Visceral White Adipose Tissue Depots Research Articles

Liraglutide modulates morpho-functional and inflammatory gastrointestinal responses in rats.

Obesity impairs homeostatic control of energy and is associated with chronic low-grade inflammation. Effects of glucagon-like peptide-1, the target in the gastrointestinal tract for anti-obesity drugs such as Liraglutide, were not properly associated with inflammation markers. This study investigated the effects of Liraglutide on metabolic and gastrointestinal parameters in a rat model of obesity. Twenty-six Wistar rats with obesity were randomly distributed to receive saline (n = 10), 400 μg (n = 8), or 1200 μg of Liraglutide/kg/day (n = 8), subcutaneously for 30 consecutive days, once a day. Weight gain, feeding efficiency, caloric consumption, gastric motility, adiposity, histomorphometric, murinometric, biochemical parameters and cytokines TNF-α and TGF-β1 in duodenal tissue were measured. Data were analysed by ANOVA, followed by Bonferroni post hoc or Kruskal-Wallis test, followed by Dunn's multiple comparison test. Liraglutide-treated animals had better feeding efficiency and higher caloric intake in a dose-dependent manner. Higher doses slowed gastric emptying and diminished the amplitude of gastric contractions. These effects were accompanied by decreases in intestinal muscle layer thickness and crypt depth. Liraglutide significantly reduced retroperitoneal and visceral white adipose tissue depots. High-dose treatment decreased levels of TNF-α and enhanced levels of TGF-β1 in duodenal tissue. Liraglutide treatment provided significant reductions in total cholesterol, triglyceride and hepatic transaminases. Liraglutide reduced fat accumulation, improved metabolic parameters and downregulated levels of inflammatory signalling in duodenal tissue. Liraglutide at high doses controlled obesity-related outcomes, and such effects seemed to be driven by its action on glucagon-like peptide-1 receptors in the gastrointestinal tract slowing gastric motility.

SARS-CoV-2 infection induces persistent adipose tissue damage in aged golden Syrian hamsters

Coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)) is primarily a respiratory illness. However, various extrapulmonary manifestations have been reported in patients with severe forms of COVID-19. Notably, SARS-CoV-2 was shown to directly trigger white adipose tissue (WAT) dysfunction, which in turn drives insulin resistance, dyslipidemia, and other adverse outcomes in patients with COVID-19. Although advanced age is the greatest risk factor for COVID-19 severity, published data on the impact of SARS-CoV-2 infection on WAT in aged individuals are scarce. Here, we characterized the response of subcutaneous and visceral WAT depots to SARS-CoV-2 infection in young adult and aged golden hamsters. In both age groups, infection was associated with a decrease in adipocyte size in the two WAT depots; this effect was partly due to changes in tissue’s lipid metabolism and persisted for longer in aged hamsters than in young-adult hamsters. In contrast, only the subcutaneous WAT depot contained crown-like structures (CLSs) in which dead adipocytes were surrounded by SARS-CoV-2-infected macrophages, some of them forming syncytial multinucleated cells. Importantly, older age predisposed to a unique manifestation of viral disease in the subcutaneous WAT depot during SARS-CoV-2 infection; the persistence of very large CLSs was indicative of an age-associated defect in the clearance of dead adipocytes by macrophages. Moreover, we uncovered age-related differences in plasma lipid profiles during SARS-CoV-2 infection. These data suggest that the WAT’s abnormal response to SARS-CoV-2 infection may contribute to the greater severity of COVID-19 observed in elderly patients.

1747-P: MicroRNA-30a Exerts Antifibrotic Effects in Subcutaneous White Adipose Tissue to Preserve Insulin Sensitivity in Obesity

White adipose tissue (WAT) is an endocrine organ that dynamically expands and contracts to meet the metabolic demands of the organism. However, prolonged excessive caloric intake overwhelms WAT depots, resulting in peripheral fat deposition, systemic glucose dysregulation, tissue fibrosis, insulin resistance, and type 2 diabetes mellitus. The chronic triggers that degrade WAT function remain undefined, hindering the development of effective strategies to treat obesity and prevent its co-morbidities. We have identified a microRNA, miR-30a, that potently stimulates subcutaneous adipose tissue metabolic flexibility and enhances systemic insulin sensitivity. In follow-up studies, we created a genetically engineered mouse model to conclusively show miR-30a expression in white adipocytes is antidiabetic. Obese mice modified to express miR-30a at elevated levels in adipose tissues maintain insulin sensitivity coupled with reduced hepatic steatosis. Proteomic profiling indicated that miR-30a targets Plasminogen Activator Inhibitor-1 (PAI-1) to limit pro-fibrotic programs that would otherwise restrict subcutaneous WAT expansion and decrease insulin sensitivity. While visceral WAT depots remain a site of significant fibrosis in mice, subcutaneous WAT fibrosis is epidemiologically linked to metabolic disease risk in adult humans. In obese humans, miR-30a expression negatively correlates with PAI-1 levels in subcutaneous WAT, supporting an anti-fibrotic role for miR-30a that ultimately defends insulin sensitivity. Collectively, our observations linking miR-30a expression to insulin sensitivity suggest a new method that restores WAT homeostasis. Disclosure N. Chernis: None. P. Saha: None. J.B. Felix: None. P.M. Masschelin: None. L. Lian: None. A. Cox: None. K. Kim: None. H. Wu: None. S.M. Hartig: None. Funding American Diabetes Association (1-18-IBS-105 to S.M.H.); National Institutes of Health (R01DK114356)

Exercise-induced FNDC5/Irisin Activation Drives Brown-like Adipocyte Phenotype in Visceral Adipose Tissue from Obese Rats

Exercise-stimulated myokines have pleiotropic effects in several tissues, including white adipose tissue (WAT). The recently discovered FNDC5/irisin is secreted into circulation in response to exercise and might induce brown adipocytes-in-WAT, which has been associated with greater whole-body energy expenditure. However, the role of exercise on FNDC5/irisin levels remains unclear. PURPOSE: To investigate whether voluntary physical activity (VPA) and endurance training (ET) induce brown-adipocyte phenotype in visceral WAT from obese rats. METHODS: Sprague-Dawley rats were allocated into sedentary, VPA and ET groups fed with a standard (STD, 35%Kcal-derived fat) or high-fat diet (HFD, 71% Kcal-derived fat) during 17 wks. VPA-animals had free access to running wheel during the study. After 9 wks of hypercaloric-diet feeding, ET-animals were submitted to 8-wks treadmill while maintained dietary treatments. Gastrocnemius muscle was removed for FNDC5 protein determination by Western Blot. Visceral WAT depots were weighted and epididymal (eWAT) was used to determine mRNA levels of Bmp7, Tmem26 and Cidea by qPCR. Diet and exercise effects were performed using two-way ANOVA. RESULTS: The caloric intake and body weight did not differ significantly between diet groups (p>0.05). HFD-induced increase in visceral adiposity (9±0.2 vs. 10.8±0.4%, p0.05). VPA had no impact either on gastrocnemius FNDC5 protein or on eWAT Bmp7, Tmem26 and Cidea gene expression (p>0.05). Although no alterations in Bmp7 and Tmem26, ET induced an increase of Cidea expression in obese animals (43.2±17.7 vs. 216.9±20.1%, p<0.01), which was positively associated with gastrocnemius FNDC5 (p<0.001; r=0.7) and negatively associated with visceral adiposity (p<0.001; r=-0.79). CONCLUSIONS: Taken together, ET-related increase in skeletal muscle FNDC5 protein could, at least, mediates brown-like adipocyte phenotype in eWAT from obese rats, which was also associated with reduced visceral fat accumulation.

Differential effects of Roux-en-Y gastric bypass surgery on brown and beige adipose tissue thermogenesis

BackgroundThere are numerous reports of increased energy expenditure after Roux-en-Y gastric bypass (RYGB) surgery in humans and rodent models but the underlying mechanisms remain poorly understood. In the present study we assessed at the gene expression level whether RYGB leads to recruitment of brown adipose tissue (BAT) and/or beige adipose tissue (BeAT) as a means of enhanced facultative thermogenesis and increased energy expenditure after surgery. MethodsDiet-induced obese male Wistar rats were randomized into RYGB-operated (n=10), sham-operated ad libitum fed (Sham) (n=7) or sham-operated body weight matched (BWM) to RYGB groups (n=7). At a stage of postoperatively stabilized weight reduction, BAT (interscapular), subcutaneous (inguinal) and visceral (epididymal and perirenal) white adipose tissue (WAT) depots were collected in the fasted state. Expression of thermoregulatory genes (UCP1, CIDEA and PRDM16) in BAT and WAT as well as specific markers of BeAT (Ear2 and TMEM26) in WAT was analyzed using RT-qPCR. ResultsCompared to Sham rats, UCP1 mRNA expression in BAT was significantly reduced in BWM, but not in RYGB rats. No differences in mRNA expression were found for thermoregulatory proteins or for markers of BeAT in subcutaneous or visceral WAT depots between RYGB and Sham groups. ConclusionThe compensatory decrease in BAT thermogenic gene expression typically associated with body weight loss is attenuated after RYGB which, as opposed to recruitment of BeAT, may contribute to overall increases in energy expenditure and weight loss maintenance after surgery.

Visceral and subcutaneous fat have different origins and evidence supports a mesothelial source

Fuelled by the obesity epidemic, there is considerable interest in the developmental origins of white adipose tissue (WAT) and the stem/progenitor cells from which it arises. While increased visceral fat mass is associated with metabolic dysfunction, increased subcutaneous WAT is protective. There are 6 visceral fat depots: perirenal, gonadal, epicardial, retroperitoneal, omental and mesenteric and it is a subject of much debate whether these have common developmental origins and whether this differs from subcutaneous WAT. Here we show that all 6 visceral WAT depots receive a significant contribution from cells expressing Wt1 late in gestation. Conversely, no subcutaneous WAT or brown adipose tissue (BAT) arises from Wt1 expressing cells. Postnatally, a subset of visceral WAT continues to arise from Wt1 expressing cells, consistent with the finding that Wt1 marks a proportion of cell populations enriched in WAT progenitors. We show all visceral fat depots have a mesothelial layer like the visceral organs with which they are associated and provide several lines of evidence that Wt1 expressing mesothelium can produce adipocytes. These results: reveal a major ontogenetic difference between visceral and subcutaneous WAT; pinpoint the lateral plate mesoderm as a major source of visceral WAT; support the notion that visceral WAT progenitors are heterogeneous; and suggest that mesothelium is a source of adipocytes.

Time-course microarrays reveal early activation of the immune transcriptome and adipokine dysregulation leads to fibrosis in visceral adipose depots during diet-induced obesity

BackgroundVisceral white adipose tissue (WAT) hypertrophy, adipokine production, inflammation and fibrosis are strongly associated with obesity, but the time-course of these changes in-vivo are not fully understood. Therefore, the aim of this study was to establish the time-course of changes in adipocyte morphology, adipokines and the global transcriptional landscape in visceral WAT during the development of diet-induced obesity.ResultsC57BL/6 J mice were fed a high-fat diet (HFD) or normal diet (ND) and sacrificed at 8 time-points over 24 weeks. Excessive fat accumulation was evident in visceral WAT depots (Epidydimal, Perirenal, Retroperitoneum, Mesentery) after 2–4 weeks. Fibrillar collagen accumulation was evident in epidydimal adipocytes at 24 weeks. Plasma adipokines, leptin, resistin and adipsin, increased early and time-dependently, while adiponectin decreased late after 20 weeks. Only plasma leptin and adiponectin levels were associated with their respective mRNA levels in visceral WAT. Time-course microarrays revealed early and sustained activation of the immune transcriptome in epididymal and mesenteric depots. Up-regulated inflammatory genes included pro-inflammatory cytokines, chemokines (Tnf, Il1rn, Saa3, Emr1, Adam8, Itgam, Ccl2, 3, 4, 6, 7 and 9) and their upstream signalling pathway genes (multiple Toll-like receptors, Irf5 and Cd14). Early changes also occurred in fibrosis, extracellular matrix, collagen and cathepsin related-genes, but histological fibrosis was only visible in the later stages.ConclusionsIn diet-induced obesity, early activation of TLR-mediated inflammatory signalling cascades by CD antigen genes, leads to increased expression of pro-inflammatory cytokines and chemokines, resulting in chronic low-grade inflammation. Early changes in collagen genes may trigger the accumulation of ECM components, promoting fibrosis in the later stages of diet-induced obesity. New therapeutic approaches targeting visceral adipose tissue genes altered early by HFD feeding may help ameliorate the deleterious effects of diet-induced obesity.

Modulation of IGFBP2 mRNA Expression in White Adipose Tissue upon Aging and Obesity

The insulin/IGF-1 signaling pathway is a determinant of aging and age-related diseases. IGF-binding protein 2 (IGFBP2) is secreted by white adipocytes and contributes to the prevention of diet-induced obesity and age-related insulin resistance in mice. However, the expression levels of IGFBP2 in insulin resistance disorders have not been evaluated. The present study was aimed at determining IGFBP2 mRNA levels in adipose tissue in conditions of insulin resistance such as aging and obesity. In visceral white adipose tissue (WAT), but not in subcutaneous WAT, IGFBP2 mRNA levels were significantly lower in obese OB/OB, DB/DB and high fat-fed mice compared with those of their respective lean and chow-fed littermates. IGFBP2 mRNA levels were also decreased in visceral WAT of 12 and 24 months old mice compared with those of their 4 months old counterparts. Visceral WAT IGFBP2 expression was significantly associated with IGFBP2 circulating levels in mice, suggesting an important contribution from this tissue. The negative effect of aging on IGFBP2 mRNA levels in visceral WAT was confirmed in obese men. These findings demonstrate that the transcription of the IGFBP2 gene is modulated in a depot-specific fashion in obesity and aging in mice and men. Because IGFBP2 is an adipokine, an altered production from visceral WAT depots could impact on IGF-1 signaling and its downstream targets. This supports the need for further molecular and clinical studies to determine the factors regulating IGFBP2 expression and its relevance to metabolic diseases.

Lean Phenotype and Resistance to Diet-Induced Obesity in Vitamin D Receptor Knockout Mice Correlates with Induction of Uncoupling Protein-1 in White Adipose Tissue

Increased adiposity is a feature of aging in both mice and humans, but the molecular mechanisms underlying age-related changes in adipose tissue stores remain unclear. In previous studies, we noted that 18-month-old normocalcemic vitamin D receptor (VDR) knockout (VDRKO) mice exhibited atrophy of the mammary adipose compartment relative to wild-type (WT) littermates, suggesting a role for VDR in adiposity. Here we monitored body fat depots, food intake, metabolic factors, and gene expression in WT and VDRKO mice on the C57BL6 and CD1 genetic backgrounds. Regardless of genetic background, both sc and visceral white adipose tissue depots were smaller in VDRKO mice than WT mice. The lean phenotype of VDRKO mice was associated with reduced serum leptin and compensatory increased food intake. Similar effects on adipose tissue, leptin and food intake were observed in mice lacking Cyp27b1, the 1alpha-hydroxylase enzyme that generates 1,25-dihydroxyvitamin D(3), the VDR ligand. Although VDR ablation did not reduce expression of peroxisome proliferator-activated receptor-gamma or fatty acid synthase, PCR array screening identified several differentially expressed genes in white adipose tissue from WT and VDRKO mice. Uncoupling protein-1, which mediates dissociation of cellular respiration from energy production, was greater than 25-fold elevated in VDRKO white adipose tissue. Consistent with elevation in uncoupling protein-1, VDRKO mice were resistant to high-fat diet-induced weight gain. Collectively, these studies identify a novel role for 1,25-dihydroxyvitamin D(3) and the VDR in the control of adipocyte metabolism and lipid storage in vivo.

Resistin expression and plasma concentration peak at different times during pregnancy in rats

Resistin has been proposed as both an anti-adipogenic factor and an inducer of insulin resistance. During late pregnancy, white adipose tissue mass increases and insulin sensitivity decreases. To check for the involvement of resistin in these processes, we measured plasma resistin in pregnant and non-pregnant rats and in lactating dams. Plasma resistin increased by day 15 of pregnancy and remained high 5 days post partum. The simultaneous increase in plasma resistin concentration and the decrease in insulin sensitivity is compatible with resistin depressing maternal insulin sensitivity. Resistin expression increased 5-15 times in visceral white adipose tissue depots by day 8 of pregnancy but was similar to pre-pregnancy values by day 19. Resistin expression in the placenta and mammary gland was similar to that in the parametrial adipose depot by day 8 but was almost null by day 19. There was therefore a time-lag between the peaks in expression and in plasma concentration. White adipose tissue mass increased without changes in adipocyte size once peaks in resistin expression had passed, which is compatible with an anti-adipogenic role for enhanced resistin expression. A bolus injection of chorionic gonadotrophin - which peaks in early pregnancy - to non-pregnant rats increased resistin expression in white adipose tissue, indicating that this hormone is involved in controlling resistin expression. Resistin was not detected in cerebrospinal fluid. Our results have suggested a role for resistin in pregnancy.