scholarly journals OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance

2020 ◽  
Vol 117 (28) ◽  
pp. 16616-16625
Author(s):  
Yunfan Yang ◽  
Xiruo Li ◽  
Harding H. Luan ◽  
Bichen Zhang ◽  
Kaisi Zhang ◽  
...  
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Nutrient Sensing ◽  
Metabolic Disturbance ◽  
Whole Body ◽  
Metabolic Dysfunction ◽  
Peripheral Tissues ◽  
Mtorc1 Signaling ◽  
Whole Body Metabolism ◽  
Glcnac Transferase

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensingO-linked β-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase inO-GlcNAc signaling in macrophages.O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. SuppressingO-GlcNAc signaling byO-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1)O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophageO-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.

scholarly journals The Role of O-GlcNAcylation in Immune Cell Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Amy Qiang ◽  
Chad Slawson ◽  
Patrick E. Fields
Keyword(s):  
Cell Activation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Nutrient Sensing ◽  
Post Translational Modification ◽  
Immune Cell Activation ◽  
Glcnac Transferase ◽  
Diabetes And Obesity ◽  
Normal Cellular Function

O-GlcNAcylation is a dynamic post-translational modification where the sugar, O-linked β-N-acetylglucosamine (O-GlcNAc) is added to or removed from various cytoplasmic, nuclear, and mitochondrial proteins. This modification is regulated by only two enzymes: O-GlcNAc transferase (OGT), which adds O-GlcNAc, and O-GlcNAcase (OGA), which removes the sugar from proteins. O-GlcNAcylation is integral to maintaining normal cellular function, especially in processes such as nutrient sensing, metabolism, transcription, and growth and development of the cell. Aberrant O-GlcNAcylation has been associated with a number of pathological conditions, including, neurodegenerative diseases, cancer, diabetes, and obesity. However, the role of O-GlcNAcylation in immune cell growth/proliferation, or other immune responses, is currently incompletely understood. In this review, we highlight the effects of O-GlcNAcylation on certain cells of the immune system, especially those involved in pro-inflammatory responses associated with diabetes and obesity.

scholarly journals OR20-02 Maternal Adiponectin Prevents Against Metabolic Dysfunction in Prenatally Androgenized PCOS-Like Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Anna Benrick ◽  
Yanling Wu ◽  
Elisabet Stener-Victorin ◽  
Ingrid Wernstedt Asterholm
Keyword(s):  
Adipose Tissue ◽  
Visceral Fat ◽  
Polycystic Ovary ◽  
Female Offspring ◽  
Whole Body ◽  
Metabolic Dysfunction ◽  
Anogenital Distance ◽  
Reproductive Dysfunction ◽  
Androgen Exposure ◽  
Whole Body Metabolism

Abstract More than 10% of women worldwide are diagnosed with polycystic ovary syndrome (PCOS), causing reproductive and metabolic disease. Hyperandrogenism is the main characteristic and elevated levels of androgens during pregnancy affect placenta function and fetal programming, which leads to reproductive and metabolic dysfunction in the offspring. Adiponectin secreted from adipose tissue improves whole-body metabolism, but its role during pregnancy is under explored. Adiponectin affects placental nutrient transport during pregnancy allowing for speculation that adiponectin can exert endocrine effects on the developing fetus. This study aims to investigate if, in prenatally androgenized (PNA) mice, adiponectin can prevent metabolic and reproductive dysfunction in female offspring. Adiponectin transgenic (APNtg) and wildtype (wt) female mice were mated with wt males, and received dihydrotestosterone or vehicle injections between gestational days 16.5-18.5 to induce a PCOS-like phenotype. The anogenital distance, a marker of in utero androgen exposure, was measured at 22 days of age, estrus cyclicity was recorded at 6 weeks of age, and metabolic measures were performed at 4 months of age. APNtg dams gave birth to significantly smaller offspring, independent of genotype, than wt dams. PNA increased f-insulin in all groups but insulin sensitivity was higher in wt mice from APNtg dams compared to wt mice from wt dams. Insulin resistance correlated with subcutaneous and visceral fat mass. PNA increased visceral fat % and adipocyte size in wt offspring from wt dams while wt and APNtg offspring from APNtg dams were protected against this effect. Visceral adipose tissue gene expression was unaltered in PNA wt offspring, regardless of the dam’s genotype, while APNtg offspring, regardless of PNA, had increased expression of adipogenic genes. Anogenital distance was increased in all PNA wt offspring independent of the dam’s genotype. There was, however, no difference between APNtg-vehicle and APNtg-PNA mice, suggesting that adiponectin overexpression protects against this effect. PNA leads to disrupted estrous cycle and fewer ovulations, but this effect was less pronounced in PNA wt mice from APNtg dams. Our data suggests that elevated maternal adiponectin protects the offspring against PNA induced metabolic dysfunction, and to a lesser extent reproductive dysfunction.

scholarly journals Alterations to mTORC1 signaling in the skeletal muscle differentially affect whole-body metabolism

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Maitea Guridi ◽  
Barbara Kupr ◽  
Klaas Romanino ◽  
Shuo Lin ◽  
Denis Falcetta ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Whole Body ◽  
Mtorc1 Signaling ◽  
Whole Body Metabolism

scholarly journals Disruption of the sugar-sensing receptor T1R2 attenuates metabolic derangements associated with diet-induced obesity

2016 ◽  
Vol 310 (8) ◽  
pp. E688-E698 ◽  
Author(s):  
Kathleen R. Smith ◽  
Tania Hussain ◽  
Elnaz Karimian Azari ◽  
Jennifer L. Steiner ◽  
Julio E. Ayala ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Balance ◽  
Fat Mass ◽  
Glucose Homeostasis ◽  
Sweet Taste ◽  
Nutrient Sensing ◽  
Whole Body ◽  
Receptor Protein ◽  
Peripheral Tissues ◽  
Diet Induced Obesity

Sweet taste receptors (STRs) on the tongue mediate gustatory sweet sensing, but their expression in the gut, pancreas, and adipose tissue suggests a physiological contribution to whole body nutrient sensing and metabolism. However, little is known about the function and contribution of these sugar sensors during metabolic stress induced by overnutrition and subsequent obesity. Here, we investigated the effects of high-fat/low-carbohydrate (HF/LC) diet on glucose homeostasis and energy balance in mice with global disruption of the sweet taste receptor protein T1R2. We assessed body composition, energy balance, glucose homeostasis, and tissue-specific nutrient metabolism in T1R2 knockout (T1R2-KO) mice fed a HF/LC diet for 12 wk. HF/LC diet-fed T1R2-KO mice gained a similar amount of body mass as did WT mice, but had reduced fat mass and increased lean mass relative to WT mice. T1R2-KO mice were also hyperphagic and hyperactive. Ablation of the T1R2 sugar sensor protected mice from HF/LC diet-induced hyperinsulinemia and altered substrate utilization, including increased rates of glucose oxidation and decreased liver triglyceride (TG) accumulation, despite normal intestinal fat absorption. Finally, STRs ( T1r2/T1r3) were upregulated in the adipose tissue of WT mice in response to HF/LC diet, and their expression positively correlated with fat mass and glucose intolerance. The chemosensory receptor T1R2, plays an important role in glucose homeostasis during diet-induced obesity through the regulation of yet to be identified molecular mechanisms that alter energy disposal and utilization in peripheral tissues.

scholarly journals Nutrient mTORC1 signaling underpins regulatory T cell control of immune tolerance

2019 ◽  
Vol 217 (1) ◽  
Author(s):  
Mytrang H. Do ◽  
Xinxin Wang ◽  
Xian Zhang ◽  
Chun Chou ◽  
Briana G. Nixon ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
Immune Tolerance ◽  
Small Gtpases ◽  
Nutrient Sensing ◽  
Amino Acid Transporters ◽  
Tcr Signaling ◽  
Peripheral Tissues ◽  
Mtorc1 Signaling ◽  
Rag Gtpase

Foxp3+ regulatory T (T reg) cells are pivotal regulators of immune tolerance, with T cell receptor (TCR)–driven activated T reg (aT reg) cells playing a central role; yet how TCR signaling propagates to control aT reg cell responses remains poorly understood. Here we show that TCR signaling induces expression of amino acid transporters, and renders amino acid–induced activation of mTORC1 in aT reg cells. T reg cell–specific ablation of the Rag family small GTPases RagA and RagB impairs amino acid–induced mTORC1 signaling, causing defective amino acid anabolism, reduced T reg cell proliferation, and a rampant autoimmune disorder similar in severity to that triggered by T reg cell–specific TCR deficiency. Notably, T reg cells in peripheral tissues, including tumors, are more sensitive to Rag GTPase–dependent nutrient sensing. Ablation of RagA alone impairs T reg cell accumulation in the tumor, resulting in enhanced antitumor immunity. Thus, nutrient mTORC1 signaling is an essential component of TCR-initiated T reg cell reprogramming, and Rag GTPase activities may be titrated to break tumor immune tolerance.

scholarly journals Altered Methylation Profile of Lymphocytes Is Concordant with Perturbation of Lipids Metabolism and Inflammatory Response in Obesity

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Mette J. Jacobsen ◽  
Caroline M. Junker Mentzel ◽  
Ann Sofie Olesen ◽  
Thierry Huby ◽  
Claus B. Jørgensen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Cell Activation ◽  
Immune Cell ◽  
Metabolic Dysfunction ◽  
Immune Functions ◽  
Dna Hypermethylation ◽  
Metabolic Complications ◽  
Macrophage Polarisation ◽  
Immune Alterations

Obesity is associated with immunological perturbations that contribute to insulin resistance. Epigenetic mechanisms can control immune functions and have been linked to metabolic complications, although their contribution to insulin resistance still remains unclear. In this study, we investigated the link between metabolic dysfunction and immune alterations with the epigenetic signature in leukocytes in a porcine model of obesity. Global DNA methylation of circulating leukocytes, adipose tissue leukocyte trafficking, and macrophage polarisation were established by flow cytometry. Adipose tissue inflammation and metabolic function were further characterised by quantification of metabolites and expression levels of genes associated with obesity and inflammation. Here we show that obese pigs showed bigger visceral fat pads, higher levels of circulating LDL cholesterol, and impaired glucose tolerance. These changes coincided with impaired metabolism, sustained macrophages infiltration, and increased inflammation in the adipose tissue. Those immune alterations were linked to global DNA hypermethylation in both B-cells and T-cells. Our results provide novel insight into the possible contribution of immune cell epigenetics into the immunological disturbances observed in obesity. The dramatic changes in the transcriptomic and epigenetic signature of circulating lymphocytes reinforce the concept that epigenetic processes participate in the increased immune cell activation and impaired metabolic functions in obesity.

scholarly journals Nutritional Modulation of AMPK-Impact upon Metabolic-Inflammation

2018 ◽  
Vol 19 (10) ◽  
pp. 3092 ◽  
Author(s):  
Claire Lyons ◽  
Helen Roche
Keyword(s):  
Immune Cell ◽  
Cell Metabolism ◽  
Nutrient Status ◽  
Whole Body ◽  
Direct Role ◽  
Insulin Metabolism ◽  
Metabolic Inflammation ◽  
Metabolic Substrates ◽  
Whole Body Metabolism ◽  
And Function

Nutritional status provides metabolic substrates to activate AMP-Activated Protein Kinase (AMPK), the energy sensor that regulates metabolism. Recent evidence has demonstrated that AMPK has wider functions with respect to regulating immune cell metabolism and function. One such example is the regulatory role that AMPK has on NLRP3-inlflammasome and IL-1β biology. This in turn can result in subsequent negative downstream effects on glucose, lipid and insulin metabolism. Nutrient stress in the form of obesity can impact AMPK and whole-body metabolism, leading to complications such as type 2 diabetes and cancer risk. There is a lack of data regarding the nature and extent that nutrient status has on AMPK and metabolic-inflammation. However, emerging work elucidates to a direct role of individual nutrients on AMPK and metabolic-inflammation, as a possible means of modulating AMPK activity. The posit being to use such nutritional agents to re-configure metabolic-inflammation towards more oxidative phosphorylation and promote the resolution of inflammation. The complex paradigm will be discussed within the context of if/how dietary components, nutrients including fatty acids and non-nutrient food components, such as resveratrol, berberine, curcumin and the flavonoid genistein, modulate AMPK dependent processes relating to inflammation and metabolism.

scholarly journals Host immune response to anti-cancer camptothecin conjugated cyclodextrin-based polymers

2019 ◽  
Vol 26 (1) ◽  
Author(s):  
Yi-Fan Chen ◽  
Yen-Hsin Wang ◽  
Cing-Syuan Lei ◽  
Chun A. Changou ◽  
Mark E. Davis ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Cell Activation ◽  
Nk Cell ◽  
Cancer Therapeutics ◽  
Drug Efficacy ◽  
Drug Carriers ◽  
Host Immune Response ◽  
Whole Body ◽  
Peripheral Tissues

Abstract Introduction Efficacy and safety are critical concerns when designing drug carriers. Nanoparticles are a particular type of carrier that has gained recent attention in cancer therapeutics. Methods In this study, we assess the safety profile of IT-101, a nanoparticle formed by self-assembly of camptothecin (CPT) conjugated cyclodextrin-based polymers. IT-101 delivers CPT to target cancer cells in animal models of numerous human cancers and in humans. Previous data from preclinical and clinical trials indicate that IT-101 has no notable immunological side effects. However, there have been no published studies focused on evaluating the effects of IT-101 on host immune systems. Results In this work, we demonstrate that IT-101 diminished initial host immune response following first injection of the nanopharmaceutical and induced NK cell activation and T cell proliferation upon further IT-101 exposure. Additionally, IT-101 could attenuate tumor growth more efficiently than CPT treatment only. Conclusions Drugs administration in whole-body circulation may lead to poorly bioavailable in central nervous system and often has toxic effects on peripheral tissues. Conjugated with cyclodextrin-based polymers not only reduce adverse effects but also modulate the immune responses to elevate drug efficacy. These immune responses may potentially facilitate actions of immune blockage, such as PD1/PDL1 in cancer treatment.

scholarly journals After‐Effects of Time‐Restricted Feeding on Whole‐Body Metabolism and Gene Expression in Four Different Peripheral Tissues

Obesity ◽  
2020 ◽  
Vol 28 (S1) ◽  
Author(s):  
Paul Goede ◽  
Tom P. Hellings ◽  
Tom V. Coopmans ◽  
Wayne I. G. R. Ritsema ◽  
Andries Kalsbeek
Keyword(s):  
Gene Expression ◽  
Whole Body ◽  
Restricted Feeding ◽  
Peripheral Tissues ◽  
After Effects ◽  
Whole Body Metabolism

scholarly journals Changes in abdominal subcutaneous adipose tissue phenotype following menopause is associated with increased visceral fat mass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Julie Abildgaard ◽  
Thorkil Ploug ◽  
Elaf Al-Saoudi ◽  
Thomas Wagner ◽  
Carsten Thomsen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Visceral Fat ◽  
Subcutaneous Adipose Tissue ◽  
Immune Cell ◽  
Whole Body ◽  
Metabolic Dysfunction ◽  
Adipocyte Hypertrophy ◽  
Subcutaneous Adipose

AbstractMenopause is associated with a redistribution of adipose tissue towards central adiposity, known to cause insulin resistance. In this cross-sectional study of 33 women between 45 and 60 years, we assessed adipose tissue inflammation and morphology in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) across menopause and related this to menopausal differences in adipose tissue distribution and insulin resistance. We collected paired SAT and VAT biopsies from all women and combined this with anthropometric measurements and estimated whole-body insulin sensitivity. We found that menopause was associated with changes in adipose tissue phenotype related to metabolic dysfunction. In SAT, postmenopausal women showed adipocyte hypertrophy, increased inflammation, hypoxia and fibrosis. The postmenopausal changes in SAT was associated with increased visceral fat accumulation. In VAT, menopause was associated with adipocyte hypertrophy, immune cell infiltration and fibrosis. The postmenopausal changes in VAT phenotype was associated with decreased insulin sensitivity. Based on these findings we suggest, that menopause is associated with changes in adipose tissue phenotype related to metabolic dysfunction in both SAT and VAT. Whereas increased SAT inflammation in the context of menopause is associated with VAT accumulation, VAT morphology is related to insulin resistance.

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