Visceral Adipose Tissue Adipocyte Research Articles

Gene and lncRNA Profiling of ω3/ω6 Polyunsaturated Fatty Acid-Exposed Human Visceral Adipocytes Uncovers Different Responses in Healthy Lean, Obese and Colorectal Cancer-Affected Individuals.

Colorectal cancer (CRC) is a major life-threatening disease, being the third most common cancer and a leading cause of death worldwide. Enhanced adiposity, particularly visceral fat, is a major risk factor for CRC, and obesity-associated alterations in metabolic, inflammatory and immune profiles in visceral adipose tissue (VAT) strongly contribute to promoting or sustaining intestinal carcinogenesis. The role of diet and nutrition in obesity and CRC has been extensively demonstrated, and AT represents the main place where diet-induced signals are integrated. Among the factors introduced with diet and processed or enriched in AT, ω3/ω6 polyunsaturated fatty acids (PUFAs) are endowed with pro- or anti-inflammatory properties and have been shown to exert either promoting or protective roles in CRC. In this study, we investigated the impact of ex vivo exposure to the ω3 and ω6 PUFAs docosahexaenoic and arachidonic acids on VAT adipocyte whole transcription in healthy lean, obese and CRC-affected individuals. High-throughput sequencing of protein-coding and long non-coding RNAs allowed us to identify specific pathways and regulatory circuits controlled by PUFAs and highlighted an impaired responsiveness of obese and CRC-affected individuals as compared to the strong response observed in healthy lean subjects. This further supports the role of healthy diets and balanced ω3/ω6 PUFA intake in the primary prevention of obesity and cancer.

Dopamine D2 receptor antagonist counteracts hyperglycemia and insulin resistance in diet-induced obese male mice.

Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.

Leptin-dependent differential remodeling of visceral and pericardial adipose tissue following chronic exercise and psychosocial stress.

Obesity is driven by an imbalance between caloric intake and energy expenditure, causing excessive storage of triglycerides in adipose tissue at different sites around the body. Increased visceral adipose tissue (VAT) is associated with diabetes, while pericardial adipose tissue (PAT) is associated with cardiac pathology. Adipose tissue can expand either through cellular hypertrophy or hyperplasia, with the former correlating with decreased metabolic health in obesity. The aim of this study was to determine how VAT and PAT remodel in response to obesity, stress, and exercise. Here we have used the male obese Zucker rats, which carries two recessive fa alleles that result in the development of hyperphagia with reduced energy expenditure, resulting in morbid obesity and leptin resistance. At 9 weeks of age, a group of lean (Fa/Fa or Fa/fa) Zucker rats (LZR) and obese (fa/fa) Zucker rats (OZR) were treated with unpredictable chronic mild stress or exercise for 8 weeks. To determine the phenotype for PAT and VAT, tissue cellularity and gene expression were analyzed. Finally, leptin signaling was investigated further using cultured 3T3-derived adipocytes. Tissue cellularity was determined following hematoxylin and eosin (H&E) staining, while qPCR was used to examine gene expression. PAT adipocytes were significantly smaller than those from VAT and had a more beige-like appearance in both LZR and OZR. In the OZR group, VAT adipocyte cell size increased significantly compared with LZR, while PAT showed no difference. Exercise and stress resulted in a significant reduction in VAT cellularity in OZR, while PAT showed no change. This suggests that PAT cellularity does not remodel significantly compared with VAT. These data indicate that the extracellular matrix of PAT is able to remodel more readily than in VAT. In the LZR group, exercise increased insulin receptor substrate 1 (IRS1) in PAT but was decreased in the OZR group. In VAT, exercise decreased IRS1 in LZR, while increasing it in OZR. This suggests that in obesity, VAT is more responsive to exercise and subsequently becomes less insulin resistant compared with PAT. Stress increased PPAR-γ expression in the VAT but decreased it in the PAT in the OZR group. This suggests that in obesity, stress increases adipogenesis more significantly in the VAT compared with PAT. To understand the role of leptin signaling in adipose tissue remodeling mechanistically, JAK2 autophosphorylation was inhibited using 5 μM 1,2,3,4,5,6-hexabromocyclohexane (Hex) in cultured 3T3-derived adipocytes. Palmitate treatment was used to induce cellular hypertrophy. Hex blocked adipocyte hypertrophy in response to palmitate treatment but not the increase in lipid droplet size. These data suggest that leptin signaling is necessary for adipocyte cell remodeling, and its absence induces whitening. Taken together, our data suggest that leptin signaling is necessary for adipocyte remodeling in response to obesity, exercise, and psychosocial stress.

Defective Visceral Adipose Tissue Adaptation in Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a complex obstetric condition affecting localized glucose metabolism, resulting in systemic metabolic dysfunction. This cross-sectional study aimed to explore visceral adipose tissue (VAT) as an integral contributor to GDM, focusing on elucidating the specific contribution of obesity and GDM pathology to maternal outcomes. Fifty-six nulliparous pregnant women were recruited, including normal glucose tolerant (NGT) (n = 30) and GDM (n = 26) participants. Participants were subgrouped as nonobese (BMI <30 kg/m2) or obese (BMI ≥30 kg/m2). Metabolic markers in circulation, VAT, and placenta were determined. Morphological analysis of VAT and immunoblotting of the insulin signaling cascade were performed. GDM participants demonstrated hyperinsulinemia and elevated homeostatic model assessment for insulin resistance (HOMA-IR) scores relative to NGT participants. The GDM-obese subgroup had significant VAT adipocyte hypoplasia relative to NGT-nonobese tissue. GDM-obese VAT had significantly lower insulin receptor substrate (IRS)-2 expression, with elevated ser312 phosphorylation of IRS-1, relative to NGT-nonobese. GDM-obese participants had significantly elevated circulating leptin levels and placental adipsin secretion, while GDM-nonobese participants had elevated circulating adipsin levels with reduced placental adiponectin secretion. These findings suggest that GDM-obese pregnancy is specifically characterized by inadequate VAT remodeling and dysfunctional molecular signaling, which contribute to insulin resistance and hinder metabolic health.

Bariatric surgery decreases the capacity of plasma from obese asthmatic subjects to augment airway epithelial cell proinflammatory cytokine production.

Obesity is a risk factor for asthma. Individuals with asthma and obesity often have poor asthma control and do not respond as well to therapies such as inhaled corticosteroids and long-acting bronchodilators. Weight loss improves asthma control, with a 5%-10% loss in body mass necessary and sufficient to lead to clinically relevant improvements. Preclinical studies have demonstrated the pathogenic contribution of adipocytes from obese mice to the augmented production of proinflammatory cytokines from airway epithelial cells and the salutary effects of diet-induced weight loss to decrease these consequences. However, the effects of adipocyte-derived products on airway epithelial function in human obesity remain incompletely understood. We utilized samples collected from a 12-mo longitudinal study of subjects with obesity undergoing weight loss (bariatric) surgery including controls without asthma and subjects with allergic and nonallergic obese asthma. Visceral adipose tissue (VAT) samples were collected during bariatric surgery and from recruited normal weight controls without asthma undergoing elective abdominal surgery. Human bronchial epithelial (HBEC3-KT) cells were exposed to plasma or conditioned media from cultured VAT adipocytes with or without agonists. Human bronchial smooth muscle (HBSM) cells were similarly exposed to adipocyte-conditioned media. Proinflammatory cytokines were augmented in supernatants from HBEC3-KT cells exposed to plasma as compared with subsequent visits. Whereas exposure to obese adipocyte-conditioned media induced proinflammatory responses, there were no differences between groups in both HBEC3-KT and HBSM cells. These data show that bariatric surgery and subsequent weight loss beneficially change the circulating factors that augment human airway epithelial and bronchial smooth muscle cell proinflammatory responses.NEW & NOTEWORTHY This longitudinal study following subjects with asthma and obesity reveals that weight loss following bariatric surgery decreases the capacity for plasma to augment proinflammatory cytokine secretion by human bronchial epithelial cells, implicating that circulating but not adipocyte-derived factors are important modulators in obese asthma.

Visceral adipocyte size links obesity with dysmetabolism more than fibrosis, and both can be estimated by circulating miRNAs.

In obesity, adipocyte hypertrophy is detrimental tohealth, but its' interrelation with fibrosis in the visceral adipose tissue (VAT) depot remains unclear. Because VAT is less accessible via biopsy, biomarkers for VAT quality are needed. The authors hypothesized that VAT adipocyte size and fibrosis are interrelated and can be estimated by circulating microRNAs (circ-miRNAs), contributing to subphenotyping obesity. Adipocyte size and AT fibrosis were estimated in n = 43 participants (BMI ≥ 30 kg/m2 ). Circ-miRNAs were sequenced (Next Generation Sequencing). Participants with above- versus below-median VAT adipocyte area exhibited metabolic dysfunction but lower total and pericellular fibrosis. VAT adipocyte size remained associated with metabolic dysfunction even when controlling for BMI or VAT fibrosis in the entire cohort, as in matched-pairs subanalyses. Next Generation Sequencing uncovered 22 and 6 circ-miRNAs associated with VAT adipocyte size and fibrosis, respectively, with miRNA-130b-3p common to both analyses. The combination of miRNA-130b-3p + miR-150-5p + high-density lipoprotein cholesterol discriminated among those with large versus small VAT adipocytes (receiver operating characteristic-area under the curve: 0.872 [95% CI: 0.747-0.996]), whereas miRNA-130b-3p + miRNA-15a-5p + high-density lipoprotein cholesterol discriminated among those with low and high fibrosis (receiver operating characteristic-area under the curve: 0.823 [95% CI: 0.676-0.97]). These findings suggest that VAT adipocyte size and fibrosis are inversely correlated in obesity and can be estimated by distinct circ-miRNAs, providing a potential tool to subphenotype obesity via a liquid biopsy-like approach to assess VAT health in nonsurgical patients.

Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes.

This study aimed to assess the causal relationship between visceral obesity and type 2 diabetes and subsequently to screen visceral adipose tissue (VAT)-specific targets for type 2 diabetes. We examined the causal relationship between VAT and type 2 diabetes using bidirectional Mendelian randomisation (MR) followed by multivariable MR. We conducted a transcriptome-wide association study (TWAS) leveraging prediction models and a large-scale type 2 diabetes genome-wide association study (74,124 cases and 824,006 controls) to identify candidate genes in VAT and used summary-data-based MR (SMR) and co-localisation analysis to map causal genes. We performed enrichment and single-cell RNA-seq analyses to determine the cell-specific localisation of the TWAS-identified genes. We also conducted knockdown experiments in 3T3-L1 pre-adipocytes. MR analyses showed a causal relationship between genetically increased VAT mass and type 2 diabetes (inverse-variance weighted OR 2.48 [95% CI 2.21, 2.79]). Ten VAT-specific candidate genes were associated with type 2 diabetes after Bonferroni correction, including five causal genes supported by SMR and co-localisation: PABPC4 (1p34.3); CCNE2 (8q22.1); HAUS6 (9p22.1); CWF19L1 (10q24.31); and CCDC92 (12q24.31). Combined with enrichment analyses, clarifying cell-type specificity with single-cell RNA-seq data indicated that most TWAS-identified candidate genes appear more likely to be associated with adipocytes in VAT. Knockdown experiments suggested that Pabpc4 likely contributes to regulating differentiation and energy metabolism in 3T3-L1 adipocytes. Our findings provide new insights into the genetic basis and biological processes of the association between VAT accumulation and type 2 diabetes and warrant investigation through further functional studies to validate these VAT-specific candidate genes.

#4331 UPREGULATION OF ADIPOSE TISSUE FATTY ACID-BINDING PROTEIN 4 IN PATIENTS WITH CHRONIC KIDNEY DISEASE: IMPLICATIONS FOR DYSFUNCTIONAL VASCULAR CELLS

Abstract Background and Aims FABP4, a fatty acid-binding protein, is predominantly expressed in adipose tissue (AT) and has been shown to be elevated in patients with chronic kidney disease (CKD). Although elevated levels of FABP4 have been linked to cardiovascular disease in end-stage renal disease (ESRD) patients, the cause of this increase is unclear. The aim of this study was to evaluate the expression of AT FABP4 under uremic conditions and its impact on the function of macrophages and vascular smooth muscle cells (VSMC). Method We measured the levels of FABP4 in the blood and urine of CKD patients. The expression of AT FABP4 under uremic conditions was analyzed using omental AT obtained from healthy kidney donors and patients with ESRD who received peritoneal catheter insertion. The effect of FABP4 on the function of macrophages and VSMC was also assessed. Results The levels of FABP4 in the blood and urine of CKD patients were inversely correlated with their estimated glomerular filtration rate (eGFR). An increase in FABP4 in the blood was detected before its increase in the urine. FABP4 expression was found to be higher in mature adipocytes in visceral AT compared to the stromal vascular fraction (SVF). Adipocytes treated with p-cresol and adipocytes isolated from CKD patients showed higher levels of FABP4 expression compared to healthy individuals. Single-cell RNA sequencing of SVF showed increased FABP4 expression in progenitor cells and macrophages from CKD patients. In THP-1 cells, FABP4 induced more foam cells and increased levels of inflammatory mediators in the presence of palmitic acid. VSMC treated with p-cresol or VSMC isolated from CKD mice induced by an adenine diet showed a pro-calcific phenotype, as indicated by increased calcium content and bone-related gene expression, which was further enhanced by FABP4. Conclusion The elevated levels of FABP4 in CKD patients are not solely a result of decreased renal clearance but also due to increased production in AT. These higher levels of circulating FABP4 may be associated with dysfunction in vascular cells.

BMPER is a marker of adipose progenitors and adipocytes and a positive modulator of adipogenesis

Autocrine and paracrine signaling regulating adipogenesis in white adipose tissue remains largely unclear. Here we used single-cell RNA-sequencing (RNA-seq) and single nuclei RNA-sequencing (snRNA-seq) to identify markers of adipose progenitor cells (APCs) and adipogenic modulators in visceral adipose tissue (VAT) of humans and mice. Our study confirmed the presence of major cellular clusters in humans and mice and established important sex and diet-specific dissimilarities in cell proportions. Here we show that bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER) is a conserved marker for APCs and adipocytes in VAT in humans and mice. Further, BMPER is highly enriched in lineage negative stromal vascular cells and its expression is significantly higher in visceral compared to subcutaneous APCs in mice. BMPER expression and release peaked by day four post-differentiation in 3T3-L1 preadipocytes. We reveal that BMPER is required for adipogenesis both in 3T3-L1 preadipocytes and in mouse APCs. Together, this study identified BMPER as a positive modulator of adipogenesis.

Differential remodelling of visceral and pericardial adipose tissue in response to stress and exercise

Obesity is driven by an imbalance between caloric intake and energy expenditure, causing excessive storage of nutrients in adipose tissue at different sites around the body. Increased visceral adipose tissue (VAT) is associated with diabetes, whilst pericardial adipose tissue (PAT) is associated with cardiac pathology. Adipose tissue can expand either through cellular hypertrophy or hyperplasia, with the former correlating with decreased metabolic health in obesity. The aim of this study was to determine how VAT and PAT remodel in response to obesity, stress and exercise.Here we have used the obese Zucker rats which develop hyperphagia with reduced energy expenditure, resulting in morbid obesity as a result of leptin resistance. At 9 weeks of age lean (LZR) and obese (OZR) Zucker male rats were treated with or without unpredictable chronic mild stress or exercise for 8 weeks. To determine the phenotype for PAT and VAT, tissue cellularity and gene expression were analyzed. Tissue cellularity was determined following haematoxylin and eosin staining, whilst qPCR was used to examine gene expression.PAT adipocytes were significantly smaller than those from VAT and had a more biege‐like appearance. In the OZR group, VAT adipocyte cell size increased significantly compared with LZR, whilst PAT showed no change. Exercise and stress resulted in a significant reduction in VAT cellularity in OZR, whilst PAT showed no change. This suggests that PAT cellularity does not remodel significantly compared with VAT. Picro sirus red staining indicated that PAT had significantly more fibrosis than VAT. However, this fibrosis was decreased following stress treatment. This data indicate that the extracellular matrix of PAT is able to remodel more readily than in VAT.Gene expression analysis showed that PAT expressed higher levels of UCP1 compared with VAT, indicating that it has a more brown‐like phenotype. In the LZR group, exercise increased insulin receptor substrate 1 (IRS1) in PAT, but was decreased in the OZR group. On the other hand, in VAT, exercise decreased IRS1 in LZR, whilst increasing it in the OZR. This suggests that in obesity, VAT is more responsive to exercise and subsequently becomes less insulin resistant compared with PAT. In VAT, stress increased PPAR‐γ expression in the OZR group but decreased it in the PAT. This suggests that in obesity, stress increases adipogenesis more significantly in the VAT compared with PAT.Taken together, our data suggest that VAT is considerably more plastic than PAT and remodels rapidly in response to obesity, exercise and psychological stress.

Mesothelial cells are not a source of adipocytes in mice.

SUMMARYVisceral adipose tissue (VAT) depots are associated with the adverse metabolic consequences of obesity, such as insulin resistance. The developmental origin of VAT depots and the identity and regulation of adipocyte progenitor cells have been active areas of investigation. In recent years, a paradigm of mesothelial cells as a source of VAT adipocyte progenitor cells has emerged based on lineage tracing studies using the Wilms’ tumor gene, Wt1, as a marker for cells of mesothelial origin. Here, we show that Wt1 expression in adipose tissue is not limited to the mesothelium but is also expressed by a distinct preadipocyte population in mice and humans. We identify keratin 19 (Krt19) as a highly specific marker for the adult mouse mesothelium and demonstrate that Krt19-expressing mesothelial cells do not differentiate into visceral adipocytes. These results contradict the assertion that the VAT mesothelium can serve as a source of adipocytes.

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.

Proteome analysis of human adipocytes identifies depot-specific heterogeneity at metabolic control points.

Adipose tissue is a primary regulator of energy balance and metabolism. The distribution of adipose tissue depots is of clinical interest because the accumulation of upper-body subcutaneous (ASAT) and visceral adipose tissue (VAT) is associated with cardiometabolic diseases, whereas lower-body glutealfemoral adipose tissue (GFAT) appears to be protective. There is heterogeneity in morphology and metabolism of adipocytes obtained from different regions of the body, but detailed knowledge of the constituent proteins in each depot is lacking. Here, we determined the human adipocyte proteome from ASAT, VAT, and GFAT using high-resolution Sequential Window Acquisition of all Theoretical (SWATH) mass spectrometry proteomics. We quantified 4,220 proteins in adipocytes, and 2,329 proteins were expressed in all three adipose depots. Comparative analysis revealed significant differences between adipocytes from different regions (6% and 8% when comparing VAT vs. ASAT and GFAT, 3% when comparing the subcutaneous adipose tissue depots, ASAT and GFAT), with marked differences in proteins that regulate metabolic functions. The VAT adipocyte proteome was overrepresented with proteins of glycolysis, lipogenesis, oxidative stress, and mitochondrial dysfunction. The GFAT adipocyte proteome predicted the activation of peroxisome proliferator-activated receptor α (PPARα), fatty acid, and branched-chain amino acid (BCAA) oxidation, enhanced tricarboxylic acid (TCA) cycle flux, and oxidative phosphorylation, which was supported by metabolomic data obtained from adipocytes. Together, this proteomic analysis provides an important resource and novel insights that enhance the understanding of metabolic heterogeneity in the regional adipocytes of humans.NEW & NOTEWORTHY Adipocyte metabolism varies depending on anatomical location and the adipocyte protein composition may orchestrate this heterogeneity. We used SWATH proteomics in patient-matched human upper- (visceral and subcutaneous) and lower-body (glutealfemoral) adipocytes and detected 4,220 proteins and distinguishable regional proteomes. Upper-body adipocyte proteins were associated with glycolysis, de novo lipogenesis, mitochondrial dysfunction, and oxidative stress, whereas lower-body adipocyte proteins were associated with enhanced PPARα activation, fatty acid, and BCAA oxidation, TCA cycle flux, and oxidative phosphorylation.

Sex Differences in Long-term Metabolic Effects of Maternal Resveratrol Intake in Adult Rat Offspring.

Maternal nutrition can affect the susceptibility of the offspring to metabolic disease later in life, suggesting that this period is a window of opportunity for intervention to reduce the risk of metabolic disease. Resveratrol, a natural polyphenol, has a wide range of beneficial properties including anti-obesogenic, anti-atherosclerotic, and anti-diabetic effects. We previously reported that maternal resveratrol intake during pregnancy and lactation has early metabolic effects in the offspring with these effects at weaning depending on the type of diet ingested by the mother and the offspring's sex. Here we analyzed whether these metabolic changes are maintained in the adult offspring and if they remain sex and maternal diet dependent. Wistar rats received a low-fat diet (LFD; 10.2% Kcal from fat) or high fat diet (HFD; 61.6% Kcal from fat) during pregnancy and lactation. Half of each group received resveratrol in their drinking water (50 mg/L). Offspring were weaned onto standard chow on postnatal day 21. Maternal resveratrol reduced serum cholesterol levels in all adult offspring from HFD mothers and increased it in adult female offspring from LFD mothers. Resveratrol increased visceral adipose tissue (VAT) in LFD offspring in both sexes but decreased it in male HFD offspring. Resveratrol shifted the distribution of VAT adipocyte size to a significantly higher incidence of large adipocytes, regardless of sex or maternal diet. These results clearly demonstrate that maternal resveratrol intake has long-lasting effects on metabolic health of offspring in a sex specific manner with these effects being highly dependent on the maternal diet.

Impact of HIV/simian immunodeficiency virus infection and viral proteins on adipose tissue fibrosis and adipogenesis

HIV-infected patients receiving antiretroviral treatment (ART) often present adipose tissue accumulation and/or redistribution. adipose tissue has been shown to be an HIV/SIV reservoir and viral proteins as Tat or Nef can be released by infected immune cells and exert a bystander effect on adipocytes or precursors. Our aim was to demonstrate that SIV/HIV infection per se could alter adipose tissue structure and/or function. Morphological and functional alterations of subcutaneous (SCAT) and visceral adipose tissue (VAT) were studied in SIV-infected macaques and HIV-infected ART-controlled patients. To analyze the effect of Tat or Nef, we used human adipose stem cells (ASCs) issued from healthy donors, and analyzed adipogenesis and extracellular matrix component production using two dimensional (2D) and three-dimensional (3D) culture models. Adipocyte size and index of fibrosis were determined on Sirius red-stained adipose tissue samples. Proliferating and adipocyte 2D-differentiating or 3D-differentiating ASCs were treated chronically with Tat or Nef. mRNA, protein expression and secretion were examined by RT-PCR, western-blot and ELISA. SCAT and VAT from SIV-infected macaques displayed small adipocytes, decreased adipogenesis and severe fibrosis with collagen deposition. SCAT and VAT from HIV-infected ART-controlled patients presented similar alterations. In vitro, Tat and/or Nef induced a profibrotic phenotype in undifferentiated ASCs and altered adipogenesis and collagen production in adipocyte-differentiating ASCs. We demonstrate here a specific role for HIV/SIV infection per se on adipose tissue fibrosis and adipogenesis, probably through the release of viral proteins, which could be involved in adipose tissue dysfunction contributing to cardiometabolic alterations of HIV-infected individuals.

Calcium reduces vitamin D and glucocorticoid receptors in the visceral fat of obese male rats

Rats overfed during lactation show higher visceral adipose tissue (VAT) mass and metabolic dysfunctions at adulthood. As both vitamin D and glucocorticoids change adipogenesis, parameters related to metabolism and action of these hormones in the adipocyte can be altered in rats raised in small litters (SL). We also studied the antiobesity effects of high calcium diet since it decreases visceral fat in obesity models. On postnatal day (PN) 3, litter size was adjusted to 3pups/dam (SL) to induce overfeeding. Control litters (NL) remained with 10pups/dam until weaning. From PN120 to PN180, half of the SL rats were fed standard chow (SL) and the other half was fed a calcium-supplemented chow (SL-Ca, 10g CaCO3/kg). Both SL groups were heavier and hyperphagic when compared with the NL group; however, SL-Ca rats ate less than SL. SL-Ca rats had decreased VAT mass and adipocyte size, associated with lower hypothalamic NPY content, VAT fat acid synthase content and leptinemia. At PN120, SL rats had increased plasma 25(OH)D3, Cyp27b1 mRNA and glucocorticoid receptor (GR-α) in the VAT, but lower vitamin D receptor (Vdr) mRNA. At PN180, Cyp27b1 and GR-α remained higher, while Vdr normalized in SL rats. SL-Ca rats had normal VAT Cyp27b1 and GR-α, but lower Vdr Thus, higher body mass and glucocorticoid receptors in the VAT of SL rats are normalized by calcium-enriched diet, and Vdr expression in this tissue is reduced, suggesting a possible role of glucocorticoids and vitamin D in calcium action in the adipocyte.

Resveratrol attenuates peripheral and brain inflammation and reduces ischemic brain injury in aged female mice

Resveratrol is known to improve metabolic dysfunction associated with obesity. Visceral obesity is a sign of aging and is considered a risk factor for ischemic stroke. In this study, we investigated the effects of resveratrol on inflammation in visceral adipose tissue and the brain and its effects on ischemic brain injury in aged female mice. Mice treated with resveratrol (0.1 mg/kg, p.o.) for 10 days showed reduced levels of interleukin-1β and tumor necrosis factor-α, as well as a reduction in the size of adipocytes in visceral adipose tissue. Resveratrol also reduced interleukin-1β and tumor necrosis factor-α protein levels and immunoglobulin G extravasation in the brain. Mice treated with resveratrol demonstrated smaller infarct size, improved neurological function, and blunted peripheral inflammation at 3 days postischemic stroke. These results showed that resveratrol counteracted inflammation in visceral adipose tissue and in the brain and reduced stroke-induced brain injury and peripheral inflammation in aged female mice. Therefore, resveratrol administration can be a valuable strategy for the prevention of age-associated and disease-provoked inflammation in postmenopausal women.

Human Adipocytes Induce Inflammation and Atrophy in Muscle Cells During Obesity.

Inflammation and lipid accumulation are hallmarks of muscular pathologies resulting from metabolic diseases such as obesity and type 2 diabetes. During obesity, the hypertrophy of visceral adipose tissue (VAT) contributes to muscle dysfunction, particularly through the dysregulated production of adipokines. We have investigated the cross talk between human adipocytes and skeletal muscle cells to identify mechanisms linking adiposity and muscular dysfunctions. First, we demonstrated that the secretome of obese adipocytes decreased the expression of contractile proteins in myotubes, consequently inducing atrophy. Using a three-dimensional coculture of human myotubes and VAT adipocytes, we showed the decreased expression of genes corresponding to skeletal muscle contractility complex and myogenesis. We demonstrated an increased secretion by cocultured cells of cytokines and chemokines with interleukin (IL)-6 and IL-1β as key contributors. Moreover, we gathered evidence showing that obese subcutaneous adipocytes were less potent than VAT adipocytes in inducing these myotube dysfunctions. Interestingly, the atrophy induced by visceral adipocytes was corrected by IGF-II/insulin growth factor binding protein-5. Finally, we observed that the skeletal muscle of obese mice displayed decreased expression of muscular markers in correlation with VAT hypertrophy and abnormal distribution of the muscle fiber size. In summary, we show the negative impact of obese adipocytes on muscle phenotype, which could contribute to muscle wasting associated with metabolic disorders.

A Lifetime on the Hips: Programming Lower-Body Fat to Protect Against Metabolic Disease

In the 60 years since Vague (1) described that an “android” pattern of adipose tissue (AT) distribution was associated with diabetes, atherosclerosis, gout, and kidney stones, many of the physiological mechanisms underlying this relationship have been illuminated. To date, most of the effort has been directed at understanding how accumulation of intra-abdominal fat, also known as visceral AT (VAT), promotes insulin resistance (IR). IR is the common defect underlying glucose intolerance, central obesity, dyslipidemia, and hypertension. This phenotypic cluster, called the metabolic syndrome, is associated with a doubling of cardiovascular disease risk and a fivefold increased risk of type 2 diabetes (2). VAT is likely to promote IR in several ways. Enlarged adipocytes in VAT were originally thought to promote hepatic, and eventually systemic, IR via increased portal free fatty acid (FFA) flux (3). Other factors are likely to be involved, however, because although FFA flux from VAT does increase in obesity, it is not the major determinant of portal FFA concentrations (4). In obesity, VAT also may contribute to IR via alterations in its secreted products (adipokines), as well as proinflammatory molecules such as tumor necrosis factor-α, interleukin-6 (IL-6), C-reactive protein (CRP), and monocyte chemoattractant protein-1 (MCP-1) (5). Independently of VAT, parallel studies have established that a gynoid pattern of AT distribution, characterized by greater amounts of subcutaneous AT (SAT) in the lower body, is associated with improved glucose tolerance and lipid profile and that this fat pattern may protect against cardiovascular disease (6,7). These protective effects often vary with sex, but …

Zidovudine Induces Visceral Mitochondrial Toxicity and Intra-Abdominal Fat Gain in a Rodent Model of Lipodystrophy

The use of zidovudine is associated with a loss of subcutaneous adipose tissue (SAT). We assessed if zidovudine treatment also affects visceral adipose tissue (VAT) and if uridine supplementation abrogates the adverse effects of zidovudine on VAT. Rats were fed zidovudine for 21 weeks with or without simultaneous uridine supplementation. Control animals did not receive zidovudine, or were treated with uridine alone. Changes in SAT and VAT were monitored by magnetic resonance imaging. Adipose tissue was examined for structural and molecular signs of mitochondrial toxicity. Zidovudine induced lipoatrophy in SAT and fat hypertrophy in VAT. Compared with controls zidovudine-exposed VAT adipocytes had increased diameters, microvesicular steatosis and enlarged mitochondria with disrupted crystal architecture on electron microscopy. VAT adipocyte mitochondrial DNA (mtDNA) copy numbers were diminished, as were mtDNA-encoded respiratory chain proteins. The 'common' mtDNA deletion was detected in high frequencies in zidovudine treated animals, but not in the controls. Although mtDNA depletion was more profound in SAT compared with VAT, the 'common' deletion tended to be more frequent in the VAT than in the SAT. Uridine coadministration abrogated all effects of zidovudine on VAT and SAT pathology. Zidovudine induces a gain of intra-abdominal fat in association with quantitative and qualitative alterations of the mitochondrial genome and impaired expression of mtDNA-encoded respiratory chain components, indicating that zidovudine may contribute to abdominal fat hypertrophy in HIV-infected patients. In this rodent model, uridine supplementation abrogates both SAT and VAT pathology induced by zidovudine.