Mesenteric White Adipose Tissue Research Articles

The Green Algal Carotenoid Siphonaxanthin Inhibits Adipogenesis in 3T3-L1 Preadipocytes and the Accumulation of Lipids in White Adipose Tissue of KK-Ay Mice1–3

Background: Siphonaxanthin, a xanthophyll present in green algae, has been shown to possess antiangiogenic and apoptosis-inducing activities.Objective: We evaluated the antiobesity effects of siphonaxanthin by using a 3T3-L1 cell culture system and in diabetic KK-Ay mice.Methods: 3T3-L1 cells were differentiated with or without 5 μmol/L siphonaxanthin, and lipid accumulation and critical gene expressions for adipogenesis were examined. In vivo, 4-wk-old male KK-Ay mice were administered daily oral treatment of 1.3 mg siphonaxanthin for 6 wk and body weight, visceral fat weight, serum variables, and gene expressions involved in lipid metabolism were evaluated.Results: Compared with the other carotenoids evaluated, siphonaxanthin potently inhibited adipocyte differentiation. Siphonaxanthin significantly suppressed lipid accumulation at noncytotoxic concentrations of 2.5 and 5 μmol/L by 29% and 43%, respectively. The effects of siphonaxanthin were largely limited to the early stages of adipogenesis. Siphonaxanthin significantly inhibited protein kinase B phosphorylation by 48% and 72% at 90 and 120 min, respectively. The expressions of key adipogenesis genes, including CCAAT/enhancer binding protein α (Cebpa), peroxisome proliferator activated receptor γ (Pparg), fatty acid binding protein 4 (Fabp4), and stearoyl coenzyme A desaturase 1 (Scd1), were elevated by 1.6- to 166-fold during adipogenesis. After 8 d of adipocyte differentiation, siphonaxanthin significantly lowered gene expression of Cebpa, Pparg, Fabp4, and Scd1 by 94%, 83%, 95%, and 90%, respectively. Moreover, oral administration of siphonaxanthin to KK-Ay mice significantly reduced the total weight of white adipose tissue (WAT) by 13%, especially the mesenteric WAT by 28%. Furthermore, siphonaxanthin administration reduced lipogenesis and enhanced fatty acid oxidation in adipose tissue. Siphonaxanthin was observed to highly accumulate in mesenteric WAT, and the accumulation in the mesenteric WAT was almost 2- and 3-fold that in epididymal (P = 0.14) and perirenal (P < 0.05) WAT, respectively.Conclusion: These results provide evidence that siphonaxanthin may effectively regulate adipogenesis in 3T3-L1 cells and diabetic KK-Ay mice.

Transcriptomics expression analysis to unveil the molecular mechanisms underlying the cocoa polyphenol treatment in diet-induced obesity rats

Cocoa polyphenol (CP), due to their biological actions, may be supplementary treatments for adipose tissue-fat gain. However, the molecular mechanism of CPs is still ambiguous. This study investigated the hypothesis that CP treatment modulates expressing of lipid metabolism genes in mesenteric white adipose tissue (MES-WAT). Sprague–Dawley (SD) rats were fed a low-fat (LF) or high-fat (HF) diet for 12weeks. Thereafter, HFD rats (n=10/group) were treated at a dose of 600mg/kgbw/day CPs (HFD+CPs) for 4weeks. DNA microarray analysis resulted in 753 genes of the 13,008 genes expressed. Bioinformatics tools showed CP treatment significantly decreased gene expression levels for lipogenic enzymes, while increased the mRNA levels responsible for lipolysis enzymes. CP administration differentially regulates gene expression involved in lipid metabolism in MES-WAT. These data unveil a new insight into the molecular mechanisms underlying the pharmacological effect of CPs on obesity biomarkers in obese rats.

Chronic consumption of dietary proanthocyanidins modulates peripheral clocks in healthy and obese rats

Circadian rhythm plays an important role in maintaining homeostasis, and its disruption increases the risk of developing metabolic syndrome. Circadian rhythm is maintained by a central clock in the hypothalamus that is entrained by light, but circadian clocks are also present in peripheral tissues. These peripheral clocks are trained by other cues, such as diet. The aim of this study was to determine whether proanthocyanidins, the most abundant polyphenols in the human diet, modulate the expression of clock and clock-controlled genes in the liver, gut and mesenteric white adipose tissue (mWAT) in healthy and obese rats. Grape seed proanthocyanidin extracts (GSPEs) were administered for 21 days at 5, 25 or 50 mg GSPE/kg body weight in healthy rats and 25 mg GSPE/kg body weight in rats with diet-induced obesity. In healthy animals, GSPE administration led to the overexpression of core clock genes in a positive dose-dependent manner. Moreover, the acetylated BMAL1 protein ratio increased with the same pattern in the liver and mWAT. With regards to clock-controlled genes, Per2 was also overexpressed, whereas Rev-erbα and RORα were repressed in a negative dose-dependent manner. Diet-induced obesity always resulted in the overexpression of some core clock and clock-related genes, although the particular gene affected was tissue specific. GSPE administration counteracted disturbances in the clock genes in the liver and gut but was less effective in normalizing the clock gene disruption in WAT. In conclusion, proanthocyanidins have the capacity to modulate peripheral molecular clocks in both healthy and obese states.

1H NMR-based profiling reveals differential immune-metabolic networks during influenza virus infection in obese mice.

Obese individuals are at greater risk for death from influenza virus infection. Paralleling human evidence, obese mice are also more susceptible to influenza infection mortality. However, the underlying mechanisms driving greater influenza severity in the obese remain unclear. Metabolic profiling has been utilized in infectious disease models to enhance prognostic or diagnostic methods, and to gain insight into disease pathogenesis by providing a more global picture of dynamic infection responses. Herein, metabolic profiling was used to develop a deeper understanding of the complex processes contributing to impaired influenza protection in obese mice and to facilitate generation of new explanatory hypotheses. Diet-induced obese and lean mice were infected with influenza A/Puerto Rico/8/34. 1H nuclear magnetic resonance-based metabolic profiling of urine, feces, lung, liver, mesenteric white adipose tissue, bronchoalveolar lavage fluid and serum revealed distinct metabolic signatures in infected obese mice, including perturbations in nucleotide, vitamin, ketone body, amino acid, carbohydrate, choline and lipid metabolic pathways. Further, metabolic data was integrated with immune analyses to obtain a more comprehensive understanding of potential immune-metabolic interactions. Of interest, uncovered metabolic signatures in urine and feces allowed for discrimination of infection status in both lean and obese mice at an early influenza time point, which holds prognostic and diagnostic implications for this methodology. These results confirm that obesity causes distinct metabolic perturbations during influenza infection and provide a basis for generation of new hypotheses and use of this methodology in detection of putative biomarkers and metabolic patterns to predict influenza infection outcome.

Metabolic profiling uncovers differential metabolic signatures and biomarkers in influenza‐infected obese mice (392.3)

Obese individuals are at greater risk for hospitalization and death from influenza virus infection. Paralleling human evidence, obese mice also exhibit greater mortality to influenza compared with lean mice. Although obesity is known to impair immunity, the mechanisms driving greater influenza severity in the obese remain unclear. Therefore, we have taken a novel approach for elucidating the underlying mechanisms contributing to altered infection responses. We conducted metabolic profiling to identify differential metabolic signatures in infected lean and obese mice, and integrated metabolite data with immune parameters to identify significant immune‐metabolic interactions. Urine, feces, serum, bronchoalveolar lavage fluid, lungs, mesenteric white adipose tissue, and livers were harvested from uninfected or influenza infected mice for subsequent 1H NMR‐based metabolic profiling. Multivariate statistical analysis revealed distinct metabolic signatures between lean and obese mice, both locally at the site of infection and systemically. Obesity caused perturbations in lipid, choline, nucleotide and carbohydrate metabolic pathways during infection. Further, activated T cells negatively correlated with 3‐hydroxybutyrate and creatine in the lungs of obese mice, possibly suggesting regulatory functions for these metabolites. Of interest, urine samples obtained from obese mice as early as two days post‐infection had a distinct metabolic signature compared with urine samples from lean infected mice. Given the rapidity of influenza transmission and the sudden onset of symptoms during infection, identification of an early infection metabolic signature and unique biomarkers in a non‐invasive biofluid, such as urine, has widespread prognostic and diagnostic implications. Further, identification of altered metabolic pathways in obese mice will facilitate better understanding of the determinants of greater influenza mortality observed in obese mice and humans.Grant Funding Source: Supported by NORC DK56350

Central sympathetic innervations to visceral and subcutaneous white adipose tissue

There is a link between visceral white adipose tissue (WAT) and the metabolic syndrome in humans, with health improvements produced with small visceral WAT reduction. By contrast, subcutaneous WAT provides a site for lipid storage that is rather innocuous relative to ectopic lipid storage in muscle or liver. The sympathetic nervous system (SNS) is the principal initiator for lipolysis in WAT by mammals. Nothing is known, however, about the central origins of the SNS circuitry innervating the only true visceral WAT in rodents, mesenteric WAT (MWAT), which drains into the hepatic portal vein. We tested whether the central sympathetic circuits to subcutaneous [inguinal WAT (IWAT)] and visceral WAT (MWAT) are separate or shared and whether they possess differential sympathetic drives with food deprivation in Siberian hamsters. Using two isogenic strains of pseudorabies virus, a retrograde transneuronal viral tract tracer within the same hamsters, we found some overlap (∼20-55% doubly infected neurons) between the two circuitries across the neural axis with lesser overlap proximal to the depots (spinal cord and sympathetic chain) and with more neurons involved in the innervation of IWAT than MWAT in some brain regions. Food deprivation triggered a greater sympathetic drive to subcutaneous (IWAT) than visceral (MWAT) depots. Collectively, we demonstrated both shared and separate populations of brain, spinal cord, and sympathetic chain neurons ultimately project to a subcutaneous WAT depot (IWAT) and the only visceral WAT depot in rodents (MWAT). In addition, the lipolytic stimulus of food deprivation only increased SNS drive to subcutaneous fat (IWAT).

The role of physical exercise in inflammatory bowel disease.

We reviewed and analyzed the relationship between physical exercise and inflammatory bowel disease (IBD) which covers a group of chronic, relapsing, and remitting intestinal disorders including Crohn's disease (CD) and ulcerative colitis. The etiology of IBD likely involves a combination of genetic predisposition and environmental risk factors. Physical training has been suggested to be protective against the onset of IBD, but there are inconsistencies in the findings of the published literature. Hypertrophy of the mesenteric white adipose tissue (mWAT) is recognized as a characteristic feature of CD, but its importance for the perpetuation of onset of this intestinal disease is unknown. Adipocytes synthesize proinflammatory and anti-inflammatory cytokines. Hypertrophy of mWAT could play a role as a barrier to the inflammatory process, but recent data suggest that deregulation of adipokine secretion is involved in the pathogenesis of CD. Adipocytokines and macrophage mediators perpetuate the intestinal inflammatory process, leading to mucosal ulcerations along the mesenteric border, a typical feature of CD. Contracting skeletal muscles release biologically active myokines, known to exert the direct anti-inflammatory effects, and inhibit the release of proinflammatory mediators from visceral fat. Further research is required to confirm these observations and establish exercise regimes for IBD patients.

Six weeks of voluntary wheel running modulates inflammatory protein (MCP-1, IL-6, and IL-10) and DAMP (Hsp72) responses to acute stress in white adipose tissue of lean rats

To prime local tissues for dealing with potential infection or injury, exposure to an acute, intense stressor evokes increases in circulating and local tissue inflammatory proteins. Regular physical activity facilitates stress-evoked innate reactivity and modulates the expression of inflammatory proteins in immuno-metabolic tissues such as white adipose tissue (WAT). The impact of regular physical activity on stress-evoked inflammatory protein expression in WAT, however, remains unclear. To investigate this question, lean male F344 rats (150-175g) were allowed voluntary access to a running wheel for 6weeks followed by exposure to an acute stressor (100, 1.5mA-5s inescapable tail shocks). Using ELISAs, corticosterone, heat shock protein 72 (Hsp72), macrophage chemoattractant protein (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and IL-10 concentrations were measured in plasma and subcutaneous, intraperitoneal (epididymal and retroperitoneal WAT depots) and visceral (omental and mesenteric WAT depots) WAT compartments. Acute stress increased plasma concentrations of all proteins except TNF-α and, depending upon the compartment examined, WAT concentrations of MCP-1, IL-1β, IL-6, and IL-10. Exercise ubiquitously increased IL-1β within WAT, potentiated stress-evoked Hsp72 in plasma and WAT, and differentially increased stress-evoked MCP-1, IL-6, and IL-10 within WAT. These data suggest: (a) inflammatory proteins in non-obese WAT may serve compartment-specific immune and metabolic roles important to the acute stress response and; (b) voluntary habitual exercise may optimize stress-induced augmentation of innate immune function through increases in stress-evoked Hsp72, MCP-1, IL-6, and IL-10 and decreases in IL-1β/IL10 and TNF-α/IL10 ratios within white adipose tissue.

Adipose tissue remodeling in rats exhibiting fructose-induced obesity

To explore the effect of a fructose-rich diet on morphological and functional changes in white adipose tissue (WAT) that could contribute to the development of insulin resistance. Adult sedentary rats were fed a fructose-rich diet for 8weeks. Glucose tolerance test was carried out together with measurement of plasma triglycerides, non-esterified fatty acids and lipid peroxidation. In subcutaneous abdominal and intra-abdominal WAT, number and size of adipocytes together with cellular insulin sensitivity and lipolytic activity were assessed. Rats fed a fructose-rich diet exhibited a significant increase in plasma insulin, triglycerides, non-esterified fatty acids and lipid peroxidation, together with significantly increased body lipids and epididymal and mesenteric WAT, compared to controls. Mean adipocyte volume in subcutaneous abdominal WAT was significantly lower, while mean adipocyte volume in intra-abdominal WAT was significantly higher, in rats fed a fructose-rich diet compared to controls. A significant increase in larger adipocytes and a significant decrease in smaller adipocytes were found in intra-abdominal WAT in rats fed a fructose-rich diet compared to controls. Insulin's ability to inhibit lipolysis was blunted in subcutaneous abdominal and intra-abdominal adipocytes from fructose-fed rats. Accordingly, lower p-Akt/Akt ratio was found in WAT in rats fed a fructose-rich diet compared to controls. Long-term consumption of high levels of fructose elicits remarkable morphological and functional modifications, particularly in intra-abdominal WAT, that are highly predictive of obesity and insulin resistance and that contribute to the worsening of metabolic alterations peculiar in a fructose-rich, hypolipidic diet.

Cell Suspension Culture of Eriobotrya japonica Regulates the Diabetic and Hyperlipidemic Signs of High-Fat-Fed Mice

The present study investigates the anti-hyperlipidemic and antihyperglycemic effects and mechanism in high-fat (HF)-fed mice of cell suspension culture of Eriobotrya japonica (TA), which contains a great number of pentacyclic terpenoids. Firstly, C57BL/6J mice were randomly divided into two groups: the control (CON) group was fed with a low-fat diet (n = 9), whereas the experimental group was fed a 45% HF diet for 8 weeks. Afterwards, the CON group was treated with vehicle, whereas the HF group was subdivided into five groups and was orally given TA or rosiglitazone or not for 4 weeks. Blood and visceral adipose tissue, liver tissue and skeletal muscle were examined. Treatment with TA reduced body weight gain, weights of white adipose tissue (WAT) (including epididymal, perirenal, mesenteric WAT and visceral fat), and hepatic triacylglycerol content significantly without affecting food intake in diet-induced diabetic mice. TA effectively prevented HF diet-induced increases in the levels of blood glucose, insulin, leptin and HOMA-IR index (p < 0.001, p < 0.05, p < 0.05, p < 0.01, respectively) and attenuated insulin resistance. Treatment with TA, adipocytes in the visceral depots showed a reduction in size. TA effectively significantly increased the protein contents of phosphorylation of AMPK-α (Thr172) both in liver and adipose tissue. It is shown that TA exhibits hypolipidemic effect in HF-fed mice by decreasing gene expressions of fatty acid synthesis, including acyl-coenzyme A: diacylglycerol acyltransferase (DGAT) 2, which catalyzes the final step in the synthesis of triglycerides, and antidiabetic properties occurred as a result of decreased hepatic glucose production via phosphenolpyruvate carboxykinase (PEPCK) down- regulation, improved insulin sensitization and TA (at 1.0 g/kg dose) decreased expression of hepatic and adipose 11-β-hydroxysteroid dehydroxygenase (11β-HSD1) gene, which contributed in attenuating diabetic state. Futhermore, TA at doses of 0.5 and 1.0 g/kg had serum lipid-lowering action characterized by the inhibition of DGAT 1 expression. Thus, amelioration of diabetic and dyslipidemic state by TA in HF-fed mice occurred by regulation of PEPCK, DGAT2 and AMPK phosphorylation.

Diet-induced changes in Ucp1 expression in bovine adipose tissues

Brown adipocytes, which regulate non-shivering thermogenesis, have been believed to exist in a limited number of mammalian species, and only under limited physiological conditions. Recent discoveries indicate that adult humans possess a significant number of functional brown adipocytes. This study explores the regulatory emergence of brown adipocytes in white adipose tissue (WAT) depots of fattening cattle. RT-PCR analyses indicated significant expression of Ucp1, a brown adipocyte-specific gene, in the WAT of 31-month-old Japanese Black steers. Immunohistochemical analysis revealed that Ucp1-positive small adipocytes were dispersed in the subcutaneous WAT. Next, we examined expression level of Ucp1 and other brown adipocyte-selective genes such as Pgc1α, Cidea, Dio2, Cox1, Cox7a1 and Cox8b in WAT of 30-month-old steers fed either diet with low protein/energy content (roughage diet) or that with high protein/energy content (concentrate diet) for 20months. Ucp1 expression in the subcutaneous WAT was significantly higher in the concentrate diet group than in the roughage diet group. Furthermore, the higher Ucp1 expression levels were limited to the subcutaneous WAT, and no differences between groups were detected in the mesenteric, perirenal, intermuscular or intramuscular WAT. Expression of Dio2, Cox1 and Cox8b was higher in the subcutaneous WAT but not in the mesenteric WAT of the concentrate diet group. Furthermore, expression of Prdm16, a positive regulator of differentiation toward brown adipocyte-lineage cells, and expression of leptin, a molecule that enhances activity of brown adipocytes, were significantly higher in the subcutaneous WAT of the concentrate diet group. This study demonstrates the presence of brown adipocytes in WAT depots of fattening cattle, and suggests the diet-related modulation of expression of genes predominantly expressed in brown adipocytes.

Effect of Dietary Polyphenols from Hop (Humulus lupulus L.) Pomace on Adipose Tissue Mass, Fasting Blood Glucose, Hemoglobin A1c, and Plasma Monocyte Chemotactic Protein-1 Levels in OLETF Rats

Hop (Humulus lupulus L.) pomace contains procyanidin-rich polyphenols, which are large oligomeric compounds of catechin. We studied the effect of high dose (1%) of dietary hop pomace polyphenols (HPs) in Otsuka Long-EvansTokushima Fatty (OLETF) rats, an animal model of type 2 diabetes. By 70 days, the rats fed HPs tended to have a lower body weight and reduced mesenteric white adipose tissue weight than the rats fed a control diet. Triglyceride levels in both plasma and liver tended to be lower in the HPs-fed group than in the control group. Dietary HPs substantially suppressed the activities of hepatic fatty acid synthetase, glucose-6-phosphate dehydrogenase, and malic enzyme, through the suppression of SREBP1c mRNA expression in OLETF rats. Moreover, in the HPs-fed group, monocyte chemotactic protein-1 (MCP-1) expression and fasting blood glucose levels at 40 days, and hemoglobin A1c (HbA1c) levels at 70 days were significantly lower than those in the control group. Thus, dietary HPs may exert an ameliorative function on hepatic fatty acid metabolism, glucose metabolism, and inflammatory response accompanying the increase of the adipose tissue mass in OLETF rats.

131. The gut microbiota modulates stress-induced cytokine concentrations in healthy, non-obese white adipose tissue

Acute stressor exposure induces a sterile inflammatory response marked by shifts in circulating and white adipose tissue (WAT) cytokines. Although the sterile inflammatory response occurs in healthy/non-obese WAT and varies in magnitude relative to the WAT depot, the mechanisms which regulate stress-induced WAT cytokines remain unclear. Because the gut microbiota modulates visceral WAT inflammation and stress-induced systemic cytokines, we hypothesized that changes to the normal microbiota environment would also affect stress-induced WAT cytokines. To test this hypothesis 8 week old male Fischer 344 rats were treated for four days with antibiotics (4 mg/mL streptomycin and 2 mg/mL penicillin G) administered via drinking water prior to receiving 100 tail-shocks (1.5 mA, 5s, every 60 s ± 25 s). Immediately before or following stress rats were sacrificed and subcutaneous, retroperitoneal, epididymal, omental, and mesenteric WAT were harvested for cytokine analyses via ELISA. Stress differentially increased interleukin-1beta (IL-1beta) in all WAT depots, decreased interleukin-10 (IL-10) in subcutaneous and mesenteric WAT and tumor necrosis factor-alpha in omental WAT. Antibiotic treatment reduced fecal colony forming units, dampened the stress-induced increase in IL-1beta in subcutaneous and retroperitoneal WAT and the stress-induced decrease in IL-10 in subcutaneous and mesenteric WAT. These data demonstrate that the gut microbiota directly affects stress-induced shifts in WAT cytokine concentrations in a depot specific manner suggesting a novel mechanism through which pro-inflammatory cytokine concentrations are regulated in healthy, stressed non-obese WAT. NSF-1022451.

Diet high in fat and sucrose induces rapid onset of obesity-related metabolic syndrome partly through rapid response of genes involved in lipogenesis, insulin signalling and inflammation in mice

BackgroundFrequent consumption of a diet high in fat and sucrose contributes to lifestyle-related diseases. However, limited information is available regarding the short-term effects of such a diet on the onset of obesity-associated metabolic abnormalities.MethodsMale C57BL/6 J mice were divided into two groups and fed a standard chow diet (control group) or a high fat–high sucrose diet containing 21% fat and 34% sucrose (HF–HS diet group) for 2 or 4 weeks.ResultsThe HF–HS diet significantly induced body weight gain beginning at week 1 and similarly increased mesenteric white adipose tissue weight and plasma insulin levels at weeks 2 and 4. Plasma resistin levels were notably elevated after feeding with the HF–HS diet for 4 weeks. Measurement of hepatic triglycerides and Oil Red O staining clearly indicated increased hepatic lipid accumulation in response to the HF–HS diet as early as 2 weeks. Quantitative PCR analysis of liver and white adipose tissue indicated that, starting at week 2, the HF–HS diet upregulated mRNA expression from genes involved in lipid metabolism and inflammation and downregulated genes involved in insulin signalling. Although plasma cholesterol levels were also rapidly increased by the HF–HS diet, no differences were found between the control and HF–HS diet–fed animals in the expression of key genes involved in cholesterol biosynthesis.ConclusionsOur study demonstrates that the rapid onset of hepatosteatosis, adipose tissue hypertrophy and hyperinsulinemia by ingestion of a diet high in fat and sucrose may possibly be due to the rapid response of lipogenic, insulin signalling and inflammatory genes.

Green Tea Prevents Obesity by Increasing Expression of Insulin-like Growth Factor Binding Protein-1 in Adipose Tissue of High-Fat Diet-Fed Mice

It is known that green tea has the ability to prevent obesity, but the underlying molecular mechanism is not fully understood to date. A preventive mechanism of green tea on obesity in C57BL/6 mice fed a high-fat (HF) diet was investigated by evaluating the expression levels of obesity-related proteins in mesenteric white adipose tissue by using protein array. An increase in the expression level of insulin-like growth factor binding protein (IGFBP)-1 by green tea was found in the white adipose tissues of both control and HF diet-fed mice by protein array and confirmed by Western blot. Moreover, the expression level was negatively correlated with adipose tissue weight. In 3T3-L1 adipocytes, treatment with green tea and its major polyphenol, (-)-epigallocatechin gallate, induced the expression of IGFBP-1 in a dose-dependent manner by Western blot. In conclusion, IGFBP-1 in adipose tissue is a novel molecule target for the prevention of obesity by green tea.

Heterogeneity Among White Adipose Tissue Depots in Male C57BL/6J Mice

The widespread prevalence of obesity has lead to extensive research on white adipose tissue (WAT), which frequently uses the C57BL/6J mouse strain as a model. In many studies, results obtained in one WAT depot are often extrapolated to all WAT. However, functional differences among WAT depots are now becoming apparent. Thus, to identify the molecular mechanisms responsible for WAT depot-specific differences under "normal" conditions, four C57BL/6J mouse WAT depots (inguinal, mesenteric, epididymal, and retroperitoneal) were analyzed. Depot proteomic profiles, along with weights, protein contents, adipocyte sizes and oxidative stress were determined. Mesenteric WAT had almost twice the protein content of the other depots analyzed. Mean adipocyte size was highest in epididymal and lowest in mesenteric and inguinal depots. The proteome of inguinal WAT displayed low levels of enzymes involved in ATP generation, glucose and lipid metabolism, and antioxidant proteins. Higher levels of these proteins were observed in mesenteric and epididymal WAT, with variable levels in the retroperitoneal depot. Some of these proteins showed depot-specific correlations with plasma levels of insulin, leptin, and adiponectin. In agreement with the proteomic data, levels of the antioxidant protein heat shock protein β1 (HSPβ1) also were lower in inguinal WAT when analyzed by western blotting and immunohistochemistry. Also, lipid peroxidation products showed similar trends. Our results are consistent with lower triglyceride turnover and lower oxidative stress in inguinal than mesenteric and epididymal WAT. The observed WAT depot-specific differences provide clues as to the mechanisms leading to these depots' respective diverse functions.

Probiotics Modulate Intestinal Expression of Nuclear Receptor and Provide Counter-Regulatory Signals to Inflammation-Driven Adipose Tissue Activation

BackgroundAdipocytes from mesenteric white adipose tissue amplify the inflammatory response and participate in inflammation-driven immune dysfunction in Crohn's disease by releasing proinflammatory mediators. Peroxisome proliferator-activated receptors (PPAR)-α and -γ, pregnane x receptor (PXR), farnesoid x receptor (FXR) and liver x-receptor (LXR) are ligand-activated nuclear receptor that provide counter-regulatory signals to dysregulated immunity and modulates adipose tissue.AimsTo investigate the expression and function of nuclear receptors in intestinal and adipose tissues in a rodent model of colitis and mesenteric fat from Crohn's patients and to investigate their modulation by probiotics.MethodsColitis was induced by TNBS administration. Mice were administered vehicle or VSL#3, daily for 10 days. Abdominal fat explants obtained at surgery from five Crohn's disease patients and five patients with colon cancer were cultured with VSL#3 medium.ResultsProbiotic administration attenuated development of signs and symptoms of colitis, reduced colonic expression of TNFα, IL-6 and IFNγ and reserved colonic downregulation of PPARγ, PXR and FXR caused by TNBS. Mesenteric fat depots isolated from TNBS-treated animals had increased expression of inflammatory mediators along with PPARγ, FXR, leptin and adiponectin. These changes were prevented by VSL#3. Creeping fat and mesenteric adipose tissue from Crohn's patients showed a differential expression of PPARγ and FXR with both tissue expressing high levels of leptin. Exposure of these tissues to VSL#3 medium abrogates leptin release.ConclusionsMesenteric adipose tissue from rodent colitis and Crohn's disease is metabolically active and shows inflammation-driven regulation of PPARγ, FXR and leptin. Probiotics correct the inflammation-driven metabolic dysfunction.

Adiponectin Enhances Insulin Sensitivity by Increasing Hepatic IRS-2 Expression via a Macrophage-Derived IL-6-Dependent Pathway

Insulin resistance is often associated with impeded insulin signaling due either to decreased concentrations or functional modifications of crucial signaling molecules including insulin receptor substrates (IRS) in the liver. Many actions of adiponectin, a well-recognized antidiabetic adipokine, are currently attributed to the activation of two critical molecules downstream of AdipoR1 and R2: AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). However, the direct effects of adiponectin on insulin signaling molecules remain poorly understood. We show here that adiponectin upregulates IRS-2 through activation of signal transducer and activator of transcription-3 (STAT3). Surprisingly, this activation is associated with IL-6 production from macrophages induced by adiponectin through NFκB activation independent of its authentic receptors, AdipoR1 and AdipoR2. These data have unraveled an insulin-sensitizing action initiated by adiponectin leading to upregulation of hepatic IRS-2 via an IL-6 dependent pathway through a still unidentified adiponectin receptor.

Modulatory effect of grape-seed procyanidins on local and systemic inflammation in diet-induced obesity rats

Chronic low-grade inflammation in obesity is characterized by macrophage accumulation in white adipose tissue (WAT) and abnormal cytokine production. We tested the hypothesis that grape-seed procyanidin extract (PE), with known anti-inflammatory and antioxidant effects, would improve local and systemic inflammation in diet-induced obesity rats. First, we analyzed the preventive effects of procyanidins (30 mg/kg per day) on rats fed a 60% kcal fat diet for 19 weeks. Second, we induced cafeteria diet obesity for 13 weeks to investigate the corrective effects of two PE doses (25 and 50 mg/kg per day) for 10 and 30 days. In the preventive model, PE group had reduced not only body weight but also plasmatic systemic markers of inflammation tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP). The PE preventive treatment significantly showed an increased adiponectin expression and decreased TNF-α, interleukin-6 and CRP expression in mesenteric WAT and muscle TNF-α. A reduced NF-κB activity in liver is also observed which can be related to low expression rates of hepatic inflammatory markers found in PE group. Finally, PE dietary supplementation is linked to a reduced expression of Emr1 (specific marker of macrophage F4/80), which suggests a reduced macrophage infiltration of WAT. In the corrective model, however, only the high dose of PE reduced CRP plasma levels in the short treatment without changes in plasmatic TNF-α. In conclusion, orally ingested PE helps preventing imbalanced obesity cytokine pattern, but its corrective effects need to be further investigated. The dietary regular intake of food or drinks containing procyanidins might help prevent low-grade inflammatory-related diseases.

Fucoxanthin regulates adipocytokine mRNA expression in white adipose tissue of diabetic/obese KK- A y mice

Fucoxanthin, a marine carotenoid found in edible brown seaweeds, attenuates white adipose tissue (WAT) weight gain and hyperglycemia in diabetic/obese KK- A y mice, although it does not affect these parameters in lean C57BL/6J mice. In perigonadal and mesenteric WATs of KK- A y mice fed fucoxanthin, mRNA expression levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α), which are considered to induce insulin resistance, were markedly reduced compared to control mice. In contrast to KK- A y mice, fucoxanthin did not alter MCP-1 and TNF-α mRNA expression levels in the WAT of lean C57BL/6J mice. Interleukin-6 (IL-6) and plasminogen activator inhibitor-1 mRNA expression levels in WAT were also decreased by fucoxanthin in KK- A y mice. In differentiating 3T3-F442A adipocytes, fucoxanthinol, which is a fucoxanthin metabolite found in WAT, attenuated TNF-α-induced MCP-1 and IL-6 mRNA overexpression and protein secretion into the culture medium. In addition, fucoxanthinol decreased TNF-α, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA expression in RAW264.7 macrophage-like cells stimulated by palmitic acid. These findings indicate that fucoxanthin regulates mRNA expression of inflammatory adipocytokines involved in insulin resistance, iNOS, and COX-2 in WAT and has specific effects on diabetic/obese KK- A y mice, but not on lean C57BL/6J mice.