The effect of caloric restriction on the increase in senescence-associated T cells and metabolic disorders in aged mice

Aging is associated with functional decline in the immune system and increases the risk of chronic diseases owing to smoldering inflammation. In the present study, we demonstrated an age-related increase in the accumulation of Programmed Death-1 (PD-1)+ memory-phenotype T cells that are considered “senescence-associated T cells” in both the visceral adipose tissue and spleen. As caloric restriction is an established intervention scientifically proven to exert anti-aging effects and greatly affects physiological and pathophysiological alterations with advanced age, we evaluated the effect of caloric restriction on the increase in this T-cell subpopulation and glucose tolerance in aged mice. Long-term caloric restriction significantly decreased the number of PD-1+ memory-phenotype cluster of differentiation (CD) 4+ and CD8+ T cells in the spleen and visceral adipose tissue, decreased M1-type macrophage accumulation in visceral adipose tissue, and improved insulin resistance in aged mice. Furthermore, the immunological depletion of PD-1+ T cells reduced adipose inflammation and improved insulin resistance in aged mice. Taken together with our previous report, these results indicate that senescence-related T-cell subpopulations are involved in the development of chronic inflammation and insulin resistance in the context of chronological aging and obesity. Thus, long-term caloric restriction and specific deletion of senescence-related T cells are promising interventions to regulate age-related chronic diseases.

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Effects of magnitude of visceral adipose tissue reduction: Impact on insulin resistance, hyperleptinemia and cardiometabolic risk in adolescents with obesity after long-term weight-loss therapy

Diabetes and Vascular Disease Research ◽

10.1177/1479164118825343 ◽

2019 ◽

Vol 16 (2) ◽

pp. 196-206 ◽

Cited By ~ 6

Author(s):

Raquel Munhoz da Silveira Campos ◽

Deborah Cristina Landi Masquio ◽

Flávia Campos Corgosinho ◽

Danielle Arisa Caranti ◽

Aline de Piano Ganen ◽

...

Keyword(s):

Insulin Resistance ◽

Weight Loss ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Visceral Fat ◽

Independent Predictor ◽

Fat Reduction ◽

Visceral Adipose ◽

Weight Loss Therapy

Aim: To investigate the association between visceral adipose tissue loss and insulin resistance and hyperleptinemia in adolescents with obesity submitted to interdisciplinary weight-loss therapy. Methods: A total of 172 post-pubertal adolescents (body mass index greater than the 95th percentile of the Centers for Disease Control and Prevention reference growth charts) were recruited for the study. The adolescents were assigned to long-term weight-loss therapy. Body composition, visceral and subcutaneous fat, glucose metabolism, lipid profile, hepatic enzymes and leptin concentration were measured. After the therapy, the adolescents were allocated to three different groups according to the tertile of visceral fat reduction. Results: Positive effects on body composition were observed in all analysed groups independent of visceral fat reduction. It was found that visceral fat was an independent predictor of insulin resistance in the investigated population. Obese adolescents who lost a higher proportion of visceral adipose tissue (>1.8 cm) demonstrated improved metabolic and inflammatory parameters twice as much than those who presented smaller losses. Positive correlations between visceral fat reduction and glucose metabolism, lipid profile, hepatic enzymes and homeostasis model assessment of insulin resistance index were demonstrated. Conclusion: The magnitude of the reduction in visceral fat was an independent predictor of insulin resistance, hyperleptinemia and metabolic disorders related to obese adolescents.

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Contribution of Visceral Obesity to the Insulin Resistance Syndrome

Canadian Journal of Applied Physiology ◽

10.1139/h01-018 ◽

2001 ◽

Vol 26 (3) ◽

pp. 273-290 ◽

Cited By ~ 27

Author(s):

Simone Lemieux

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Significant Proportion ◽

Visceral Obesity ◽

Insulin Resistance Syndrome ◽

Tissue Accumulation ◽

Age Related ◽

Insulin Homeostasis ◽

Visceral Adipose

A high visceral adipose tissue accumulation has been associated with many metabolic perturbations typical of the insulin resistance syndrome, such as dyslipidemia, impaired glucose-insulin homeostasis, hypertension, and impaired fibrinolysis. It has been documented that male gender, aging, and a hyperglycemic state are conditions that increase the likelihood of displaying features of the insulin resistance syndrome. Accordingly, studies have demonstrated that the variation in visceral adipose tissue accumulation explains a significant proportion of the gender differences in the metabolic risk profile. Age-related differences in metabolic components of the insulin resistance syndrome have also been shown to be partly explained by the concomitant increase in visceral adipose tissue accumulation found with age. Studies have suggested that a high visceral adipose tissue accumulation contributes significantly to the deterioration in the plasma lipid-lipoprotein profile found in hyperglycemic subjects. Finally, it appears that the clustering of metabolic alterations of the insulin resistance syndrome is more pronounced in obese subjects with high levels of visceral fat than in those with a lower visceral adipose tissue accumulation. Key Words: abdominal fat, dyslipidemia, glucose-insulin homeostasis, type 2 diabetes, cardiovascular disease

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Effect of Long-Term Whole Body Vibration Training on Visceral Adipose Tissue: A Preliminary Report

Obesity Facts ◽

10.1159/000301785 ◽

2010 ◽

Vol 3 (2) ◽

pp. 7-7 ◽

Cited By ~ 49

Author(s):

Dirk Vissers ◽

An Verrijken ◽

Ilse Mertens ◽

Caroline Van Gils ◽

Annemie Van de Sompel ◽

...

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Preliminary Report ◽

Whole Body Vibration ◽

Whole Body ◽

Body Vibration ◽

Vibration Training ◽

Whole Body Vibration Training ◽

Visceral Adipose

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Association of Upper Trunk and Visceral Adipose Tissue Volume With Insulin Resistance in Control and HIV-Infected Subjects in the FRAM Study

JAIDS Journal of Acquired Immune Deficiency Syndromes ◽

10.1097/qai.0b013e31814b94e2 ◽

2007 ◽

Vol 46 (3) ◽

pp. 283-290 ◽

Cited By ~ 73

Author(s):

Carl Grunfeld ◽

David Rimland ◽

Cynthia L Gibert ◽

William G Powderly ◽

Stephen Sidney ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Tissue Volume ◽

Adipose Tissue Volume ◽

Visceral Adipose

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CD8+ T Cells Involved in Metabolic Inflammation in Visceral Adipose Tissue and Liver of Transgenic Pigs

Frontiers in Immunology ◽

10.3389/fimmu.2021.690069 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kaiyi Zhang ◽

Cong Tao ◽

Jianping Xu ◽

Jinxue Ruan ◽

Jihan Xia ◽

...

Keyword(s):

Adipose Tissue ◽

T Cell ◽

Visceral Adipose Tissue ◽

Antigen Processing ◽

Metabolic Diseases ◽

Early Stage ◽

Large Animal ◽

Transgenic Pigs ◽

Inflammatory Signaling ◽

Visceral Adipose

Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, GIPRdn, hIAPP and PNPLA3I148M. Transgenic effect increased the risk of metabolic disorders. Triple-transgenic pigs with short-term diet intervention showed early symptoms of type 2 diabetes, including glucose intolerance, pancreatic lipid infiltration, islet hypertrophy, hepatic lobular inflammation and adipose tissue inflammation. Molecular pathways related to CD8+ T cell function were significantly activated in the liver and visceral adipose samples from triple-transgenic pigs, including antigen processing and presentation, T-cell receptor signaling, co-stimulation, cytotoxicity, and cytokine and chemokine secretion. The similar pro-inflammatory signaling in liver and visceral adipose tissue indicated that there might be a potential immune crosstalk between the two tissues. Moreover, genes that functionally related to liver antioxidant activity, mitochondrial function and extracellular matrix showed distinct expression between the two groups, indicating metabolic stress in transgenic pigs’ liver samples. We confirmed that triple-transgenic pigs had high coincidence with human metabolic diseases, especially in the scope of inflammatory signaling at early stage metaflammation. Taken together, this study provides a valuable large animal model for the clinical study of metaflammation and metabolic diseases.

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Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2103730118 ◽

2021 ◽

Vol 118 (23) ◽

pp. e2103730118

Author(s):

Yuka Nakajima ◽

Kenji Chamoto ◽

Takuma Oura ◽

Tasuku Honjo

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Critical Role ◽

Cell Subset ◽

Effector Memory ◽

T Cell Subset ◽

Aged Mice ◽

Age Related

CD8+ T cells play a central role in antitumor immune responses that kill cancer cells directly. In aged individuals, CD8+ T cell immunity is strongly suppressed, which is associated with cancer and other age-related diseases. The mechanism underlying this age-related decrease in immune function remains largely unknown. This study investigated the role of T cell function in age-related unresponsiveness to PD-1 blockade cancer therapy. We found inefficient generation of CD44lowCD62Llow CD8+ T cell subset (P4) in draining lymph nodes of tumor-bearing aged mice. In vitro stimulation of naive CD8+ T cells first generated P4 cells, followed by effector/memory T cells. The P4 cells contained a unique set of genes related to enzymes involved in one-carbon (1C) metabolism, which is critical to antigen-specific T cell activation and mitochondrial function. Consistent with this finding, 1C-metabolism–related gene expression and mitochondrial respiration were down-regulated in aged CD8+ T cells compared with young CD8+ T cells. In aged OVA-specific T cell receptor (TCR) transgenic mice, ZAP-70 was not activated, even after inoculation with OVA-expressing tumor cells. The attenuation of TCR signaling appeared to be due to elevated expression of CD45RB phosphatase in aged CD8+ T cells. Surprisingly, strong stimulation by nonself cell injection into aged PD-1–deficient mice restored normal levels of CD45RB and ameliorated the emergence of P4 cells and 1C metabolic enzyme expression in CD8+ T cells, and antitumor activity. These findings indicate that impaired induction of the P4 subset may be responsible for the age-related resistance to PD-1 blockade, which can be rescued by strong TCR stimulation.

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Elevated serum uric acid is a facilitating mechanism for insulin resistance mediated accumulation of visceral adipose tissue

10.1101/2020.09.20.20198499 ◽

2020 ◽

Author(s):

Luisa Fernández-Chirino ◽

Neftali Eduardo Antonio-Villa ◽

Arsenio Vargas-Vázquez ◽

Paloma Almeda-Valdés ◽

Donají Gómez-Velasco ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Uric Acid ◽

Serum Uric Acid ◽

Visceral Adipose Tissue ◽

Visceral Obesity ◽

Causal Mechanism ◽

Mediation Analyses ◽

Bidirectional Relationship ◽

Visceral Adipose

BACKGROUND: Serum uric acid (SUA) has a relationship with cardiometabolic conditions such as insulin resistance (IR) and visceral adipose tissue (VAT) accumulation. Here, we aimed to clarify the nature of this relationship and the underlying causality mechanism. METHODS: We conducted a population-based cross-sectional study comprising 8,504 subjects joining both NHANES 2003-2004 and 2011-2012 cycles and ENSANUT Medio Camino 2016. We performed mixed effects linear regression models using HOMA2-IR, adipoIR, and METS-VF as indicators of IR and VAT accumulation. Furthermore, we performed mediation analyses to assess a potential causal mechanism and ROC curves to establish cut-off points for identification of IR and visceral obesity using SUA. Finally, with an additional dataset comprised of 226 subjects with both euglycemic hyperinsulinemic clamp (EHC) and dual X-ray absorptiometry (DXA) measurements for IR and VAT accumulation, we performed a network of confirmatory mediation analyses. RESULTS:We found that SUA has a mediating role inside the bidirectional relationship between IR and visceral obesity, and it is part of an underlying causality mechanism which includes adiponectin. The proportion of the mechanism mediated by SUA is greater when stated that IR (in either peripheral or adipose tissue) leads to VAT accumulation (14.90%[13.20%-17.00%] and 15.54%[13.61% - 18.00%] to 4.88%[3.06%-7.00%] and 8.13%[5.91% - 10.00%]) instead of the opposite direction. This result was confirmed by mediation analyses using gold-standard measurements. CONCLUSIONS:Elevated SUA acts as mediator inside the bidirectional relationship between IR andVAT accumulation. Its role appears to be larger when considering adipose tissue IR as the promoter for VAT accumulation.

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Protocatechuic acids protects against high glucose- induced insulin resistance in human visceral adipose tissue

Problems of Endocrinology ◽

10.14341/probl201662545-46 ◽

2016 ◽

Vol 62 (5) ◽

pp. 45-46

Author(s):

Paulina Ormazabal ◽

Beatrice Scazzocchio ◽

Rosaria Varì ◽

Annunziata Iacovelli ◽

Roberta Masella

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

High Glucose ◽

Protective Role ◽

Insulin Sensitizer ◽

20 Nm ◽

Visceral Adipose

Adipocytes exposed to high glucose concentrations exhibit impaired insulin signaling. Binding of insulin to its membrane receptor activates insulin metabolic pathway leading to IRS-1 and AKT phosphorylations. The accumulation of visceral adipose tissue (VAT) correlates with insulin resistance and metabolic syndrome. Anthocyanins (ACN) are bioactive food compounds of great nutritional interest. We have shown that protocatechuic acid (PCA), a major metabolite of ACN, might exert insulin-sensitizer activities in human visceral adipose tissue. The aim of this work was to define the protective role of PCA against insulin-resistance induced by high glucose in VAT.Methodology: VAT obtained from control subject (BMI≤25) were separated in four experimental groups: i) PCA: samples treated for 24 h with 100 μM PCA, ii) GLU: VAT treated with 30 mM glucose for 24 h, iii) PCA+GLU: 1 hour incubation with 100 μM PCA before adding glucose (30 mM, 24 h), iv) CTR: vehicle. After treatment, VAT groups were (or not) acutely stimulated with insulin (20 nM, 20 min). Tyr-IRS-1 and Ser-Akt phosphorylations were assessed by Western blotting (WB) in basal or insulin stimulated tissues in all experimental groups. Samples were assessed for IRS-1, IR, Akt and GLUT4 protein content by WB. Results: No differences in protein contents between experimental groups were found. GLU tissues showed a lower increment in insulin-stimulated phosphorylation of IRS-1 and Akt compared to CTR and PCA samples. This impaired activation was completely reversed by the pretreatment with PCA.Conclusion: An in-vitro insulin-resistance condition induced by high glucose was established in biopsies of VAT. PCA restores the ability of GLU-tissues to fully respond to insulin by increasing IRS-1 and Akt phosphorylations. These results confirm the insulin-sensitizer effect of PCA on VAT previously reported by our group. An anthocyanin rich diet might help to protect against insulin-resistance in VAT.

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