipomatosis (FIL) is a congenital disorder that causes overgrowth of one side of the face. The purpose of this study was to determine whether PIK3CA mutations are present in tissues outside of the subcutaneous adipose.MethodsFIL tissues from three patients were dissected to enrich for cells from skin, subcutaneous tissue, orbicularis oris muscle, buccal fat, zygomatic bone, and mucosal neuroma. Endothelial cells within the affected tissue also were enriched using CD31 microbeads. Laser capture microdissection on formalin-fixed paraffin-embedded histologic sections was performed to collect specific cell types. DNA was extracted from each tissue and cell type, and measured for the abundance of mutant PIK3CA alleles using droplet digital PCR.ResultsWe detected mutant PIK3CA alleles in every tissue and cell type tested from each overgrown face; frequencies ranged from 1.5 to 53%. There were fewer mutant endothelial cells compared with nonendothelial cells, and the stromal cell compartment had the highest frequency of mutant cells in each tissue.ConclusionsPIK3CA mutations are not restricted to a single tissue or cell type in FIL. Overgrowth in this condition is likely due to the mutation arising in a cell that contributes to several different facial structures during embryogenesis.

Emerging evidence suggests that microbes resident in the human intestine represent a key environmental factor contributing to obesity-associated disorders. Here, we demonstrate that the gut microbiota-initiated trimethylamine N-oxide (TMAO)-generating pathway is linked to obesity and energy metabolism. In multiple clinical cohorts, systemic levels of TMAO were observed to strongly associate with type 2 diabetes. In addition, circulating TMAO levels were associated with obesity traits in the different inbred strains represented in the Hybrid Mouse Diversity Panel. Further, antisense oligonucleotide-mediated knockdown or genetic deletion of the TMAO-producing enzyme flavin-containing monooxygenase 3 (FMO3) conferred protection against obesity in mice. Complimentary mouse and human studies indicate a negative regulatory role for FMO3 in the beiging of white adipose tissue. Collectively, our studies reveal a link between the TMAO-producing enzyme FMO3 and obesity and the beiging of white adipose tissue., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Epicardial adipose tissue (EAT) is a visceral adipose tissue (AT) surrounding and infiltrating myocardium and coronary arteries. Increased EAT may represent a chronic inflammatory injury and a link with coronary artery disease (CAD). Metalloproteinases (MMPs) are involved in expansion of AT., Objective: To evaluate MMP-2 and -9 behaviour in EAT from CAD patients., Methods: In EAT and subcutaneous AT (SAT) from patients undergoing coronary artery bypass graft (CABG, n=26) or valve replacement (No CABG, n=18), MMP-2 and -9 activity and localization, inflammatory cells and vascular endothelial growth factor (VEGF) levels were determined., Results: In EAT from CABG, MMP-2 and -9 activity was increased compared with No CABG (p=0.041 and p=0.027, respectively) and compared with SAT (p=0.005 and p=0.048, respectively). In CABG patients EAT showed higher infiltration of macrophages and T lymphocytes than SAT (p=0.01 and p=0.002, respectively). In No CABG patients no sign of cellular retention was observed in EAT or SAT. Vascular density was higher in EAT from CABG than No CABG (p=0.015) and it was directly correlated with MMP-2 (p=0.006) and MMP-9 (p=0.02). VEGF levels in EAT were directly associated with MMP-2 (p=0.016)., Conclusion: In EAT from CABG patients the increase of MMP-2 and -9 activity and the presence of inflammatory cells would be partially responsible for extracellular matrix (ECM) remodeling and major vascular density necessary for EAT expansion. Improved knowledge of EAT behaviour may allow to identify new therapeutic targets for the treatment of CAD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The present study aimed to evaluate the infiltration of macrophages in form of crown-line structures (CLS) in subcutaneous adipose tissue (SAT) of obese individuals, and to investigate the effect of these on both metabolic parameters and adipose tissue 11-beta-hydroxysteroid dehydrogenase type 1 (11BHSD1) enzyme levels. A total of 53 obese (10 men, 43 woman) enrolled in the study. Body mass index (BMI), waist circumference (WC), hip circumfrence, and systolic (SBP) and diastolic blood pressures (DBP) of all subjects were recorded. Insulin resistance was determined using the homeostasis model assessment (HOMA). The concentration of SAT, tumor necrosis factor (TNF)-α, interleukin (IL)-6, 11BHSD1 were performed by enzyme-linked immunosorbent assay (ELISA) method. The infiltration of macrophages in form of CLS in adipose tissue were determined using cell-specific stains against CD68. There was no significant difference between the CLS + group and the CLS - group in terms of age, gender, BMI, WC, waist-to-hip circumference ratio (WHR), SBP and DBP levels. Fasting plasma glucose (FPG), HOMA-IR, insulin and SAT TNF-α levels were higher in the CLS + group compared to the CLS - group. FPG and SAT TNF-α levels were significantly higher in participants with high CLS density compared to participants with low density CLS. SAT 11BHSD1 levels was significant higher in the CLS + group compare to the CLS - group and in the high CLS density group compared to the low density group. In conclusion, the infiltration of macrophages in the form of CLS in SAT is associated with increased 11BHSD1 levels. It may be an important mechanism in the development of metabolic disorders., (© Georg Thieme Verlag KG Stuttgart · New York.)

Sirtuin type 1 (Sirt1) and protein kinase B (Akt2) are associated with development of obesity and inflammation, but the molecular mechanisms of Sirt1 and Akt2 interaction on adipose inflammation remain unclear. To explore these mechanisms, a mouse model was used. Mice were fed with a high-fat diet (HFD) for 8 weeks, with interventions of resveratrol (RES) or nicotinamide (NAM) during the last 15 days. The HFD reduced Sirt1 mRNA in adipose tissue and elevated interleukin-6 (IL-6) expression. RES reduced the adipose tissue weight, increased the Sirt1 mRNA level, and reduced both mRNA and protein levels of IL-6, MCP-1, inducible nitric oxide synthase, and TNF-α by inhibiting phosphorylation of Akt2 in adipose tissue. Additionally, macrophage type I marker genes were reduced while macrophage type II marker genes were elevated by RES addition. Moreover, activation of Akt2 signal by using insulin significantly blunted the inhibitory effect of RES on adipose inflammation. Immunoprecipitation assay demonstrated that RES enhances the protein-protein interaction between Sirt1 and Akt2, but NAM inhibits this interaction. Furthermore, Sirt1 significantly reduced the levels of raptor and inactivated mammalian target of rapamycin (mTOR)C1 signal by interacting with Akt2, and confirmed that RES attenuated adipose inflammation by inhibiting the mTOR/S6K1 pathway via rapamycin., (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.)

Aim: Peroxisome proliferator-activated receptor (PPAR) γ activation is associated with preferential lipoprotein lipase (LPL)-mediated fatty acid storage in peripheral subcutaneous fat depots. How PPARγ agonism acts upon the multi-level modulation of depot-specific lipid storage remains incompletely understood., Methods: We evaluated herein triglyceride-derived lipid incorporation into adipose tissue depots, LPL mass and activity, mRNA levels and content of proteins involved in the modulation of LPL activity and fatty acid transport, and the expression/activity of enzymes defining adipose tissue lipogenic potential in rats treated with the PPARγ ligand rosiglitazone (30 mg kg(-1)  day(-1) , 23 days) after either a 10-h fasting period or a 17-h fast followed by 6 h of ad libitum refeeding., Results: Rosiglitazone stimulated lipid accretion in subcutaneous fat (SF) ~twofold and significantly reduced that of visceral fat (VF) to nearly half. PPARγ activation selectively increased LPL mass, activity and the expression of its chaperone LMF1 in SF. In VF, rosiglitazone had no effect on LPL activity and downregulated the mRNA levels of the transendothelial transporter GPIHBP1. Overexpression of lipid uptake and fatty acid transport proteins (FAT/CD36, FATP1 and FABP4) and stimulation of lipogenic enzyme activities (GPAT, AGPAT and DGAT) upon rosiglitazone treatment were of higher magnitude in SF., Conclusions: Together these findings demonstrate that the depot-specific transcriptional control of LPL induced by PPARγ activation extends to its key interacting proteins and post-translational modulators to favour subcutaneous lipid storage., (© 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Aims: To assess the safety and pharmacokinetic and pharmacodynamic characteristics of BI 135585, a selective 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibitor, after single- and repeated-dose administration., Methods: The single-dose study included open-label administration of 200 mg BI 135585 in healthy volunteers, while in the multiple-dose study, we carried out randomized, double-blind administration of 5-200 mg BI 135585 or placebo once daily over 14 days in patients with type 2 diabetes (T2DM). Assessments included 11β-HSD1 inhibition in the liver (urinary tetrahydrocortisol (THF)/tetrahydrocotisone (THE) ratio) and in subcutaneous adipose tissue (AT) ex vivo and determination of hypothalamus-pituitary-adrenal (HPA) axis hormone levels., Results: No major safety issues occurred with BI 135585 administration. The HPA axis was mildly activated with slightly increased, but still normal adrenocorticotropic hormone levels, increased total urinary corticoid excretion but unchanged plasma cortisol levels. After multiple doses of 5-200 mg BI 135585, exposure (area under the curve) increased dose-proportionally and half-life was 55-65 h. The urinary THF/THE ratio decreased, indicating liver 11β-HSD1 inhibition. Median 11β-HSD1 enzyme inhibition in the AT reached 90% after a single dose of BI 135585, but was low (31% or lower) after 14 days of continuous treatment., Conclusions: BI 135585 was safe and well tolerated over 14 days and can be dosed once daily. Future studies are required to clarify the therapeutic potential of BI 135585 in view of its effects on 11β-HSD1 inhibition in AT after single and multiple doses. Enzyme inhibition in the AT was not adequately predicted by the urinary THF/THE ratio., (© 2016 John Wiley & Sons Ltd.)

Objective: Adipose tissue is an important extragonadal site for steroid hormone biosynthesis. After menopause, estrogens are synthesized exclusively in peripheral tissues from circulating steroid precursors, of which the most abundant is dehydroepiandrosterone sulfate (DHEAS). Our aim was to study activity of steroid sulfatase, an enzyme hydrolyzing DHEAS, and expression of steroid-converting enzyme genes in subcutaneous and visceral adipose tissue derived from pre- and postmenopausal women., Design: Serum and paired abdominal subcutaneous and visceral adipose tissue samples were obtained from 18 premenopausal and seven postmenopausal women undergoing elective surgery for non-malignant reasons in Helsinki University Central Hospital., Methods: To assess steroid sulfatase activity, radiolabeled DHEAS was incubated in the presence of adipose tissue homogenate and the liberated dehydroepiandrosterone (DHEA) was measured. Gene mRNA expressions were analyzed by quantitative RT-PCR. Serum DHEAS, DHEA, and estrogen concentrations were determined by liquid chromatography-tandem mass spectrometry., Results: Steroid sulfatase activity was higher in postmenopausal compared to premenopausal women in subcutaneous (median 379 vs 257 pmol/kg tissue per hour; P=0.006) and visceral (545 vs 360 pmol/kg per hour; P=0.004) adipose tissue. Visceral fat showed higher sulfatase activity than subcutaneous fat in premenopausal (P=0.035) and all (P=0.010) women. The mRNA expression levels of two estradiol-producing enzymes, aromatase and 17β-hydroxysteroid dehydrogenase type 12, were higher in postmenopausal than in premenopausal subcutaneous adipose tissue., Conclusions: Steroid sulfatase activity in adipose tissue was higher in postmenopausal than in premenopausal women suggesting that DHEAS, derived from the circulation, could be more efficiently utilized in postmenopausal adipose tissue for the formation of biologically active sex hormones., (© 2016 European Society of Endocrinology.)

Aromatase plays an important role in the estrogen biosynthesis. Its gen (CYP19A1) is expressed in preadipocytes (stromal vascular fraction, SVF) of adipose tissue. Estrogens are found to be protective for metabolism homeostasis, and cardiovascular system. Disturbed dietary and endogenous fatty acids (FAs) turnover is responsible for development of metabolic syndrome and it complications. Aim of the work was to investigate the effect of physiological concentrations of acids: arachidonic (AA), oleic (OA), palmitynoic (PA) and eikozapentaenoic (EPA) on CYP19A1 expression in differentiating human SVF, able to form adipocytes as well as endothelial cells., Material and Methods: Human (n=38 healthy woman) SVF cells were isolated from subcutaneous adipose tissue harvested intrasurgery. SVF cells were incubated in proadipogenic or angiogenic media to obtain adipocytes (Adipo-SVF) or endothelial (Angio-SVF) cells (confirmed by microarray). Changes in the CYP19A1 expression induced by 24hs incubation in the presence of FAs (10 – 30 μM )were monitored by the Real time PCR (qRT -PCR)., Results: The aromatase gene expression correlated positively with BMI of patients, but only in group of obese or overweight women. The negative correlation was found in the group of young, slim women. The highest expression of aromatase was found in the fresh, not differentiated SVF. In differentiating to endothelial cells (Angio - SVF) OA inhibited (p=0.008), when n-3 polyunsaturated AA activated (p=0.003) the CYP19A1 gene expression. In differentiating to preadipocytes (Adipo-SVF) AA significantly (p=0.031) inhibited CYP19A1 expression., Conclusion: The changes in the aromatase gene expression in differentiating SVF has been confirmed. The different effect of the dietary FA (OA vs. AA) on the aromatase gene expression argue for the role of the locally formed proangiogenic estrogens.

Fatty acids (FAs) are a major energy source in the body. White adipose tissue (WAT) is a primary site where FAs are stored as triacylglycerols. Brown adipose tissue also stores and recruits FAs as a carbon source for uncoupled β-oxidation during thermogenesis. The deletion of the vitamin D nuclear hormone receptor (VDR) gene in mice (VDRKO) results in a lean WAT phenotype with increased levels of expression of the brown adipose tissue marker Ucp1 in the WAT. However, the impact of vitamin D/VDR on FA composition in WAT has not been explored in detail. To address this question, we examined the FA composition of sc and visceral white adipose depots of VDRKO mice. We found that the levels of a subset of saturated and monounsaturated FAs of C18-C24 are specifically increased in the sc adipose depot in VDRKO mice. We revealed that a specific elongase enzyme (Elovl3), which has an important role in brown fat biology, is directly regulated by VDR and likely contributes to the altered FA composition in VDRKO mice. We also demonstrate that Elovl3 is regulated by vitamin D in vivo and tissue specifically in the sc WAT depot. We discovered that regulation of Elovl3 expression is mediated by ligand-dependent VDR occupancy of a negative-response element in the promoter proximal region of the Elovl3 gene. These data suggest that vitamin D/VDR tissue specifically modulates FA composition in sc WAT through direct regulation of Elovl3 expression.

The present study aimed to evaluate the role of subcutaneous adipose tissue (SAT) type II deiodinase enzyme gene (DIO2) expression in developing metabolic syndrome (MetS). A total of 51 obese patients with MetS and without MetS and 13 healthy subjects enrolled in the study. Body mass index (BMI), waist circumference (WC), waist-to-hip circumference ratio (WHR), hip circumference, and systolic (SBP) and diastolic blood pressures (DBP) of all subjects were recorded. Fasting plasma glucose (FPG), fasting plasma insulin, high density lipoprotein- cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), total cholesterol (TC) and triglyceride (TG) of all subjects were analyzed. Expression of the DIO2 gene in adipose tissue was determined by reverse transcription polymerase chain reaction (qRT-PCR). BMI, WC and WHR were not significantly difference between obese with and without MetS. SBP, DBP, FPG and TG were significantly higher in obese with MetS group than obese without MetS group. While the free triiodothyronine (T3) level was in the normal range in all group, it was significantly lower in the obese with MetS than both obese without MetS and control group. DIO2 expression was significantly lower in the obese with MetS group compared to the control. In correlation analysis, DIO2 expression was negatively correlated with DBP, TG and homeostasis model assessment of insulin resistance (HOMA-IR) levels and positively correlated with free T3. In conclusion, the reduction of SAT DIO2 expression is negatively correlated with DBP and TG levels that are associated with the MetS. This might have an effect on developing MetS. We believe that DIO2 gene may be an important molecular target for future studies in developing targeted treatment options for obese people with MetS., (© Georg Thieme Verlag KG Stuttgart · New York.)

The purpose of this work was to evaluate the expression of fatty acid metabolism-related genes in human adipose tissue from moderately obese women. We used qRT-PCR and Western Blot to analyze visceral (VAT) and subcutaneous (SAT) adipose tissue mRNA expression involved in de novo fatty acid synthesis (ACC1, FAS), fatty acid oxidation (PPARα, PPARδ) and inflammation (IL6, TNFα), in normal weight control women (BMI < 25 kg/m², n = 35) and moderately obese women (BMI 30-38 kg/m², n = 55). In SAT, ACC1, FAS and PPARα mRNA expression were significantly decreased in moderately obese women compared to controls. The downregulation reported in SAT was more pronounced when BMI increased. In VAT, lipogenic-related genes and PPARα were similar in both groups. Only PPARδ gene expression was significantly increased in moderately obese women. As far as inflammation is concerned, TNFα and IL6 were significantly increased in moderate obesity in both tissues. Our results indicate that there is a progressive downregulation in lipogenesis in SAT as BMI increases, which suggests that SAT decreases the synthesis of fatty acid de novo during the development of obesity, whereas in VAT lipogenesis remains active regardless of the degree of obesity.

Occurrence of oxidative stress in white adipose tissues contributes to its dysfunction and the development of obesity-related metabolic complications. Coenzyme Q10 (CoQ10) is the single lipophilic antioxidant synthesized in humans and is essential for electron transport during mitochondrial respiration. To understand the role of CoQ10 in adipose tissue physiology and dysfunction, the abundance of the oxidized and reduced (CoQ10red) isoforms of the CoQ10 were quantified in subcutaneous and omental adipose tissues of women covering the full range of BMI (from 21.5 to 53.2 kg/m(2)). Lean women displayed regional variations of CoQ10 redox state between the omental and subcutaneous depot, despite similar total content. Obese women had reduced CoQ10red concentrations in the omental depot, leading to increased CoQ10 redox state and higher levels of lipid hydroperoxide. Women with low omental CoQ10 content had greater visceral and subcutaneous adiposity, increased omental adipocyte diameter, and higher circulating interleukin-6 and C-reactive protein levels and were more insulin resistant. The associations between abdominal obesity-related cardiometabolic risk factors and CoQ10 content in the omental depot were abolished after adjustment for omental adipocyte diameter. This study shows that hypertrophic remodeling of visceral fat closely relates to depletion of CoQ10, lipid peroxidation, and inflammation., (Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.)

Obese women with type 2 diabetes mellitus (T2DM) have more inflammation in their subcutaneous white adipose tissue (sWAT) than age-and-BMI similar obese women with normal glucose tolerance (NGT). We aimed to investigate whether WAT fatty acids and/or oxylipins are associated with the enhanced inflammatory state in WAT of the T2DM women. Fatty acid profiles were measured in both subcutaneous and visceral adipose tissue (vWAT) of 19 obese women with NGT and 16 age-and-BMI similar women with T2DM. Oxylipin levels were measured in sWAT of all women. Arachidonic acid (AA) and docosahexaenoic acid (DHA) percentages were higher in sWAT, but not vWAT of the T2DM women, and AA correlated positively to the gene expression of macrophage marker CD68. We found tendencies for higher oxylipin concentrations of the 5-LOX leukotrienes in sWAT of T2DM women. Gene expression of the 5-LOX leukotriene biosynthesis pathway was significantly higher in sWAT of T2DM women. In conclusion, AA and DHA content were higher in sWAT of T2DM women and AA correlated to the increased inflammatory state in sWAT. Increased AA content was accompanied by an upregulation of the 5-LOX pathway and seems to have led to an increase in the conversion of AA into proinflammatory leukotrienes in sWAT.

Glitazones are peroxisome proliferator-activated receptor gamma (PPARγ) agonists widely used as antidiabetic drugs also known as thiazolidinediones. Most of them exert other effects such as anti-inflammatory actions via mechanisms supposed to be independent from PPARγ activation (e.g., decreased plasma monocyte chemoattractant protein-1 (MCP-1) levels). Recently, pioglitazone has been shown to inhibit the B form of monoamine oxidase (MAO) in mouse, while rosiglitazone and troglitazone were described as non-covalent inhibitors of both human MAO A and MAO B. Since molecules interacting with MAO might also inhibit semicarbazide-sensitive amine oxidase (SSAO), known as vascular adhesion protein-1 (VAP-1), and since VAP-1/SSAO inhibitors exhibit anti-inflammatory activity, our aim was to elucidate whether VAP-1/SSAO inhibition could be a mechanism involved in the anti-inflammatory behaviour of glitazones. To this aim, MAO and SSAO activities were measured in human subcutaneous adipose tissue biopsies obtained from overweight women undergoing plastic surgery. The production of hydrogen peroxide, an end-product of amine oxidase activity, was determined in tissue homogenates using a fluorometric method. The oxidation of 1 mM tyramine was inhibited by pargyline and almost resistant to semicarbazide, therefore predominantly MAO-dependent. Rosiglitazone was more potent than pioglitazone in inhibiting tyramine oxidation. By contrast, benzylamine oxidation was only abolished by semicarbazide: hence SSAO-mediated. Pioglitazone hampered SSAO activity only when tested at 1 mM while rosiglitazone was inefficient. However, rosiglitazone exhibited anti-inflammatory activity in human adipocytes by limiting MCP-1 expression. Our observations rule out any involvement of VAP-1/SSAO inhibition and subsequent limitation of leukocyte extravasation in the anti-inflammatory action of glitazones.

Morbidly obese individuals are predisposed to a wide range of disorders, including type 2 diabetes, atherosclerotic cardiovascular disease, fatty liver disease, and certain cancers. Remarkably, all of these disorders can be improved or prevented by Roux-en-Y gastric bypass (RYGB) surgery. We have reported that decreased AMPK activity, together with increased oxidative stress and inflammation in adipose tissue, is associated with insulin resistance in morbidly obese bariatric surgery patients. In the current study, we assessed how these parameters are affected by RYGB surgery. Eleven patients (average age of 46 ± 4 years) were studied immediately prior to surgery and 3 months postoperatively. We measured subcutaneous adipose tissue AMPK phosphorylation (threonine 172, an index of its activation), malonyl-CoA content, protein carbonylation (a marker of oxidative stress), plasma adiponectin, and mRNA expression of several inflammatory cytokines. After surgery, AMPK activity increased 3.5-fold and oxidative stress decreased by 50% in subcutaneous adipose tissue. In addition, malonyl-CoA levels were reduced by 80%. Furthermore, patients had improvements in their BMI and insulin sensitivity (HOMA) and had increased circulating high-molecular weight adiponectin and decreased fasting plasma insulin levels. In contrast, the expression of inflammatory markers in subcutaneous adipose tissue was unchanged postoperatively, although plasma CRP was diminished by 50%., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Scope: The gut microbiota is able to modulate host physiology through the production of bioactive metabolites. Our recent studies suggest that changes in gut microbiota composition upon prebiotics supplementation alter tissue levels of PUFA-derived metabolites in mice. However, in vivo evidence that gut microbes produces PUFA-derived metabolites is lacking. This study aimed to decipher the contribution of gut microbes versus that of the host in PUFA-derived metabolite production., Methods and Results: To achieve this goal, we compared the proportion of PUFA-derived metabolites and the expression of fatty acid desaturases in germ-free (GF) and conventionalized (CONV) mice fed either a low fat or Western diet. Higher concentrations of PUFA-derived metabolites were found in the colonic contents of conventionalized mice (CONV) mice compared to GF mice. The abundance of these metabolites in host tissues was modulated by dietary treatments but not by microbial status. Although microbial status did significantly influence desaturase expression, no correlations between host enzymes and tissue PUFA-derived metabolite levels were observed., Conclusion: Together, these results highlight the ability of the gut microbiota to produce PUFA-derived metabolites from dietary PUFA. However, microbial production of these metabolites in colonic contents is not necessarily associated with modifications of their concentration in host tissues., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

To characterize mechanisms responsible for fat accumulation we used a selectively bred obesity-prone (OP) and obesity-resistant (OR) rat model where the rats were fed a Western diet for 76 days. Body composition was assessed by magnetic resonance imaging scans, and as expected, the OP rats developed a higher degree of fat accumulation compared with OR rats. Indirect calorimetry showed that the OP rats had higher respiratory exchange ratio (RER) compared with OR rats, indicating an impaired ability to oxidize fat. The OP rats had lower expression of carnitine palmitoyltransferase 1b in intra-abdominal fat, and higher expression of stearoyl-CoA desaturase 1 in subcutaneous fat compared with OR rats, which could explain the higher fat accumulation and RER values. Basal metabolic parameters were also examined in juvenile OP and OR rats before and during the introduction of the Western diet. Juvenile OP rats likewise had higher RER values, indicating that this trait may be a primary and contributing factor to their obese phenotype. When the adult obese rats were exposed to the orexigenic and adipogenic hormone ghrelin, we observed increased RER values in both OP and OR rats, while OR rats were more sensitive to the orexigenic effects of ghrelin as well as ghrelin-induced attenuation of activity and energy expenditure. Thus increased fat accumulation characterizing obesity may be caused by impaired oxidative capacity due to decreased carnitine palmitoyltransferase 1b levels in the white adipose tissue, whereas ghrelin sensitivity did not seem to be a contributing factor., (Copyright © 2015 the American Physiological Society.)

White adipose tissue has now been recognized as an important endocrine organ secreting bioactive molecules termed adipocytokines. In obesity, anti-inflammatory adipocytokines like adiponectin are decreased while pro-inflammatory factors are over-produced. These changes contribute to the development of insulin resistance and obesity-associated diseases. Since members of the casein kinase 1 (CK1) family are involved in the regulation of various signaling pathways we ask here whether they are able to modulate the functions of adiponectin. We show that CK1δ and ε are expressed in adipose tissue and that the expression of CK1 isoforms correlates with that of adiponectin. Furthermore, adiponectin co-immunoprecipitates with CK1δ and CK1ε and is phosphorylated by CK1δ at serine 174 and threonine 235, thereby influencing the formation of adiponectin oligomeric complexes. Furthermore, inhibition of CK1δ in human adipocytes by IC261 leads to an increase in basal and insulin-stimulated glucose uptake. In summary, our data indicate that site-specific phosphorylation of adiponectin, especially at sites targeted by CK1δ in vitro, provides an additional regulatory mechanism for modulating adiponectin complex formation and function., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims/hypothesis: Nicotinamide-N-methyltransferase (NNMT) was recently shown to be upregulated in mouse models of insulin resistance and obesity. So far, it is unknown whether NNMT is regulated in human disease. We have explored the hypothesis that white adipose tissue (WAT) NNMT expression and plasma 1-methylnicotinamide (MNA) concentration are increased in human insulin resistance and type 2 diabetes., Methods: NNMT expression and plasma MNA were analysed in three groups of individuals: (1) 199 patients undergoing abdominal surgery; (2) 60 individuals on a 12-week exercise programme and (3) 55 patients on a two-step bariatric surgery programme., Results: Patients with manifest type 2 diabetes have a significantly (approximately twofold) higher NNMT expression both in omental and subcutaneous WAT compared with controls. Notably, plasma MNA correlated significantly with WAT NNMT expression in patients with type 2 diabetes (women, r = 0.59, p < 0.001; men, r = 0.61, p < 0.001) but not in healthy control individuals. In insulin-resistant individuals, there was an inverse correlation between insulin sensitivity and plasma MNA (r = 0.44, p = 0.01) or adipose tissue NNMT mRNA (r = 0.64, p < 0.001). The latter association was confirmed in a second cohort (n = 60, r = 0.78, p < 0.001). Interventions improving insulin sensitivity--exercise and bariatric surgery--were associated with a significant (p < 0.001) reduction in WAT NNMT expression. Bariatric surgery was also associated with a significant decrease in plasma MNA., Conclusions/interpretation: We demonstrate that WAT NNMT expression is regulated in human insulin resistance and type 2 diabetes and that plasma MNA correlates with increased tissue NNMT expression and the degree of insulin resistance, making it a potential biomarker for loss of insulin sensitivity.

Fatty acid composition is an economically important trait in meat-producing livestock. To gain insight into the molecular genetics of fatty acid desaturase (FADS) genes in pigs, we investigated the genomic structure of the porcine FADS gene family on chromosome 2. We also examined the tissue distribution of FADS gene expression. The genomic structure of FADS family in mammals consists of three isoforms FADS1, FADS2 and FADS3. However, porcine FADS cluster in the latest pig genome assembly (Sscrofa 10.2) containing some gaps is distinct from that in other mammals. We therefore sought to determine the genomic structure, including the FADS cluster in a 200-kbp range by sequencing gap regions. The structure we obtained was similar to that in other mammals. We then investigated the porcine FADS1 transcription start site and identified a novel isoform named FADS1b. Phylogenetic analysis revealed that the three members of the FADS cluster were orthologous among mammals, whereas the various FADS1 isoforms identified in pigs, mice and cattle might be attributable to species-specific transcriptional regulation with alternative promoters. Porcine FADS1b and FADS3 isoforms were predominantly expressed in the inner layer of the subcutaneous adipose tissue. Additional analyses will reveal the effects of these functionally unknown isoforms on fatty acid composition in pig fat tissues., (© 2014 Japanese Society of Animal Science.)

Context: The role of 11β-hydroxysteroid dehydrogenase types 1 (11β-HSD-1) and 2 (11β-HSD-2) enzymes in sc adipose tissue is controversial., Objective: 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., Design: 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., Setting: The study was conducted at the Mayo Clinic Clinical Research Unit., Participants: Lean nondiabetic (n = 13), overweight/obese nondiabetic (n = 15), and overweight/obese participants with type 2 diabetes mellitus (n = 15) participated in the study., Main Outcome Measures: 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., Results: 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., Conclusions: 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.

Acetyl CoA Carboxylase 1 (ACC1) is a biotin-dependent enzyme that catalyzes the carboxylation of Acetyl CoA to form Malonyl CoA, the key intermediate metabolite in fatty acid synthesis. In this study, the mRNA expression of the ACC1 gene was evaluated in four different tissues (liver, visceral fat, subcutaneous fat, and longissimus muscle) of the domestic goat (Capra hircus) kids feeding on four different levels of trivalent chromium (0, 0.5, 1, and 1.5mg/day) as food supplementation. RT-qPCR technique was used for expression analyses and heat shock protein 90 gene (HSP-90) was considered as reference gene for data normalization. Our results revealed that 1.5mg/day chromium significantly reduced the expression of the ACC1 gene in liver, visceral fat, and subcutaneous fat tissues, but not in longissimus muscles (P<0.05). We measured some phenotypic traits of kid's carcasses to detect their probable correlations with chromium-mediated downregulation of ACC1 expression. Interestingly, changes in ACC1 expression were accompanied with decreased accumulation of fats in adipose tissues such that the subcutaneous fat thickness and heart fat percentage decreased in kids feeding on chromium. By contrast, chromium supplemented kids showed higher percentage of muscles despite the fact that their total body weight did not differ from that of non-supplemented kids. Our study suggests that trivalent chromium alters the direction of energy accumulation towards muscles rather than fats and provides insights into application of chromium supplementation as a useful strategy for improvement of meat quality in domestic animals., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Glucocorticoids (GCs) are well known to induce fat distribution, which is consistent with the central adiposity phenotype seen in Cushing's syndrome. GCs have been proposed to be both adipogenic and lipolytic in action within adipose tissues. Different adipogenic and lipolytic effects between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are likely to play a role in GCs induced fat differential distribution. Wnt/β-catenin signaling pathway is one of the most important regulators in adipogenesis. Adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL) are the major lipases contributing to lipolysis. In the present study, we measured fat depot masses and the expression of Wnt/β-catenin signaling pathway and lipolytic enzymes of female Sprague-Dawley rats treated with or without methylprednisolone. We assessed the roles of Wnt/β-catenin signaling pathway and lipolytic enzymes in fat differential distribution between SAT and VAT. Our data suggested that methylprednisolone could inhibit Wnt/β-catenin signaling pathway in SAT and VAT, increase the expression of ATGL and HSL in SAT, and decrease the expression of ATGL and HSL in VAT. The differential expression of lipolysis enzymes induced by methylprednisolone between SAT and VAT might play a crucial role in fat distribution. Those findings would offer novel insights into the mechanisms of GCs induced fat distribution., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Based on previous research with bovine peadipocytes, we hypothesized that infusion of arginine into the abomasum of Angus steers stimulates stearoyl-CoA desaturase (SCD) gene expression in bovine subcutaneous (s.c.) adipose tissue, and that this would be attenuated by conjugated linoleic acid (CLA). Growing Angus steers were infused abomasally with L-arginine 50 g/day; n = 13; provided as L-arginine HCl) or L-alanine (isonitrogenous control, 100 g/day; n = 11) for 14 days. For the subsequent 14 days, half of the steers in each amino acid group were infused with CLA (100 g/day). Body weight gain and average daily gain were unaffected (P > 0.15) by infusion of arginine or CLA into the abomasum. The plasma concentrations of cis-9, trans-11 and trans-10, cis-12 CLA were increased CLA infusion (P = 0.001) and infusion of arginine increased plasma arginine (P = 0.01). Compared with day 0, fatty acid synthase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase enzyme activities in s.c. adipose tissue increased by day 14 in steers infused with either alanine or arginine (all P < 0.01). NADP-MDH activity was higher (P = 0.01) in steers infused with arginine than in steers infused with arginine plus CLA by day 28, but lipid synthesis in vitro from glucose and acetate was unaffected by infusion of either arginine or CLA (P > 0.40). By day 28, C/EBPβ and SCD gene expression was higher, and CPT1β gene expression was lower, in s.c. adipose tissue of steers infused with arginine than in steers infused with alanine (±CLA) (P = 0.05). CLA decreased adipose tissue oleic acid (18:1n-9) in alanine- or arginine-infused steers (P = 0.05), although CLA had no effect on SCD gene expression. The data indicate that supplemental arginine promotes adipogenic gene expression and may promote lipid accumulation in bovine adipose tissue. L-Arginine may beneficially improve beef quality for human consumption.

Excess fat storage in adipocytes is associated with increased generation of reactive oxygen species (ROS) and impaired activity of antioxidant mechanisms. Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme involved in detoxification of ROS, and objective of the current study is to analyze expression and regulation of MnSOD in obesity. MnSOD is increased in visceral but not subcutaneous fat depots of rodents kept on high fat diets (HFD) and ob/ob mice. MnSOD is elevated in visceral adipocytes of fat fed mice and exposure of differentiating 3T3-L1 cells to lipopolysaccharide, IL-1α, saturated, monounsaturated and polyunsaturated free fatty acids (FFA) upregulates its level. FFA do not alter cytochrome oxidase 4 arguing against overall induction of mitochondrial enzymes. Upregulation of MnSOD in fat loaded cells is not mediated by IL-6, TNF or sterol regulatory element binding protein 2 which are induced in these cells. MnSOD is similarly abundant in perirenal fat of Zucker diabetic rats and non-diabetic animals with similar body weight and glucose has no effect on MnSOD in 3T3-L1 cells. To evaluate whether MnSOD affects adipocyte fat storage, MnSOD was knocked-down in adipocytes for the last three days of differentiation and in mature adipocytes. Knock-down of MnSOD does neither alter lipid storage nor viability of these cells. Heme oxygenase-1 which is induced upon oxidative stress is not altered while antioxidative capacity of the cells is modestly reduced. Current data show that inflammation and excess triglyceride storage raise adipocyte MnSOD which is induced in epididymal adipocytes in obesity.

Objective: To study expression of the recently identified adipokine dipeptidyl peptidase-4 (DPP4) in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of patients with various BMIs and insulin sensitivities, as well as to assess circulating DPP4 in relation to obesity and insulin sensitivity., Research Design and Methods: DPP4 expression was measured in SAT and VAT from 196 subjects with a wide range of BMIs and insulin sensitivities. DPP4 release was measured ex vivo in paired biopsies from SAT and VAT as well as in vivo from SAT of lean and obese patients. Circulating DPP4 was measured in insulin-sensitive and insulin-resistant BMI-matched obese patients., Results: DPP4 expression was positively correlated with BMI in both SAT and VAT, with VAT consistently displaying higher expression than SAT. Ex vivo release of DPP4 from adipose tissue explants was higher in VAT than in SAT in both lean and obese patients, with obese patients displaying higher DPP4 release than lean controls. Net release of DPP4 from adipose tissue was also demonstrated in vivo with greater release in obese subjects than in lean subjects and in women than in men. Insulin-sensitive obese patients had significantly lower circulating DPP4 than did obesity-matched insulin-resistant patients. In this experiment, DPP4 positively correlated with the amount of VAT, adipocyte size, and adipose tissue inflammation., Conclusions: DPP4, a novel adipokine, has a higher release from VAT that is particularly pronounced in obese and insulin-resistant patients. Our data suggest that DPP4 may be a marker for visceral obesity, insulin resistance, and the metabolic syndrome.

Objective: The double-stranded RNA-dependent protein kinase (PKR) was recently implicated in regulating molecular integration of nutrient- and pathogen-sensing pathways in obese mice. However, its modulation in human tissues in situations of insulin resistance has not been investigated. The present study was performed to first determine the tissue expression and phosphorylation levels of PKR in the liver, muscle, and adipose tissue in obese humans, and also the modulation of this protein in the adipose tissue of obese patients after bariatric surgery., Design and Methods: Eleven obese subjects who were scheduled to undergo Roux-en-Y Gastric Bypass Procedure participated in this study. Nine apparently healthy lean subjects as a control group were also included., Results: Our data show that PKR is activated in liver, muscle, and adipose tissue of obese humans and, after bariatric surgery, there is a clear reduction in PKR activation accompanied by a decrease in protein kinase-like endoplasmic reticulum kinase, c-Jun N-terminal kinase, inhibitor of kappa β kinase, and insulin receptor substrate-1 serine 312 phosphorylation in subcutaneous adipose tissue from these patients., Conclusion: Thus, it is proposed that PKR is an important mediator of obesity-induced insulin resistance and a potential target for the therapy., (Copyright © 2013 The Obesity Society.)

This study explored sex differences in 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity and gene expression in isolated adipocytes and adipose tissue (AT), obtained via subcutaneous biopsies from non-diabetic subjects [58 M, 64 F; age 48.3 ± 15.3 years, body mass index (BMI) 27.2 ± 3.9 kg/m²]. Relationships with adiposity and insulin resistance (IR) were addressed. Males exhibited higher 11β-HSD1 activity in adipocytes than females, but there was no such difference for AT. In both men and women, adipocyte 11β-HSD1 activity correlated positively with BMI, waist circumference, % body fat, adipocyte size and with serum glucose, triglycerides and low-density lipoprotein:high-density lipoprotein (LDL:HDL) ratio. Positive correlations with insulin, HOMA-IR and haemoglobin A1c (HbA1c) and a negative correlation with HDL-cholesterol were significant only in males. Conversely, 11β-HSD1 activity in AT correlated with several markers of IR and adiposity in females but not in males, but the opposite pattern was found with respect to 11β-HSD1 mRNA expression. This study suggests that there are sex differences in 11β-HSD1 regulation and in its associations with markers of obesity and IR., (© 2013 John Wiley & Sons Ltd.)

The aim of the work was to investigate the expression of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and 2, hexose-6-phosphate dehydrogenase (H6PDH), and glucocorticoids receptor (GR) mRNA in subcutaneous adipose tissue (SAT) from obese women with or without polycystic ovary syndrome (PCOS), and the association between their expression and the adipocytokines' concentration. Sixteen women with PCOS (group P) and 18 age- and BMI-matched control women (group C) were enrolled for the study. Subcutaneous adipose tissue was collected from the abdomen. The genes' expression was detected by real-time PCR, and the adipocytokines' concentration was measured by ELISA. Peripheral insulin sensitivity was assessed by homeostatic assessment model of insulin resistance (HOMA-IR). β-cell function was assessed by homeostasis model assessment of β-cell function (HOMA-IS). The expression of 11β-HSD1 mRNA was significantly higher in PCOS subjects (p<0.05) than controls; there was no difference for the expression of 11β-HSD2, GR, and H6PDH mRNA between the 2 groups. The stepwise multiple linear regression analysis showed that the mRNA level of 11β-HSD1 was positively correlated to the concentration of the serum tumor necrosis factor-alpha (TNF-α). Expression of 11β-HSD1 mRNA was increased in the SAT from the women with PCOS, which may contribute to the increased local active glucocorticoids (cortisol), and subsequently affects the secretion of the local adipose tissue., (© Georg Thieme Verlag KG Stuttgart · New York.)

The present study was investigated whether increasing amounts of glucose supply have a stimulatory effect on the mRNA abundance and activity of key lipogenic enzymes in adipose tissue of midlactation dairy cows. Twelve Holstein-Friesian dairy cows in midlactation were cannulated in the jugular vein and infused with either a 40% glucose solution (n=6) or saline (n=6). For glucose infusion cows, the infusion dose increased by 1.25%/d relative to the initial net energy for lactation (NEL) requirement until a maximum dose equating to a surplus of 30% NEL was reached on d 24. This maximum dose was maintained until d 28 and stopped thereafter (between d 29-32). Cows in the saline infusion group received an equivalent volume of 0.9% saline solution. Samples of subcutaneous adipose tissue were taken on d 0, 8, 16, 24, and 32 when surplus glucose reached 0, 10, 20, and 30% of the NEL requirement, respectively. The mRNA abundance of fatty acid synthase, cytoplasmic acetyl-coenzyme A synthetase, cytoplasmic glycerol 3-phosphate dehydrogenase-1, and glucose 6-phosphate dehydrogenase showed linear treatment × dose interactions with increasing mRNA abundance with increasing glucose dose. The increased mRNA abundance was paralleled by a linear treatment × dose interaction for fatty acid synthase and acetyl-coenzyme A synthetase enzymatic activities. The mRNA abundance of ATP-citrate lyase showed a tendency for linear treatment × dose interaction with increasing mRNA abundance with increasing glucose dose. The mRNA abundance of all tested enzymes, as well as the activities of fatty acid synthase and acetyl-coenzyme A synthetase, correlated with plasma glucose and serum insulin levels. In a multiple regression model, the predictive value of insulin was dominant over that of glucose. In conclusion, gradual increases in glucose supply upregulate key lipogenic enzymes in adipose tissue of midlactating dairy cows with linear dose dependency. Insulin appears to be critically involved in this regulation., (Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is involved in the pathogenesis of type 2 diabetes by generating active glucocorticoids (cortisol and corticosterone) that are strong inhibitors of angiogenesis. However, the mechanism of 11β-HSD1 gene expression and its relationship to adipose angiogenesis are largely unknown. To address this issue, we examined 11β-HSD1 expression in visceral and subcutaneous adipose tissue (AT) of diet-induced obese (DIO) mice during weight gain and investigated the gene regulation by hypoxia in vitro. 11β-HSD1 mRNA was reduced in the adipose tissues during weight gain in DIO mice, and the reduction was associated with an elevated expression of angiogenic factors. In vitro, 11β-HSD1 expression was induced in mRNA and protein by hypoxia. Of the two transcription factors activated by hypoxia, the nuclear factor-κB (NF-κB) enhanced but the hypoxia inducible factor-1α (HIF-1α) reduced 11β-HSD1 expression. 11β-HSD1 expression was elevated by NF-κB in epididymal fat of aP2-p65 mice. The hypoxia-induced 11β-HSD1 expression was attenuated by NF-κB inactivation in p65-deficient cells but enhanced by HIF-1 inactivation in HIF-1α-null cells. These data suggest that 11β-HSD1 expression is upregulated by NF-κB and downregulated by HIF-1α. During AT expansion in DIO mice, the reduction of 11β-HSD1 expression may reflect a dominant HIF-1α activity in the adipose tissue. This study suggests that NF-κB may mediate the inflammatory cytokine signal to upregulate 11β-HSD1 expression.

Adipose metabolism is an essential contributor to the efficiency of milk production, and metabolism is controlled by several mechanisms, including gene expression of critical proteins; therefore, the objective of this study was to determine how lactational state and the genetic merit of dairy cattle affects adipose tissue (AT) metabolism and mRNA expression of genes known to control metabolism. Animals of high (HGM) and low genetic merit (LGM) were fed to requirements, and weekly dry matter intake, milk production, blood glucose, and nonesterified fatty acids were measured. Subcutaneous AT biopsies were collected at -21, 7, 28 and 56 d in milk (DIM). The mRNA expression of genes coding for lipogenic enzymes [phosphoenolpyruvate carboxykinase 1 (soluble) (PCK1), fatty acid synthase (FASN), diacylglycerol O-acyltransferase 2 (DGAT2), and stearoyl-coenzyme A desaturase (SCD)], transcription regulators [peroxisome proliferator-activated receptor γ (PPARG), thyroid hormone responsive (THRSP), wingless-type MMTV integration site family, member 10B (WNT10B), sterol regulatory element binding transcription factor 1 (SREBF1), and adiponectin (ADIPOQ)], lipolytic enzymes [hormone-sensitive lipase (LIPE), patatin-like phospholipase domain containing 2 (PNPLA2), monoglyceride lipase (MGLL), adrenoceptor β-2 (ADRB2), adipose differentiation-related protein (ADFP), and α-β-hydrolase domain containing 5 (ABHD5)], and genes controlling the sensing of intracellular energy [phosphodiesterase 3A (PDE3A); PDE3B; protein kinase, AMP-activated, α-1 catalytic subunit (PRKAA1); PRKAA2; and growth hormone receptor (GHR)] was measured. Dry matter intake, blood glucose, and nonesterified fatty acid concentrations did not differ between genetic merit groups. Milk production was greater for HGM cows from 6 to 8 wk postpartum. As expected, the rates of lipogenesis decreased in early lactation, whereas stimulated lipolysis increased. At 7 DIM, lipogenesis in HGM cows increased as a function of substrate availability (0.5, 1, 2, 3, 4, or 8mM acetic acid), whereas the response in LGM cows was much less pronounced. However, the lipogenic response at 28 DIM reversed and rates were greater in tissue from LGM than HGM cows. Peak lipolytic response, regardless of DIM, was observed at the lowest dose of isoproterenol (10(-8)M), and -21 d tissue had a greater lipolysis rate than tissue at 7, 28, and 56 d. In HGM compared with LGM cows, stimulated lipolysis at 7 and 28 DIM was greater but peaked at 10(-7)M isoproterenol, suggesting differences in tissue responsiveness due to genetic merit. Regardless of genetic merit, the expression of lipogenic genes decreased markedly in early lactation, whereas those controlling lipolysis stayed similar or decreased slightly. Cows of HGM had lower expression of lipogenic genes after parturition and through 56 DIM. In contrast, the expression of most of the lipolytic enzymes, receptors and proteins was similar in all cows pre- and postpartum. These results confirm that gene transcription is a major control mechanism for AT lipogenesis during early lactation, but that control of lipolysis is likely primarily by posttranslational mechanisms., (Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Ghrelin is a potent orexigenic brain-gut peptide with lipogenic and diabetogenic effects, possibly mediated by growth hormone secretagogue receptor (GHS-R1a). Cannabinoids also have orexigenic and lipogenic effects. AMPK is a regulator of energy homeostasis and we have previously shown that ghrelin and cannabinoids stimulate hypothalamic AMPK activity while inhibiting it in the liver and adipose tissue, suggesting that AMPK mediates both the central appetite-inducing and peripheral effects of ghrelin and cannabinoids., Aims: Using GHS-R KO mice, we investigated whether the known ghrelin receptor GHS-R1a is required for the tissue-specific effects of ghrelin on AMPK activity, and if an intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity., Methods: Wild-type and GHS-R KO mice were treated intraperitoneally with ghrelin 500 ng/g bodyweight or CB1 agonist HU210 20 ng/g and hypothalamic, hepatic and adipose AMPK activity was studied using a functional kinase assay., Results: Ghrelin and HU210 significantly stimulated hypothalamic AMPK activity in wild-type animals (mean±SEM, 122.5±5.2% and 128±11.6% of control, p<0.05) and inhibited it in liver (55.1±4.8% and 62.2±14.5%, p<0.01) and visceral fat (mesenteric fat (MF): 54.6±16% and 52.0±9.3%, p<0.05; epididymal fat (EF): 47.9±12.1% and 45.6±1.7%, p<0.05). The effects of ghrelin, and interestingly also HU210, on hypothalamic, visceral fat and liver AMPK activity were abolished in the GHS-R KO mice (hypothalamus: 107.9±7.7% and 87.4±13.3%, liver: 100.5±11.6% and 116.7±5.4%, MF: 132.1±29.9% and 107.1±32.7%, EF: 89.8±7.3% and 91.7±18.3%, p>0.05)., Conclusions: Ghrelin requires GHS-R1a for its effect on hypothalamic, liver and adipose tissue AMPK activity. An intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Since renal replacement therapy has started to be a routine procedure in chronic kidney disease (CKD), patients no longer die of end-stage renal disease (ESRD). Today, patients with CKD live longer and the most important causes of morbidity and mortality in this group are cardiovascular events. Lipid abnormalities, such as hypertriglyceridemia (HT), are an important factor of high cardiovascular risk in this group. It is known that HT is partially caused by inhibition of lipolysis, but it is also postulated that increased lipogenesis is another cause of HT. Previous studies performed in our center has provided evidence that lipogenesis is increased in the animal model of ESRD. , Objectives: The aim of this study was to investigate the activities of lipogenic enzymes in the subcutaneous white adipose tissue in patients with CKD., Patients and Methods: The study was performed on 36 patients (17 women and 19 men). Patients with ESRD were divided into 2 groups: patients on conservative treatment in the prehemodialysis period (pre‑HD group, n = 18) and patients on maintenance hemodialysis (HD group, n = 18). The control group consisted of 22 patients without ESRD. The activities of lipogenic enzymes in the subcutaneous white adipose tissue (fatty acid synthase, adenosine triphosphate citrate lyase, malic enzyme, glucose‑6‑phosphate dehydrogenase, and 6‑phosphogluconate dehydrogenase) were assessed by spectrophotometry. , Results: There were no statistically significant differences in the activities of lipogenic enzymes in a fat tissue sample between patients with ESRD and the control group., Conclusions: The results did not confirm increased lipogenesis in patients with ESRD.

Background/aims: Cytosolic glycerol 3-phosphate dehydrogenase (cGPDH) is a key enzyme providing glycerol 3-phosphate for triacylglycerol synthesis in adipose tissue and is regarded as a marker for adipocyte differentiation. The aim of this study was to test the hypothesis that an increase in cGPDH gene expression in subcutaneous adipose tissue is associated with obesity., Methods: mRNA levels in human subcutaneous adipose tissue were analysed by Real-Time PCR., Results: We found that human subcutaneous adipose tissue cGPDH activity and cGPDH mRNA level were greater in obese patients than in lean subjects and were positively correlated with BMI and fat mass. Moreover, a strong positive correlation between subcutaneous adipose tissue cGPDH mRNA level and cGPDH activity was found. The data presented here indicates also that PPARγ mRNA level is positively correlated with body mass index and fat mass as well as with adipose tissue cGPDH mRNA level. Moreover, the association between subcutaneous adipose tissue cGPDH mRNA level and fatty acid translocase (FAT/CD36) mRNA level was also observed., Conclusion: The obtained results suggest that in comparison to lean subjects the increase in subcutaneous adipose tissue cGPDH gene expression in the obese, is probably the result of adipose tissue expansion during obesity., (Copyright © 2013 S. Karger AG, Basel.)

Study Background: Insulin resistance plays an important role in the pathogenesis of type 2 diabetes and the metabolic syndrome. Many of the genes and pathways involved have been identified but some remain to be defined. Metallothioneins (Mts) are a family of anti-oxidant proteins and metallothionein 2a (Mt2a) polymorphims have been recently associated with type 2 diabetes and related complications. Our objective was to determine the Mt2a gene expression levels in adipose tissues from diabetic patients and the effect of Mt treatment on adipocyte insulin sensitivity., Methods: Samples of subcutaneous and visceral adipose tissues from lean, type 2 diabetic and non-diabetic obese patients were analysed using RT-qPCR for Mt2a mRNA abundance. The regulation of Mt2a expression was further studied in 3T3-L1 adipocytes treated or not with TNFα (10 ng/ml, 72 h) to induce insulin resistance. The effects of Mt on glucose uptake were investigated in cultured adipocytes treated with recombinant Mt protein., Results: We found that the Mt2a gene expression was significantly higher in adipose tissue of type 2 diabetic patients in comparison to that of lean (p=0.003) subjects. In 3T3-L1 adipocytes, insulin resistance induced by TNFα increased Mt2a mRNA levels (p=3×10(-4)) and insulin-stimulated glucose uptake was significantly inhibited by 53% (p=8×10(-4)) compared to vehicle, when 3T3-L1 adipocytes were treated with Mt protein., Conclusions: These data suggest that Mt2a might be involved in insulin resistance through the up-regulation of Mt gene expression, which may lead to the modulation of insulin action in fat cells. These results suggest the concept of considering Mt proteins as markers and potential targets in type 2 diabetes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Visceral fat deposition and its associated atherogenic complications are mediated by glucocorticoids. Cardiac visceral fat comprises mediastinal adipose tissue (MAT) and epicardial adipose tissue (EAT), and MAT is a potential biomarker of risk for obese patients., Aim: Our objective was to evaluate the role of EAT and MAT 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and glucocorticoid receptor (GCR) expression in comparison with subcutaneous adipose tissue (SAT) in the development of coronary atherosclerosis in obese patients with coronary artery disease (CAD), and to assess their correlations with CD68 and fatty acids from these tissues., Methods and Results: Expression of 11β-HSD-1 and GCR was measured by qRT-PCR in EAT, MAT and SAT of thirty-one obese patients undergoing coronary artery bypass grafting due to CAD (obese CAD group) and sixteen obese patients without CAD undergoing heart valve surgery (controls). 11β-HSD-1 and GCR expression in MAT were found to be significantly increased in the obese CAD group compared with controls (p < 0.05). In the obese CAD group, 11β-HSD-1 and GCR mRNA levels were strongly correlated in MAT. Stearidonic acid was significantly increased in EAT and MAT of the obese CAD group and arachidonic acid was significantly expressed in MAT of the obese male CAD group (p < 0.05)., Conclusions: We report for the first time the increased expression of 11β-HSD-1 and GCR in MAT compared with EAT and SAT, and also describe the interrelated effects of stearidonic acid, HOMA-IR, plasma cortisol and GCR mRNA levels, explaining 40.2% of the variance in 11β-HSD-1 mRNA levels in MAT of obese CAD patients. These findings support the hypothesis that MAT contributes locally to the development of coronary atherosclerosis via glucocorticoid action.

Background: Inflammation and increased ceramide concentrations characterise adipose tissue of obese women with high liver fat content compared to equally obese women with normal liver fat content. The present study characterises enzymes involved in ceramide metabolism in subcutaneous and intra-abdominal adipose tissue., Methods: Pathways leading to increased ceramide concentrations in inflamed versus non-inflamed adipose tissue were investigated by quantifying expression levels of key enzymes involved in ceramide metabolism. Sphingomyelinases (sphingomyelin phosphodiesterases SMPD1-3) were investigated further using immunohistochemistry to establish their location within adipose tissue, and their mRNA expression levels were determined in subcutaneous and intra-abdominal adipose tissue from both non-obese and obese subject., Results: Gene expression levels of sphingomyelinases, enzymes that hydrolyse sphingomyelin to ceramide, rather than enzymes involved in de novo ceramide synthesis, were higher in inflamed compared to non-inflamed adipose tissue of obese women (with high and normal liver fat contents respectively). Sphingomyelinases were localised to both macrophages and adipocytes, but also to blood vessels and to extracellular regions surrounding vessels within adipose tissue. Expression levels of SMPD3 mRNA correlated significantly with concentrations of different ceramides and sphingomyelins. In both non-obese and obese subjects SMPD3 mRNA levels were higher in the more inflamed intra-abdominal compared to the subcutaneous adipose tissue depot., Conclusions: Generation of ceramides within adipose tissue as a result of sphingomyelinase action may contribute to inflammation in human adipose tissue.

Endothelial lipase (EL), a member of the triglyceride lipase gene family, has been shown to be a key player in HDL metabolism. Northern blots revealed that EL was highly expressed in endothelium, thyroid, lung, placenta, liver, and testis. In liver and adrenal gland, EL protein was localized with vascular endothelial cells but not parenchymal cells. EL was shown to be upregulated in tissues such as atherosclerotic plaque where it was located in macrophages, endothelial cells, and medial smooth muscle cells. The purpose of this study was to investigate the cellular localization of EL in thyroid and other tissues where EL is known to be expressed. Besides its presence in vascular endothelial and smooth muscle cells, EL protein was detected in the epithelial cells that line the follicles within the thyroid gland. EL-specific immunostaining was also found near the cell surface as well as in the cytoplasm of adipocytes. Using immunoblots, EL expression was confirmed in cultured human omental and subcutaneous adipocytes. EL expression, however, was not found in preadipocytes. These findings suggest that EL plays a role in thyroid and adipocyte biology in addition to its well-known role in endothelial function and HDL metabolism.

Objective: To investigate total and promoter expression of aromatase in subcutaneous and omental (visceral) fat and compare this expression in pregnant and obese women., Design: Cross-sectional study., Setting: Academic hospital., Patient(s): Six women undergoing elective cesarean section and three women undergoing bariatric surgery., Intervention(s): Subcutaneous and omental fat obtained during surgery., Main Outcome Measure(s): Total aromatase and promoter expression was measured by polymerase chain reaction and protein levels by Western blotting., Result(s): Total aromatase expression was significantly higher in omental compared with subcutaneous fat from pregnant women; this pattern was reversed in obese women. Aromatase messenger RNA in omentum was significantly higher in pregnancy than obesity, and this was linked to an up-regulation of promoter II (PII). Promoter 1.4 (P1.4) expression was lower than PII, and there was no difference in P1.4 expression between the two fat depots from pregnant subjects. In obese women both P1.4 and PII were up-regulated in subcutaneous compared with omental depots, with P1.4 expression greater than that of PII. Aromatase protein levels were extremely low in fat depots of pregnant women and undetectable in obese women., Conclusion(s): There are differences between total aromatase and promoter expression in subcutaneous and omental fat from pregnant compared with obese women. These differences support the evidence that the fat depots are derived from different cell lineages and that the promoter-derived aromatase translation varies according to physiologic/pathophysiologic status., (Copyright © 2012 American Society for Reproductive Medicine. All rights reserved.)

Background: Nicotinamide phosphoribosyltransferase (NAMPT)/visfatin is a widely expressed protein with various effects on glucose and lipid metabolism, cell survival, and inflammation., Aim: We hypothesized that NAMPT was related to metabolic disturbances in active acromegaly., Methods: Body composition, glucose metabolism, and NAMPT levels were measured in 47 patients with active, untreated acromegaly and 24 age-, sex-, and body mass index-matched controls. The in vitro effects of GH/IGF-I on NAMPT expression in human sc adipocytes (SCA), visceral adipocytes, osteoblasts, and hepatocytes were studied. The effects of overnight incubation with the highly specific NAMPT inhibitor FK866 on the GH-stimulated monocyte chemotactic protein-1 and IL-6 expression in mature SCA were evaluated., Results: NAMPT was increased in active acromegaly (P = 0.004) and correlated negatively with limb (arms + legs) fat percentage (% fat, r = -0.32; P = 0.032). After adjusting for age, gender, leptin, and GH, the circulating NAMPT correlated negatively with limb and total body fat percentage (% fat limbs, r = -0.43, P = 0.006; % fat total body, r = -0.36, P = 0.022) and correlated positively with limb and total body lean percentage (% lean limbs, r = 0.31, P = 0.047; % lean total body, r = 0.33, P = 0.034). No correlation between NAMPT and glucose metabolic parameters was found. In vitro studies revealed that GH increased NAMPT expression in adipocytes. The inhibition of NAMPT enzymatic activity attenuated GH-induced monocyte chemotactic protein-1 expression in SCA., Conclusions: NAMPT is increased in active acromegaly and may be an inflammatory mediator that causes monocyte infiltration in adipose tissue.

Context: The pathogenesis and function of dorsocervical sc adipose tissue (DSAT) accumulation in HIV-infected patients is not known. Previous investigations using either UCP-1 expression or positron emission tomography have been inconclusive as to whether this depot represents brown adipose tissue (BAT). We investigated DSAT gene expression, including DIO2, a deiodinase that contributes to increased thermogenesis in brown fat, and simultaneously determined [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) uptake in lipodystrophic HIV and healthy control subjects., Design: Thirteen HIV-infected and three non-HIV-infected men were recruited. HIV-infected subjects had evidence of significant lipodystrophy, including fat atrophy of the face, arms, and legs, and/or fat accumulation of the neck and abdomen. Subjects were cooled, followed by [¹⁸F]FDG positron emission tomography/computed tomography, fat biopsy of DSAT, and measurement of resting energy expenditure (REE). HIV-infected subjects were characterized as lipohypertrophic and lipoatrophic and compared., Results: Mean standardized uptake value of [¹⁸F]FDG and UCP-1 expression were not significantly different in DSAT among the groups. However, lipohypertrophic subjects demonstrated increased expression of DIO2 in DSAT compared with lipoatrophic subjects (P = 0.03). Among HIV-infected patients, DIO2 expression was strongly related to REE (r = 0.78, P = 0.002) and was a predictor of REE in multivariate modeling controlling for age, TSH, and lean body mass (r² = 0.79, P = 0.008). One control subject demonstrated typical BAT in the supraclavicular area., Conclusions: Adipose tissue accumulating in the dorsocervical area in HIV lipodystrophy does not appear to be classical BAT. However, DIO2 expression is increased in DSAT among patients with HIV lipodystrophy, particularly those with increased visceral adiposity, and is positively associated with energy expenditure.