Visceral Adipose Tissue Expansion Research Articles

Visceral Adipose Tissue: The Hidden Culprit for Type 2 Diabetes.

Type 2 diabetes (T2D) is a chronic metabolic disorder characterized by insulin resistance in various tissues. Though conventionally associated with obesity, current research indicates that visceral adipose tissue (VAT) is the leading determining factor, wielding more influence regardless of individual body mass. The heightened metabolic activity of VAT encourages the circulation of free fatty acid (FFA) molecules, which induce insulin resistance in surrounding tissues. Individuals most vulnerable to this preferential fat deposition are older males with ancestral ties to Asian countries because genetics and sex hormones are pivotal factors for VAT accumulation. However, interventions in one's diet and lifestyle have the potential to strategically discourage the growth of VAT. This illuminates the possibility that the expansion of VAT and, subsequently, the risk of T2D development are preventable. Therefore, by reducing the amount of VAT accumulated in an individual and preventing it from building up, one can effectively control and prevent the development of T2D.

Visceral adipose tissue triggers tau pathogenesis in transgenic mice

AbstractBackgroundAlzheimer’s disease (AD) is a complex disorder and multiple cellular and molecular mechanisms are involved in AD onset and progression. Recent evidences have suggested that metabolic alterations are an important pathological feature in disease progression in AD. Likewise, diabetes and obesity, two mayor metabolic illnesses, are risk factors for AD. These two overwhelming diseases are associated with a significant expansion of visceral adipose tissue. Here, we hypothesize that the visceral adipose tissue may serve as a key communicator organ between the brain and peripheral metabolic illnesses and affecting both types of disorders.MethodWe used histological stains, immunohistochemistry and biochemical means to determine changes in the visceral adipose tissue from WT and db/db mice. Moreover, similar techniques were used in 3xTg‐AD mice that received white fat pads from WT and db/db donors to determine any changes in amyloid and tau pathology.ResultOur study shows that recipient 3xTg‐AD mice from db/db fat pads mice develop profound changes in tau pathology due to increased CDK5 expression compared to 3xTg‐AD mice that received fad pads from WT mice. This increment in tau level was associated with elevated levels in IL‐1β and profound microglia activation. Moreover, we found the opposite effect on amyloid pathology, in which insoluble Aβ levels and Thioflavin positive plaques were reduced in recipient 3xTg‐AD mice from db/db fat pads compared to 3xTg‐AD mice that received fad pads from WT mice. These reduction in Aβ levels were correlated with an increment in microglia phagocytic capacity.ConclusionOverall, our study demonstrate a novel important crosstalk between Alzheimer´s disease and obesity/diabetes type II through visceral adipose cells and a differential effect on tau and Aβ pathology mediated by an activated immune response.This study was supported by Minister of Science and Innovation grant PID2019‐108911RA‐100 (D.B.V.), Alzheimer’s Association grant AARG‐22‐9282/9, Beatriz Galindo program BAGAL18/00052 (D.B.V.), University of Malaga grant PPIT.UMA.B1‐2021_32(LTE) and Institute of Health Carlos III (ISCiii) grant PI18/01557 (A.G.) co‐financed by FEDER funds from European Union.

CX3CR1hi macrophages sustain metabolic adaptation by relieving adipose-derived stem cell senescence in visceral adipose tissue

Adipose-derived stem cells (ASCs) drive healthy visceral adipose tissue (VAT) expansion via adipocyte hyperplasia. Obesity induces ASC senescence that causes VAT dysfunction and metabolic disorders. It is challenging to restrain this process by biological intervention, as mechanisms of controlling VAT ASC senescence remain unclear. We demonstrate that a population of CX3CR1hi macrophages is maintained in mouse VAT during short-term energy surplus, which sustains ASCs by restraining their senescence, driving adaptive VAT expansion and metabolic health. Long-term overnutrition induces diminishment of CX3CR1hi macrophages in mouse VAT accompanied by ASC senescence and exhaustion, while transferring CX3CR1hi macrophages restores ASC reservoir and triggers VAT beiging to alleviate the metabolic maladaptation. Mechanistically, visceral ASCs attract macrophages via MCP-1 and shape their CX3CR1hi phenotype via exosomes; these macrophages relieve ASC senescence by promoting the arginase1-eIF5A hypusination axis. These findings identify VAT CX3CR1hi macrophages as ASC supporters and unravel their therapeutic potential for metabolic maladaptation to obesity.

Identification of major hub genes involved in high-fat diet-induced obese visceral adipose tissue based on bioinformatics approach

ABSTRACT High-fat diet (HFD) can cause obesity, inducing dysregulation of the visceral adipose tissue (VAT). This study aimed to explore potential biological pathways and hub genes involved in obese VAT, and for that, bioinformatic analysis of multiple datasets was performed. The expression profiles (GSE30247, GSE167311 and GSE79434) were downloaded from Gene Expression Omnibus. Overlapping differentially expressed genes (ODEGs) between normal diet and HFD groups in GSE30247 and GSE167311 were selected to run protein–protein interaction network, GO and KEGG analysis. The hub genes in ODEGs were screened by Cytoscape software and further verified in GSE79434 and obese mouse model. A total of 747 ODEGs (599 up-regulated and 148 down-regulated) were screened, and the GO and KEGG analysis showed that the up-regulated ODEGs were significantly enriched in inflammatory response and extracellular matrix receptor interaction pathways. On the other hand, the down-regulated ODEGs were involved in metabolic pathways; however, there were no significant KEGG pathways. Furthermore, six hub genes, Mki67, Rac2, Itgb2, Emr1, Tyrobp and Csf1r were acquired. These pathways and genes were verified in GSE79434 and VAT of obese mice. This study revealed that HFD induced VAT expansion, inflammation and fibrosis, and the hub genes could be used as therapeutic biomarkers in obesity.

Angiotensin(1–7) attenuates visceral adipose tissue expansion and lipogenesis by suppression of endoplasmic reticulum stress via Mas receptor

BackgroundWhite adipose tissue can be classified based on its location as subcutaneous and visceral fat, and the latter accumulation is reported to be more detrimental to metabolism. Endoplasmic reticulum (ER) stress has been demonstrated to regulate lipogenesis. The peptide angiotensin(1–7) [Ang(1–7)], which can be produced from angiotensin II (AngII) by angiotensin-converting enzyme 2 (ACE2), plays its role through Mas receptor, also participates in the regulation of lipid metabolism in adipose tissue, however, whether ER stress is involved in the mechanism remains unclear. Therefore, we aimed to explore the role of Ang(1–7) pathway in regulating visceral adipose tissue expansion and ER stress.MethodsACE2 knockout (KO), Mas KO and C57BL/6 J mice were fed with high fat diet. Db/db mice were treated with either normal saline, Ang(1–7) or Ang(1–7) combined with Mas receptor inhibitor A779 using mini osmotic pumps. Fat mass was weighted, fat distribution was evaluated by MRI, and lipid profile and adipokines in epididymal adipose tissue were measured by ELISA kits, and histology of epididymal adipose tissue was also analyzed in multiple animal models. Additionally, differentiated 3T3-L1 cells were pre-loaded with palmitic acid to induce ER stress, then treated with drugs as those administrated to db/db mice. ER stress and lipogenesis related proteins in mice adipose and differentiated 3T3L-1 cells were analyzed by Western blot.ResultsACE2 or Mas KO mice exhibited increased visceral adipose tissue, adipocyte size and protein expression of lipogenesis and ER stress related markers in epididymal adipose tissue compared to wild-type mice. Db/db mice treated with Ang(1–7) displayed decreased visceral fat mass, adipocyte size and protein expression of lipogenesis and ER stress markers in epididymal adipose tissue compared to those treated with normal saline, while A779 partly attenuated these effects. Additionally, Ang(1–7) improved ER stress and lipogenesis markers in differentiated 3T3-L1 cells pre-loaded with palmitic acid.ConclusionsOur findings indicated that Ang(1–7) attenuated visceral adipose tissue expansion and lipogenesis by suppression of ER stress via Mas receptor. The present study provides a potential perspective for Ang(1–7) for the therapeutics of obesity and related disorders.

Effects of ACTH-Induced Long-Term Hypercortisolism on the Transcriptome of Canine Visceral Adipose Tissue.

Cushing’s syndrome, or hypercortisolism (HC), a common endocrinopathy in adult dogs, is caused by chronic hypercortisolemia. Among different metabolic disorders, this syndrome is associated with enhanced subcutaneous lipolysis and visceral adiposity. However, effects of HC in adipose tissue, especially regarding visceral adipose tissue (VAT), are still poorly understood. Herein, the transcriptomic effects of chronic HC on VAT of dogs were evaluated. For this, subcutaneously implanted ACTH-releasing pumps were used, followed by deep RNA sequencing of the canine VAT. Prolonged HC seems to affect a plethora of regulatory mechanisms in VAT of treated dogs, with 1190 differentially expressed genes (DEGs, p and FDR < 0.01) being found. The 691 downregulated DEGs were mostly associated with functional terms like cell adhesion and migration, intracellular signaling, immune response, extracellular matrix and angiogenesis. Treatment also appeared to modulate local glucocorticoid and insulin signaling and hormonal sensitivity, and several factors, e.g., TIMP4, FGF1, CCR2, CXCR4 and HSD11B1/2, were identified as possible important players in the glucocorticoid-related expansion of VAT. Modulation of their function during chronic HC might present interesting targets for further clinical studies. Similarities in the effects of chronic HC on VAT of dogs and humans are highlighted.

Vasodilator Dysfunction in Human Obesity: Established and Emerging Mechanisms.

Human obesity is associated with insulin resistance and often results in a number of metabolic abnormalities and cardiovascular complications. Over the past decades, substantial advances in the understanding of the cellular and molecular pathophysiological pathways underlying the obesity-related vascular dysfunction have facilitated better identification of several players participating in this abnormality. However, the complex interplay between the disparate mechanisms involved has not yet been fully elucidated. Moreover, in medical practice, the clinical syndromes stemming from obesity-related vascular dysfunction still carry a substantial burden of morbidity and mortality; thus, early identification and personalized clinical management seem of the essence. Here, we will initially describe the alterations of intravascular homeostatic mechanisms occurring in arteries of obese patients. Then, we will briefly enumerate those recognized causative factors of obesity-related vasodilator dysfunction, such as vascular insulin resistance, lipotoxicity, visceral adipose tissue expansion, and perivascular adipose tissue abnormalities; next, we will discuss in greater detail some emerging pathophysiological mechanisms, including skeletal muscle inflammation, signals from gut microbiome, and the role of extracellular vesicles and microRNAs. Finally, it will touch on some gaps in knowledge, as well as some current acquisitions for specific treatment regimens, such as glucagon-like peptide-1 enhancers and sodium-glucose transporter2 inhibitors, that could arrest or slow the progression of this abnormality full of unwanted consequences.

LMO3 reprograms visceral adipocyte metabolism during obesity

Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. We recently identified LIM domain only 3 (LMO3) in human mature visceral adipocytes; however, its function in these cells is currently unknown. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high-fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics, as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain or loss of LMO3 expression, respectively. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. LMO3 expression in eWAT significantly improved insulin sensitivity and healthy visceral adipose tissue expansion in diet-induced obesity, paralleled by increased serum adiponectin. In vitro, LMO3 expression in 3T3-L1 adipocytes increased PPARγ transcriptional activity, insulin-stimulated GLUT4 translocation and glucose uptake, as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. Mechanistically, LMO3 induced the PPARγ coregulator Ncoa1, which was required for LMO3 to enhance glucose uptake and mitochondrial oxidative gene expression. In human mature adipocytes, LMO3 overexpression promoted, while silencing of LMO3 suppressed mitochondrial oxidative capacity. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose metabolism, insulin sensitivity, mitochondrial function, and adiponectin secretion. Together with increased PPARγ activity and Ncoa1 expression, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity.Key messagesLMO3 increases beneficial visceral adipose tissue expansion and insulin sensitivity in vivo.LMO3 increases glucose uptake and oxidative mitochondrial activity in adipocytes.LMO3 increases nuclear coactivator 1 (Ncoa1).LMO3-enhanced glucose uptake and mitochondrial gene expression requires Ncoa1.

Lineage‐tracing Reveals Multiple Roles of Tcf21 Lineage Cells in the Development and Expansion of Visceral Adipose Tissue

The specific correlation between visceral adipose tissue (VAT) and insulin resistance makes VAT a potential target for treating type 2 diabetes. Recent studies have shown that Tcf21, a basic helix-loop-helix transcription factor, is expressed in VAT but not in subcutaneous AT (SAT). Thus, we hypothesized that cells expressing Tcf21 played a critical role in VAT. Using tamoxifen-inducible Tcf21 lineage-tracing mouse lines, we identified that Tcf21 was exclusively expressed in progenitor cells in VAT but not those in SAT. Lineage-tracing showed that most Tcf21 lineage progenitor cells also express Pdgfra, a marker of mesenchymal stem cell. Tcf21 expression was abolished upon adipogenic differentiation. Tcf21 lineage-tracing induced at embryonic day 11.2 (E11.5) revealed that progenitor cells of Tcf21 lineage give rise to all visceral adipocytes. Tamoxifen treatment during postnatal days 2-4 (P2-4) lineage-traced ~40% adipocytes in epididymal VAT (eVAT) at weaning, indicating high adipogenic activity in VAT during the neonatal stage. EdU assay showed that Tcf21 lineage-traced cells actively proliferated during the first 2 weeks after birth followed by a phase of robust adipogenic differentiation between P14 and P21. Tcf21 lineage-tracing induced at 6 weeks of age only labeled less than 1% of adipocytes in eVAT of mice after 12 weeks of high-fat diet (HFD) treatment regardless of a significant expansion of Tcf21 lineage-traced cells, indicating that Tcf21 lineage cells in adult mice were less adipogenic in vivo. In addition, it was found Tcf21 lineage cells also gave rise to a small portion of vascular smooth muscle cells (VSMCs). However, these cells lacked the expression of PDGFRα. RNA-seq analysis of Tcf21 lineage-traced PDGFRα+ cells isolated from mice at different developmental and growth stages showed distinct gene expression profiles. Proliferation genes were highly active in Tcf21 lineage cells at P12, while genes associated with adipogenic differentiation were more active at P12 and P21. Interestingly, some inflammatory genes that are commonly expressed in inflammatory cells were highly enriched in Tcf21 lineage cells isolated from mice after long-term HFD treatment. Single-cell RNA-seq of Tcf21 lineage-traced cells isolated from mice of different ages showed that the gene expression of individual cells became increasingly diverse as the age of the mice increased. Single-cell RNA-seq analysis confirmed the presence of a small subpopulation of Tcf21 lineage-traced VSMCs as well as a Tcf21 lineage-traced inflammatory cell subpopulation that was exclusive to HFD-treated mice. IHC staining showed that Tcf21 lineage-traced inflammatory cells were located in crown-like structures and might play a role in inflammation and phagocytosis. Several additional subpopulations of Tcf21 lineage-traced cells were also identified and are currently being investigated. Our study clearly showed the critical roles of Tcf21 lineage cells in the growth and development of VAT as well as in the development of VAT inflammation in obese mice.

Recent data on adipose tissue, insulin resistance, diabetes and dyslipidaemia in antiretroviral therapy controlled HIV-infected persons.

Increased total body fat with truncal redistribution is common in antiretroviral therapy (ART)-controlled persons living with HIV(PLWH), leading to insulin resistance, prediabetes/diabetes and dyslipidaemia. We address these topics here. Most antiretrovirals are associated with gain in trunk fat, including visceral adipose tissue (VAT). Protease-inhibitors could inhibit white fat ability to dissipate energy (i.e. beiging) favouring fat gain. Expansion of VAT is associated with a pro-inflammatory profile linked to the tryptophan-kynurenine pathway and CD4+ subtypes. ART-associated increased adipose tissue (AT) quantity leads to decreased AT density, insulin resistance and dyslipidaemia that could be improved by lifestyle modifications.PLWH present high level of insulin resistance, regardless of their treatment, and a higher prevalence of prediabetes, but not diabetes, than noninfected persons. Otherwise, HbA1c values appear inaccurate to diagnose prediabetes/diabetes in PLWH.ART-related-dyslipidaemia is characterized by elevated LDL-C and/or high triglycerides and reduced HDL-C. Whereas treatment with protease inhibitors generally results in worsened lipid values, treatment with integrase-strand-transfer-inhibitors is associated with a better profile. Tenofovir-alafenamide is associated with higher lipid levels than tenofovir-disoproxil-fumarate. Treatment of LDL-C-dyslipidaemia could benefit, in statin-insufficiently controlled patients, from the class of proprotein-convertase-subtilsin-kenin-type-9 (PCSK-9) inhibitors. Lifestyle modifications are mandatory to reduce fat and improve dysglycaemia/dyslipidaemia. New drugs can efficiently control diabetes and LDL-C-dyslipidaemia.

Reduced SIRT1 and SIRT2 expression promotes adipogenesis of human visceral adipose stem cells and associates with accumulation of visceral fat in human obesity.

The histone deacetylases SIRT1 and SIRT2 have been shown to be involved in the differentiation of rodent adipocyte precursors. In light of the differences in gene expression and metabolic function of visceral (V) and subcutaneous (S) adipose tissue (AT) and their resident cells, the aim of this study was to investigate the role of SIRT1 and SIRT2 in the differentiation of adipose stem cells (ASCs) isolated from SAT and VAT biopsies of nondiabetic obese and nonobese individuals. Human ASCs were isolated from paired SAT and VAT biopsies obtained from 83 nonobese and 92 obese subjects and were differentiated in vitro. Adipogenesis was evaluated by analyzing the lipid deposition using an image processing software, and gene expression by RT-qPCR. SIRT1 and SIRT2 protein expression was modified by using recombinant adenoviral vectors. Visceral but not subcutaneous ASCs from obese subjects showed an intrinsic increase in both adipogenesis and lipid accumulation when compared with ASCs from nonobese subjects, and this was associated with reduced SIRT1 and SIRT2 mRNA and protein levels. Moreover, adipose tissue mRNA levels of SIRT1 and SIRT2 showed an inverse correlation with BMI in the visceral but not subcutaneous depot. Overexpression of SIRT1 or SIRT2 in visceral ASCs from obese subjects resulted in inhibition of adipocyte differentiation, whereas knockdown of SIRT1 or SIRT2 in visceral ASCs from nonobese subjects enhanced this process. Changes in SIRT1 or SIRT2 expression and adipocyte differentiation were paralleled by corresponding changes in PPARG, CEBPA, and other genes marking terminal adipocyte differentiation. SIRT1 and SIRT2 modulate the differentiation of human ASC. Reduced expression of SIRT1 and SIRT2 may enhance the differentiation capacity of visceral ASC in human obesity, fostering visceral adipose tissue expansion.

1763-P: The Secretome from Visceral Adipose Stem Cells of Obese Subjects Induces Apoptosis and Insulin Resistance in Cardiac Progenitor Cells

Increased abdominal visceral adipose tissue (VAT) is associated with cardiovascular risk in metabolically unhealthy subjects. The viability of cardiac progenitor cells (CPC) is essential for myocardial tissue turnover. This study aimed to assess whether the secretome of visceral adipose stem cells (ASC) and ASC-derived mature adipocytes may affect the viability and insulin signaling of CPC in human obesity. ASC were isolated from VAT biopsies of nondiabetic subjects with varying levels of BMI and used before and after differentiation into adipocytes in vitro. CPC isolated from right auricle biopsies of healthy non-obese subjects were exposed or not to conditioned media (CM) of ASC or ASC-derived adipocytes. Apoptosis was assessed by caspase-3 cleavage and ELISA for oligonucleosomes, and insulin signaling by immunoblotting analysis of Akt Ser473 phosphorylation. The CM of ASC isolated from obese subjects (Ob-ASC) induced CPC apoptosis in a time-dependent manner (4-8-24 h) (p&amp;lt;0.05 vs. control CPC). Moreover, exposure of CPC to CM of Ob-ASC resulted in marked inhibition of insulin-stimulated Akt phosphorylation (p&amp;lt;0.05 vs. control CPC). In contrast, the CM of ASC isolated from non-obese subjects (nOb-ASC) did not induce apoptosis nor impaired insulin signaling (p&amp;gt;0.05 vs. control CPC). Similarly to Ob-ASC, exposure of CPC to the CM of ASC-derived adipocytes from obese subjects also induced apoptosis and inhibited insulin-mediated Akt phosphorylation (p&amp;lt;0.05 vs. control CPC), whereas no effects on apoptosis or insulin signaling were observed when CPC were exposed to CM of ASC-derived adipocytes from non-obese subjects (p&amp;gt;0.05 vs. control CPC). In conclusion, human obesity is associated with the secretion of factors from visceral ASC that impair insulin action in CPC and CPC survival. This property is retained in ASC-derived adipocytes, providing a potential link between expansion of VAT and development of myocardial dysfunction. Disclosure S. Porro: None. S. Perrini: None. C. Caccioppoli: None. R. Doria: None. V. Genchi: None. A. Cignarelli: Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. A. Natalicchio: Other Relationship; Self; Novo Nordisk Inc., Sanofi-Aventis. L. Laviola: Advisory Panel; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc. Board Member; Self; AstraZeneca, Roche Diabetes Care, Sanofi-Aventis. Speaker's Bureau; Self; Medtronic, Mundipharma, Takeda Pharmaceutical Company Limited. F. Giorgino: Advisory Panel; Self; Aegerion Pharmaceuticals, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, MedImmune, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Consultant; Self; Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Pharmaceutical Company Limited. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Sanofi.

Visceral and Ectopic Fat Expansion and the Risk of Incident Type 2 Diabetes Mellitus

Background: Excess visceral adipose tissue (VAT) is associated with an increased risk of prediabetes and type 2 diabetes (T2D) independent of body mass index (BMI). Whether expansion of VAT or other fat depots is associated with diabetes risk independent of weight gain is not fully known. Methods: Among participants without prevalent diabetes or cardiovascular disease enrolled in the Dallas Heart Study, we measured body fat distribution by dual energy x-ray absorptiometry and biomarkers of glycemia at baseline (2000-2002) and repeated 7 years later. The incidence of prediabetes and T2D per ADA definitions were assessed at follow-up. Results: The study included 1661 participants (mean age 44, 58% women, 45% black, 39% obese) with median weight gain of 3.0 (-1.1 to 7.2) kg. Eight percent of participants developed T2D and, among those with normal fasting glucose at baseline (n=1551), 36% developed prediabetes or T2D. Changes in fat depots are shown in the Table. VAT and SAT gain were associated with incident T2D and with prediabetes or T2D independent of traditional risk factors, baseline BMI, change in BMI, and baseline fat depot (Table). Increasing lower body fat was not associated with incident diabetes. Conclusions: Expansion of VAT and SAT are both associated with incident T2D independent of weight gain. Abdominal adiposity may be a modifiable target for diabetes prevention even in the absence of generalized weight loss. Disclosure I.J. Neeland: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Novo Nordisk A/S, National Institute of Diabetes and Digestive and Kidney Diseases. Advisory Panel; Self; Advanced MR Analytics AB. C. Ayers: None. K.V. Patel: None. P.H. Joshi: Consultant; Self; Regeneron Pharmaceuticals, Inc. D.K. McGuire: Consultant; Self; AstraZeneca, Sanofi-Aventis, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Pfizer Inc., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Sanofi-Aventis, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk A/S, Lexicon Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Esperion Therapeutics. S.M. Grundy: None. A. Rohatgi: Research Support; Self; Merck Sharp &amp; Dohme Corp., American Heart Association. Consultant; Self; CSL Behring. Research Support; Self; National Heart, Lung, and Blood Institute. G.L. Vega: None.

Siah2 Expression in Adipocyte Progenitor Cells

Obesity-related insulin resistance is associated with adipose tissue inflammation and visceral adipose tissue expansion via adipocyte hypertrophy and impaired recruitment of new progenitor cells to undergo adipogenesis (hyperplasia). Deletion of the ubiquitin ligase Seven-in-absentia homolog 2 (Siah2) in obese mice significantly reduced adipose tissue inflammation and insulin resistance compared to obese wild type mice. However, larger adipocyte size accompanied this phenotype and subsequent experiments with adipose tissue stromal vascular fraction (SVF) cells showed adipogenesis required Siah2. In an earlier study, we found Siah2 affects adipogenesis by enhancing gene expression of the PPARγ coactivator, Zfp423 via proteasome-dependent degradation of ZFP521, a transcriptional repressor of Zfp423. ZFP423 is an early marker of preadipocyte determination that is expressed in adipocyte progenitor cells. Although Siah2 mediates adipogenesis and is highly expressed in the adipose tissue stromal vascular cell fraction, cell-specific expression of Siah2 in adipose tissue is not well characterized. We found that Siah2 is highly expressed in macrophage. RNA-seq and microarray data from the Immunological Genome Project (Immgen.org) also reported Siah2 expression in lymphocytes. To identify Siah2 expression profile in adipose tissue, unsorted cells and magnetically sorted macrophage, T-cell, B-cell, and SCA-1 positive progenitor cells from mouse adipose tissues SVF were analyzed for Siah2 expression. In parallel, in situ hybridization RNAscope of fat pads was employed to inspect Siah2 mRNA localization in adipose tissue. Since our evidence indicates Siah2 acts upstream of ZFP423, we predict Siah2 is expressed in adipocyte progenitor cells as well as immune cells in adipose tissue. This work will provide the groundwork to better understand how Siah2 controls commitment of progenitor cells to the adipocyte lineage and links obesity to adipose tissue inflammation and insulin resistance. Disclosure T. Dang: None. G.E. Kilroy: None. J.L. Taylor: None. Y. Yu: None. E. Floyd: None.

Involvement of glucocorticoid prereceptor metabolism and signaling in rat visceral adipose tissue lipid metabolism after chronic stress combined with high-fructose diet.

Both fructose overconsumption and increased glucocorticoids secondary to chronic stress may contribute to overall dyslipidemia. In this study we specifically assessed the effects and interactions of dietary fructose and chronic stress on lipid metabolism in the visceral adipose tissue (VAT) of male Wistar rats. We analyzed the effects of 9-week 20% high fructose diet and 4-week chronic unpredictable stress, separately and in combination, on VAT histology, glucocorticoid prereceptor metabolism, glucocorticoid receptor subcellular redistribution and expression of major metabolic genes. Blood triglycerides and fatty acid composition were also measured to assess hepatic Δ9 desaturase activity. The results showed that fructose diet increased blood triglycerides and Δ9 desaturase activity. On the other hand, stress led to corticosterone elevation, glucocorticoid receptor activation and decrease in adipocyte size, while phosphoenolpyruvate carboxykinase, adipose tissue triglyceride lipase, FAT/CD36 and sterol regulatory element binding protein-1c (SREBP-1c) were increased, pointing to VAT lipolysis and glyceroneogenesis. The combination of stress and fructose diet was associated with marked stimulation of fatty acid synthase and acetyl-CoA carboxylase mRNA level and with increased 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase protein levels, suggesting a coordinated increase in hexose monophosphate shunt and de novo lipogenesis. It however did not influence the level of peroxisome proliferator-activated receptor-gamma, SREBP-1c and carbohydrate responsive element-binding protein. In conclusion, our results showed that only combination of dietary fructose and stress increase glucocorticoid prereceptor metabolism and stimulates lipogenic enzyme expression suggesting that interaction between stress and fructose may be instrumental in promoting VAT expansion and dysfunction.

Intra‐Abdominal Lipectomy Reduces Large Arterial Stiffness and Blood Pressure in Metabolic Syndrome

Increased intra‐abdominal (visceral) adipose tissue is a key feature of the metabolic syndrome. Expansion of visceral adipose tissue and the associated altered adipokine profile are linked to the development of hypertension. While reduction in visceral adipose tissue volume offers cardioprotective effects, the mechanisms underlying these effects remain understudied and unclear. In this study, we removed ~90% of visceral adipose tissue (=~5% body weight) by intra‐abdominal lipectomy and assessed large arterial stiffness, large artery structural matrix components, and blood pressure in a metabolic syndrome rat model (JCR:LA‐cp, JCR). Large artery compliance was significantly decreased in JCR vs. normal (Sprague Dawley, SD) rats (75±2% JCR vs. SD (carotid)) with a concomitant significant increase in MMP12‐dependent elastin degradation (3–6 fold vs. SD). Intra‐abdominal lipectomy normalized large artery stiffness, blocked MMP12 activation and reduced elastin degradation in JCR animals (~75% (carotid) vs. untreated JCR). Likewise, hypertension in JCR animals was significantly attenuated by intra‐abdominal lipectomy (MABP=156±3 mmHg JCR vs. 90±6 mmHg SD vs. 132±4 mmHg JCR+lipectomy). 20‐hydroxyeicosatetraeonic acid (20‐HETE), an arachidonic acid metabolite known to be a potent vasoconstrictor in resistance arteries, was significantly elevated in the visceral adipose tissue of JCR rats (~6 fold vs. SD). Like intra‐abdominal lipectomy, 20‐HETE antagonists restored large artery elasticity, blocked MMP12 activation and elastin degradation and significantly decreased blood pressure (125±3 mmHg JCR+20‐HETE antagonists) in JCR rats. Thus, 20‐HETE may be an important adipokine that mediates, in part, the adverse effects of expanded visceral fat volume in the metabolic syndrome. Its removal and inhibition may provide therapeutic and pharmacological approaches, respectively, for the management of central obesity‐driven large artery stiffness and hypertension in the metabolic syndrome.Support or Funding InformationNational Heart, Lung and Blood Institute (NHLBI): 1F31HL137356‐01This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract P211: Intra-abdominal Lipectomy Normalizes Arterial Stiffness and Blood Pressure via Reduction in 20-HETE

Increased intra-abdominal (visceral) adipose tissue is a key feature of the metabolic syndrome affecting over 30% of the U.S. population. Expansion of visceral adipose tissue is linked to the development of hypertension and is a risk factor for cardiovascular disease that can ultimately lead to end-organ damage. While reduction in visceral adipose tissue volume offers cardioprotective effects, the cardiovascular mechanisms behind these beneficial effects remain unclear. In this study, we removed ~90% of visceral adipose tissue (=~5% body weight) by intra-abdominal lipectomy and assessed large arterial stiffness, large artery structural matrix components, and blood pressure in a metabolic syndrome rat model (JCR:LA-cp, JCR). Large artery stiffness was significantly elevated in JCR vs. normal (Sprague Dawley, SD) rats (75±2% JCR vs. SD (carotid)) with a concomitant significant increase in MMP12-dependent elastin degradation (3-6 fold vs. SD). Intra-abdominal lipectomy normalized large artery stiffness, blocked MMP12 activation and reduced elastin degradation in JCR animals (~75% (carotid) vs. untreated JCR). Likewise, hypertension in JCR animals was significantly attenuated by intra-abdominal lipectomy (MABP=156±3 mmHg JCR vs. 90±6 mmHg SD vs. 132±4 mmHg JCR+lipectomy). 20-hydroxyeicosatetraeonic acid (20-HETE), an arachidonic acid metabolite known to be a potent vasoconstrictor in resistance arteries, was significantly elevated in the visceral adipose tissue of JCR rats (~6 fold vs. SD). Intra-abdominal lipectomy normalized 20-HETE levels in JCR rats. Like intra-abdominal lipectomy, 20-HETE antagonists restored large artery elasticity, blocked MMP12 activation and elastin degradation, and significantly decreased blood pressure (125±3 mmHg JCR+20-HETE antagonists) in JCR rats. Thus, 20-HETE may be an important adipokine that mediates the adverse effects of expanded visceral fat volume in the metabolic syndrome and its inhibition may provide a pharmacological approach for the management of central obesity-driven large artery stiffness and hypertension.

APMAP interacts with lysyl oxidase-like proteins, and disruption of Apmap leads to beneficial visceral adipose tissue expansion.

Adipocyte plasma membrane–associated protein (APMAP) has been described as an adipogenic factor in 3T3-L1 cells with unknown biochemical function; we therefore aimed to investigate the physiologic function of APMAP in vivo. We generated Apmap-knockout mice and challenged them with an obesogenic diet to investigate their metabolic phenotype. We identified a novel truncated adipocyte-specific isoform of APMAP in mice that is produced by alternative transcription. Mice lacking the full-length APMAP protein, the only isoform that is expressed in humans, have an improved metabolic phenotype upon diet-induced obesity, indicated by enhanced insulin sensitivity, preserved glucose tolerance, increased respiratory exchange ratio, decreased inflammatory marker gene expression, and reduced adipocyte size. At the molecular level, APMAP interacts with the extracellular collagen cross-linking matrix proteins lysyl oxidase–like 1 and 3. On a high-fat diet, the expression of lysyl oxidase–like 1 and 3 is strongly decreased in Apmap-knockout mice, paralleled by reduced expression of profibrotic collagens and total collagen content in epididymal white adipose tissue, indicating decreased fibrotic potential. Together, our data suggest that APMAP is a novel regulator of extracellular matrix components, and establish that APMAP is a potential target to mitigate obesity-associated insulin resistance.—Pessentheiner, A. R., Huber, K., Pelzmann, H. J., Prokesch, A., Radner, F. P. W., Wolinski, H., Lindroos-Christensen, J., Hoefler, G., Rülicke, T., Birner-Gruenberger, R., Bilban, M., Bogner-Strauss, J. G. APMAP interacts with lysyl oxidase–like proteins, and disruption of Apmap leads to beneficial visceral adipose tissue expansion.

Obesity-induced vascular inflammation involves elevated arginase activity.

Obesity-induced vascular dysfunction involves pathological remodeling of the visceral adipose tissue (VAT) and increased inflammation. Our previous studies showed that arginase 1 (A1) in endothelial cells (ECs) is critically involved in obesity-induced vascular dysfunction. We tested the hypothesis that EC-A1 activity also drives obesity-related VAT remodeling and inflammation. Our studies utilized wild-type and EC-A1 knockout (KO) mice made obese by high-fat/high-sucrose (HFHS) diet. HFHS diet induced increases in body weight, fasting blood glucose, and VAT expansion. This was accompanied by increased arginase activity and A1 expression in vascular ECs and increased expression of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-10 (IL-10), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) mRNA and protein in both VAT and ECs. HFHS also markedly increased circulating inflammatory monocytes and VAT infiltration by inflammatory macrophages, while reducing reparative macrophages. Additionally, adipocyte size and fibrosis increased and capillary density decreased in VAT. These effects of HFHS, except for weight gain and hyperglycemia, were prevented or reduced in mice lacking EC-A1 or treated with the arginase inhibitor 2-(S)-amino-6-boronohexanoic acid (ABH). In mouse aortic ECs, exposure to high glucose (25 mM) and Na palmitate (200 μM) reduced nitric oxide production and increased A1, TNF-α, VCAM-1, ICAM-1, and MCP-1 mRNA, and monocyte adhesion. Knockout of EC-A1 or ABH prevented these effects. HFHS diet-induced VAT inflammation is mediated by EC-A1 expression/activity. Limiting arginase activity is a possible therapeutic means of controlling obesity-induced vascular and VAT inflammation.

Cardiovascular Risk Reduction in Patients with Nonalcoholic Fatty Liver Disease: The Potential Role of Ezetimibe.

Nonalcoholic fatty liver disease (NAFLD) is widely considered to be the hepatic manifestation of the metabolic syndrome and is closely linked to dyslipidemia, obesity, and insulin resistance. Patients with NAFLD have increased mortality when compared to the general population, primarily related to cardiovascular disease or malignancy. The biologic mechanisms that link NAFLD to cardiovascular disease include expansion of visceral adipose tissue, atherogenic dyslipidemia, impaired insulin signaling, systemic inflammation, and endothelial dysfunction. Currently, there are no approved therapies for NAFLD. It has recently been hypothesized that reducing the delivery of dietary cholesterol using the hypolipidemic agent, ezetimibe, could benefit patients with NAFLD. By potently inhibiting the Niemann-Pick C1-Like 1 (NPC1L1) sterol receptor on intestinal enterocytes and within the liver, ezetimibe blocks exogenous cholesterol absorption and has been shown to improve biochemical markers of NAFLD, improve insulin sensitivity and decrease hepatic steatosis. This review summarizes the clinical and epidemiological evidence for the relationship between NAFLD and cardiovascular risk and examines the potential therapeutic role of ezetimibe.