Abstract 293: Id3 Regulates High-Fat-Diet--Induced IgG2c Production

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Daniel B Harmon ◽  
Stephanie N Oldham ◽  
Loren D Erickson ◽  
Coleen A McNamara
Keyword(s):  
Adipose Tissue ◽  
B Cells ◽  
B Cell ◽  
High Fat Diet ◽  
Fold Increase ◽  
Cell Number ◽  
Metabolic Effects ◽  
High Fat ◽  
Helix Loop Helix

Background: High-fat diet (HFD)-induced adipose tissue inflammation leads to insulin resistance and glucose intolerance, increasing the risk of cardiovascular disease. Recently, B cells and IgG antibodies have been shown to promote the metabolic consequences of obesity. HFD induces IgG2c production - an IgG isotype that promotes inflammatory disorders. Mice null for Id3, a helix-loop-helix protein known to mediate IgG2c responses in vivo, develop significantly attenuated HFD-induced obesity; raising the interesting hypothesis that Id3 promotes HFD-induced obesity by mediating HFD-induced IgG2c production. Methods and results: Western Blot analysis revealed that primary splenic B cells stimulated with IFN + CD40L (an IgG2c-inducing cocktail) expressed significantly greater amounts of Id3 protein compared to B cells treated with CD40L alone ((1.26+/-0.05 vs 0.88+/-0.03; n=3; p=0.003). ELISA determination of immunoglobulin levels from whole adipose tissue of fed C57Bl/6J (WT) mice fed a HFD (60% kcal fat) revealed a 4 fold increase in IgG2c (3810+/-789 ng vs 993+/-422 ng; n=5; p=0.01) - but not IgM, IgG1, or IgG2b - compared to chow-fed controls. No differences in serum IgG2c were observed. In contrast, HFD-induced adipose tissue IgG2c levels were significantly attenuated in Id3 -/- mice (1643+/-493 vs 889+/-272 ng; n=6-7; p=0.19), despite the fact that Id3 -/- mice had significantly more adipose tissue B cells per (g) fat compared to WT (1.6E5+/-0.2E5 vs 0.5E5+/-0.09E5; n=5; p=0.001). Conclusions: Id3 promotes HFD-induced local adipose tissue IgG2c production; an effect not dependent on B cell number. Studies in animals with B cell-specific loss of Id3 are ongoing to identify the mechanisms whereby Id3 mediates HFD-induced IgG2c production and downstream metabolic effects.

scholarly journals Browning Effects of a Chronic Pterostilbene Supplementation in Mice Fed a High-Fat Diet

2019 ◽  
Vol 20 (21) ◽  
pp. 5377 ◽  
Author(s):  
Martina La Spina ◽  
Eva Galletta ◽  
Michele Azzolini ◽  
Saioa Gomez Zorita ◽  
Sofia Parrasia ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
Uncoupling Protein ◽  
Protein A ◽  
Health Concern ◽  
Marker Genes ◽  
High Fat ◽  
Protein Levels

Obesity and related comorbidities are a major health concern. The drugs used to treat these conditions are largely inadequate or dangerous, and a well-researched approach based on nutraceuticals would be highly useful. Pterostilbene (Pt), i.e., 3,5-dimethylresveratrol, has been reported to be effective in animal models of obesity, acting on different metabolic pathways. We investigate here its ability to induce browning of white adipose tissue. Pt (5 µM) was first tested on 3T3-L1 mature adipocytes, and then it was administered (352 µmol/kg/day) to mice fed an obesogenic high-fat diet (HFD) for 30 weeks, starting at weaning. In the cultured adipocytes, the treatment elicited a significant increase of the levels of Uncoupling Protein 1 (UCP1) protein—a key component of thermogenic, energy-dissipating beige/brown adipocytes. In vivo administration antagonized weight increase, more so in males than in females. Analysis of inguinal White Adipose Tissue (WAT) revealed a trend towards browning, with significantly increased transcription of several marker genes (Cidea, Ebf2, Pgc1α, PPARγ, Sirt1, and Tbx1) and an increase in UCP1 protein levels, which, however, did not achieve significance. Given the lack of known side effects of Pt, this study strengthens the candidacy of this natural phenol as an anti-obesity nutraceutical.

scholarly journals Minor role of mature adipocyte mineralocorticoid receptor in high-fat diet-induced obesity

2018 ◽  
Vol 239 (2) ◽  
pp. 229-240 ◽  
Author(s):  
A Feraco ◽  
A Armani ◽  
R Urbanet ◽  
A Nguyen Dinh Cat ◽  
V Marzolla ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Mouse Model ◽  
High Fat Diet ◽  
Mineralocorticoid Receptor ◽  
Metabolic Effects ◽  
Minor Role ◽  
High Fat ◽  
Mature Adipocyte ◽  
Diet Induced Obesity ◽  
Significant Difference

Obesity is a major risk factor that contributes to the development of cardiovascular disease and type 2 diabetes. Mineralocorticoid receptor (MR) expression is increased in the adipose tissue of obese patients and several studies provide evidence that MR pharmacological antagonism improves glucose metabolism in genetic and diet-induced mouse models of obesity. In order to investigate whether the lack of adipocyte MR is sufficient to explain these beneficial metabolic effects, we generated a mouse model with inducible adipocyte-specific deletion of Nr3c2 gene encoding MR (adipo-MRKO). We observed a significant, yet not complete, reduction of Nr3c2 transcript and MR protein expression in subcutaneous and visceral adipose depots of adipo-MRKO mice. Notably, only mature adipocyte fraction lacks MR, whereas the stromal vascular fraction maintains normal MR expression in our mouse model. Adipo-MRKO mice fed a 45% high-fat diet for 14 weeks did not show any significant difference in body weight and fat mass compared to control littermates. Glucose and insulin tolerance tests revealed that mature adipocyte MR deficiency did not improve insulin sensitivity in response to a metabolic homeostatic challenge. Accordingly, no significant changes were observed in gene expression profile of adipogenic and inflammatory markers in adipose tissue of adipo-MRKO mice. Moreover, pharmacological MR antagonism in mature primary murine adipocytes, which differentiated ex vivo from WT mice, did not display any effect on adipokine expression. Taken together, these data demonstrate that the depletion of MR in mature adipocytes displays a minor role in diet-induced obesity and metabolic dysfunctions.

scholarly journals Oleacein Prevents High Fat Diet-Induced A Diposity and Ameliorates Some Biochemical Parameters of Insulin Sensitivity in Mice

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1829 ◽  
Author(s):  
Lepore ◽  
Maggisano ◽  
Bulotta ◽  
Mignogna ◽  
Arcidiacono ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
High Fat Diet ◽  
Fatty Acid Synthase ◽  
Glucose Transporter ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
High Fat

Oleacein is one of the most abundant polyphenolic compounds of olive oil, which has been shown to play a protective role against several metabolic abnormalities, including dyslipidemia, insulin resistance, and glucose intolerance. Herein, we investigated the effects of oleacein on certain markers of adipogenesis and insulin-resistance in vitro, in 3T3-L1 adipocytes, and in vivo in high-fat diet (HFD)-fed mice. During the differentiation process of 3T3-L1 preadipocytes into adipocytes, oleacein strongly inhibited lipid accumulation, and decreased protein levels of peroxisome proliferator-activated receptor gamma (PPARγ) and fatty acid synthase (FAS), while increasing Adiponectin levels. In vivo, treatment with oleacein of C57BL/6JOlaHsd mice fed with HFD for 5 and 13 weeks prevented the increase in adipocyte size and reduced the inflammatory infiltration of macrophages and lymphocytes in adipose tissue. These effects were accompanied by changes in the expression of adipose tissue-specific regulatory elements such as PPARγ, FAS, sterol regulatory element-binding transcription factor-1 (SREBP-1), and Adiponectin, while the expression of insulin-sensitive muscle/fat glucose transporter Glut-4 was restored in HFD-fed mice treated with oleacein. Collectively, our findings indicate that protection against HFD-induced adiposity by oleacein in mice is mediated by the modulation of regulators of adipogenesis. Protection against HFD-induced obesity is effective in improving peripheral insulin sensitivity.

scholarly journals CTRP9 transgenic mice are protected from diet-induced obesity and metabolic dysfunction

2013 ◽  
Vol 305 (5) ◽  
pp. R522-R533 ◽  
Author(s):  
Jonathan M. Peterson ◽  
Zhikui Wei ◽  
Marcus M. Seldin ◽  
Mardi S. Byerly ◽  
Susan Aja ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Transgenic Mice ◽  
High Fat Diet ◽  
Fat Oxidation ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
High Fat ◽  
Diet Induced Obesity

CTRP9 is a secreted multimeric protein of the C1q family and the closest paralog of the insulin-sensitizing adipokine, adiponectin. The metabolic function of this adipose tissue-derived plasma protein remains largely unknown. Here, we show that the circulating levels of CTRP9 are downregulated in diet-induced obese mice and upregulated upon refeeding. Overexpressing CTRP9 resulted in lean mice that dramatically resisted weight gain induced by a high-fat diet, largely through decreased food intake and increased basal metabolism. Enhanced fat oxidation in CTRP9 transgenic mice resulted from increases in skeletal muscle mitochondrial content, expression of enzymes involved in fatty acid oxidation (LCAD and MCAD), and chronic AMPK activation. Hepatic and skeletal muscle triglyceride levels were substantially decreased in transgenic mice. Consequently, CTRP9 transgenic mice had a greatly improved metabolic profile with markedly reduced fasting insulin and glucose levels. The high-fat diet-induced obesity, insulin resistance, and hepatic steatosis observed in wild-type mice were prevented in transgenic mice. Consistent with the in vivo data, recombinant protein significantly enhanced fat oxidation in L6 myotubes via AMPK activation and reduced lipid accumulation in H4IIE hepatocytes. Collectively, these data establish CTRP9 as a novel metabolic regulator and a new component of the metabolic network that links adipose tissue to lipid metabolism in skeletal muscle and liver.

scholarly journals Cytochrome P-450 CYP2E1 knockout mice are protected against high-fat diet-induced obesity and insulin resistance

2012 ◽  
Vol 302 (5) ◽  
pp. E532-E539 ◽  
Author(s):  
Haihong Zong ◽  
Michal Armoni ◽  
Chava Harel ◽  
Eddy Karnieli ◽  
Jeffrey E. Pessin
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Whole Body ◽  
High Fat ◽  
Normal Chow ◽  
Glucose Output ◽  
Fat Diets

Conventional (whole body) CYP2E1 knockout mice displayed protection against high-fat diet-induced weight gain, obesity, and hyperlipidemia with increased energy expenditure despite normal food intake and spontaneous locomotor activity. In addition, the CYP2E1 knockout mice displayed a marked improvement in glucose tolerance on both normal chow and high-fat diets. Euglycemic-hyperinsulinemic clamps demonstrated a marked protection against high-fat diet-induced insulin resistance in CYP2E1 knockout mice, with enhanced adipose tissue glucose uptake and insulin suppression of hepatic glucose output. In parallel, adipose tissue was protected against high-fat diet-induced proinflammatory cytokine production. Taken together, these data demonstrate that the CYP2E1 deletion protects mice against high-fat diet-induced insulin resistance with improved glucose homeostasis in vivo.

scholarly journals Chemokine Receptor-6 Promotes B-1 Cell Trafficking to Perivascular Adipose Tissue, Local IgM Production and Atheroprotection

2021 ◽  
Vol 12 ◽  
Author(s):  
Prasad Srikakulapu ◽  
Aditi Upadhye ◽  
Fabrizio Drago ◽  
Heather M. Perry ◽  
Sai Vineela Bontha ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
B Cells ◽  
B Cell ◽  
Chemokine Receptor ◽  
Immune Cell ◽  
Cell Number ◽  
Cell Trafficking ◽  
Perivascular Adipose Tissue ◽  
Major Mechanism ◽  
High Level

Chemokine receptor-6 (CCR6) mediates immune cell recruitment to inflammatory sites and has cell type-specific effects on diet-induced atherosclerosis in mice. Previously we showed that loss of CCR6 in B cells resulted in loss of B cell-mediated atheroprotection, although the B cell subtype mediating this effect was unknown. Perivascular adipose tissue (PVAT) harbors high numbers of B cells including atheroprotective IgM secreting B-1 cells. Production of IgM antibodies is a major mechanism whereby B-1 cells limit atherosclerosis development. Yet whether CCR6 regulates B-1 cell number and production of IgM in the PVAT is unknown. In this present study, flow cytometry experiments demonstrated that both B-1 and B-2 cells express CCR6, albeit at a higher frequency in B-2 cells in both humans and mice. Nevertheless, B-2 cell numbers in peritoneal cavity (PerC), spleen, bone marrow and PVAT were no different in ApoE−/−CCR6−/− compared to ApoE−/−CCR6+/+ mice. In contrast, the numbers of atheroprotective IgM secreting B-1 cells were significantly lower in the PVAT of ApoE−/−CCR6−/− compared to ApoE−/−CCR6+/+ mice. Surprisingly, adoptive transfer (AT) of CD43− splenic B cells into B cell-deficient μMT−/−ApoE−/− mice repopulated the PerC with B-1 and B-2 cells and reduced atherosclerosis when transferred into ApoE−/−CCR6+/+sIgM−/− mice only when those cells expressed both CCR6 and sIgM. CCR6 expression on circulating human B cells in subjects with a high level of atherosclerosis in their coronary arteries was lower only in the putative human B-1 cells. These results provide evidence that B-1 cell CCR6 expression enhances B-1 cell number and IgM secretion in PVAT to provide atheroprotection in mice and suggest potential human relevance to our murine findings.

scholarly journals An ethanolic extract of Artemisia scoparia inhibits lipolysis in vivo and has antilipolytic effects on murine adipocytes in vitro

2018 ◽  
Vol 315 (5) ◽  
pp. E1053-E1061 ◽  
Author(s):  
Anik Boudreau ◽  
Allison J. Richard ◽  
Jasmine A. Burrell ◽  
William T. King ◽  
Ruth Dunn ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Microarray Analysis ◽  
High Fat Diet ◽  
Ethanolic Extract ◽  
High Fat ◽  
Artemisia Scoparia

An ethanolic extract of Artemisia scoparia (SCO) has metabolically favorable effects on adipocyte development and function in vitro and in vivo. In diet-induced obese mice, SCO supplementation significantly reduced fasting glucose and insulin levels. Given the importance of adipocyte lipolysis in metabolic health, we hypothesized that SCO modulates lipolysis in vitro and in vivo. Free fatty acids and glycerol were measured in the sera of mice fed a high-fat diet with or without SCO supplementation. In cultured 3T3-L1 adipocytes, the effects of SCO on lipolysis were assessed by measuring glycerol and free fatty acid release. Microarray analysis, qPCR, and immunoblotting were used to assess gene expression and protein abundance. We found that SCO supplementation of a high-fat diet in mice substantially reduces circulating glycerol and free fatty acid levels, and we observed a cell-autonomous effect of SCO to significantly attenuate tumor necrosis factor-α (TNFα)-induced lipolysis in cultured adipocytes. Although several prolipolytic and antilipolytic genes were identified by microarray analysis of subcutaneous and visceral adipose tissue from SCO-fed mice, regulation of these genes did not consistently correlate with SCO’s ability to reduce lipolytic metabolites in sera or cell culture media. However, in the presence of TNFα in cultured adipocytes, SCO induced antilipolytic changes in phosphorylation of hormone-sensitive lipase and perilipin. Together, these data suggest that the antilipolytic effects of SCO on adipose tissue play a role in the ability of this botanical extract to improve whole body metabolic parameters and support its use as a dietary supplement to promote metabolic resiliency.

BAFF Promotes Heightened BCR Responsiveness and Manifestations of Chronic GVHD after Allogeneic Stem Cell Transplantation

Blood ◽  
2021 ◽  
Author(s):  
Wei Jia ◽  
Jonathan C. Poe ◽  
Hsuan Su ◽  
Sarah Anand ◽  
Glenn K. Matsushima ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Chronic Gvhd ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Receptor ◽  
Cell Number ◽  
Allogeneic Bone ◽  
Donor Cells

Chronic graft versus host disease (cGVHD) patients have increased B cell-activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major MHC-mismatched model with cGVHD-like manifestations we first examined B-lymphopenic mMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B cell number. Mice that later developed cGVHD, had significantly increased numbers of recipient fibroblastic reticular cells (FRCs) with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD since BAFF transcript in CD4+ T cells from diseased mice and patients was increased. Chronic GVHD manifestations in mice associated with high BAFF/B cell ratios and persistence of B Cell Receptor (BCR)-activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR-responsiveness to surrogate antigen and NOTCH ligand. BAFF-Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR-activation or when alloantigen was present in vivo. Using T-cell depleted (BM only) BAFF-Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells and alloantibody production. We demonstrate that pathological production of BAFF promotes an altered B-cell compartment and augments BCR-responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in cGVHD patients.

High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice

2013 ◽  
Vol 304 (10) ◽  
pp. E1053-E1063 ◽  
Author(s):  
Johanna L. Barclay ◽  
Anton Shostak ◽  
Alexei Leliavski ◽  
Anthony H. Tsang ◽  
Olaf Jöhren ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Secretion ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Genetic Manipulation ◽  
Metabolic Effects ◽  
Lipid Uptake ◽  
High Fat ◽  
Obesity And Diabetes ◽  
Deficient Mice

Perturbation of circadian rhythmicity in mammals, either by environmental influences such as shiftwork or by genetic manipulation, has been associated with metabolic disturbance and the development of obesity and diabetes. Circadian clocks are based on transcriptional/translational feedback loops, comprising positive and negative components. Whereas the metabolic effects of deletion of the positive arm of the clock gene machinery, as in Clock- or Bmal1-deficient mice, have been well characterized, inactivation of Period genes ( Per1–3) as components of the negative arm have more complex, sometimes contradictory effects on energy homeostasis. The CRYPTOCHROMEs are critical interaction partners of PERs, and simultaneous deletion of Cry1 and - 2 results in behavioral and molecular circadian arrhythmicity. We show that, when challenged with a high-fat diet, Cry1/2−/− mice rapidly gain weight and surpass that of wild-type mice, despite displaying hypophagia. Transcript analysis of white adipose tissue reveals upregulated expression of lipogenic genes, many of which are insulin targets. High-fat diet-induced hyperinsulinemia, as a result of potentiated insulin secretion, coupled with selective insulin sensitivity in adipose tissue of Cry1/2−/− mice, correlates with increased lipid uptake. Collectively, these data indicate that Cry deficiency results in an increased vulnerability to high-fat diet-induced obesity that might be mediated by increased insulin secretion and lipid storage in adipose tissues.

scholarly journals Pasture v. standard dairy cream in high-fat diet-fed mice: improved metabolic outcomes and stronger intestinal barrier

2014 ◽  
Vol 112 (4) ◽  
pp. 520-535 ◽  
Author(s):  
Bérengère Benoit ◽  
Pascale Plaisancié ◽  
Alain Géloën ◽  
Monique Estienne ◽  
Cyrille Debard ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
High Fat Diet ◽  
Dairy Products ◽  
Uncoupling Protein ◽  
Intestinal Barrier ◽  
Metabolic Effects ◽  
High Fat ◽  
Protective Mechanisms ◽  
Protective Function ◽  
Metabolic Outcomes

Dairy products derived from the milk of cows fed in pastures are characterised by higher amounts of conjugated linoleic acid and α-linolenic acid (ALA), and several studies have shown their ability to reduce cardiovascular risk. However, their specific metabolic effects compared with standard dairy in a high-fat diet (HFD) context remain largely unknown; this is what we determined in the present study with a focus on the metabolic and intestinal parameters. The experimental animals were fed for 12 weeks a HFD containing 20 % fat in the form of a pasture dairy cream (PDC) or a standard dairy cream (SDC). Samples of plasma, liver, white adipose tissue, duodenum, jejunum and colon were analysed. The PDC mice, despite a higher food intake, exhibited lower fat mass, plasma and hepatic TAG concentrations, and inflammation in the adipose tissue than the SDC mice. Furthermore, they exhibited a higher expression of hepatic PPARα mRNA and adipose tissue uncoupling protein 2 mRNA, suggesting an enhanced oxidative activity of the tissues. These results might be explained, in part, by the higher amounts of ALA in the PDC diet and in the liver and adipose tissue of the PDC mice. Moreover, the PDC diet was found to increase the proportions of two strategic cell populations involved in the protective function of the intestinal epithelium, namely Paneth and goblet cells in the small intestine and colon, compared with the SDC diet. In conclusion, a PDC HFD leads to improved metabolic outcomes and to a stronger gut barrier compared with a SDC HFD. This may be due, at least in part, to the protective mechanisms induced by specific lipids.

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