Rab4b Deficiency in T Cells Promotes Adipose Treg/Th17 Imbalance, Adipose Tissue Dysfunction, and Insulin Resistance

Despite the well-established association of obesity with insulin resistance and inflammation, the underlying mechanisms and sequence of events leading to inflammation and insulin resistance remain unknown. Adipose tissue hypoxia has been proposed as one of the possible key events during the process of fat expansion that leads to adipose tissue dysfunction. The focus of this paper is reviewing the evidence on adipose tissue hypoxia in obesity and its relation to insulin resistance.

Download Full-text

Adipose Tissue Insulin Resistance Is Longitudinally Associated With Adipose Tissue Dysfunction, Circulating Lipids, and Dysglycemia: The PROMISE Cohort

Diabetes Care ◽

10.2337/dc20-1918 ◽

2021 ◽

pp. dc201918

Author(s):

Zhila Semnani-Azad ◽

Philip W. Connelly ◽

Richard P. Bazinet ◽

Ravi Retnakaran ◽

David J. A. Jenkins ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Adipose Tissue Dysfunction

Download Full-text

The obesity-induced adipokine sST2 exacerbates adipose Treg and ILC2 depletion and promotes insulin resistance

Science Advances ◽

10.1126/sciadv.aay6191 ◽

2020 ◽

Vol 6 (20) ◽

pp. eaay6191 ◽

Cited By ~ 4

Author(s):

Xu-Yun Zhao ◽

Linkang Zhou ◽

Zhimin Chen ◽

Yewei Ji ◽

Xiaoling Peng ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

T Cells ◽

Adipose Tissue ◽

Lymphoid Cells ◽

Adipose Tissue Inflammation ◽

Pathological Changes ◽

Immune Signaling Pathway ◽

Group 2 ◽

Molecular Nature

Depletion of fat-resident regulatory T cells (Tregs) and group 2 innate lymphoid cells (ILC2s) has been causally linked to obesity-associated insulin resistance. However, the molecular nature of the pathogenic signals suppress adipose Tregs and ILC2s in obesity remains unknown. Here, we identified the soluble isoform of interleukin (IL)–33 receptor ST2 (sST2) as an obesity-induced adipokine that attenuates IL-33 signaling and disrupts Treg/ILC2 homeostasis in adipose tissue, thereby exacerbates obesity-associated insulin resistance in mice. We demonstrated sST2 is a target of TNFα signaling in adipocytes that is countered by Zbtb7b. Fat-specific ablation of Zbtb7b augments adipose sST2 gene expression, leading to diminished fat-resident Tregs/ILC2s, more pronounced adipose tissue inflammation and fibrosis, and impaired glucose homeostasis in mice. Mechanistically, Zbtb7b suppresses NF-κB activation in response to TNFα through destabilizing IκBα. These findings uncover an adipokine-immune signaling pathway that is engaged in obesity to drive the pathological changes of the immunometabolic landscape.

Download Full-text

Direct renin inhibition improved insulin resistance and adipose tissue dysfunction in type 2 diabetic KK-Ay mice

Journal of Hypertension ◽

10.1097/hjh.0b013e32833bc420 ◽

2010 ◽

Vol 28 (7) ◽

pp. 1471-1481 ◽

Cited By ~ 36

Author(s):

Masaru Iwai ◽

Harumi Kanno ◽

Yumiko Tomono ◽

Shinji Inaba ◽

Izumi Senba ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Adipose Tissue Dysfunction ◽

Renin Inhibition ◽

Type 2 Diabetic ◽

Ay Mice

Download Full-text

Obesity, inflammation, and insulin resistance

Brazilian Journal of Pharmaceutical Sciences ◽

10.1590/s1984-82502014000400003 ◽

2014 ◽

Vol 50 (4) ◽

pp. 677-692 ◽

Cited By ~ 8

Author(s):

Luana Mota Martins ◽

Ana Raquel Soares Oliveira ◽

Kyria Jayanne Clímaco Cruz ◽

Francisco Leonardo Torres-Leal ◽

Dilina do Nascimento Marreiro

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Biologically Active ◽

Endocrine Organ ◽

Adipose Tissue Dysfunction ◽

Current Review ◽

Increased Risk ◽

Anti Inflammatory ◽

Inflammatory Molecules ◽

Inflammatory Action

White adipose tissue (WAT) is considered an endocrine organ. When present in excess, WAT can influence metabolism via biologically active molecules. Following unregulated production of such molecules, adipose tissue dysfunction results, contributing to complications associated with obesity. Previous studies have implicated pro- and anti-inflammatory substances in the regulation of inflammatory response and in the development of insulin resistance. In obese individuals, pro-inflammatory molecules produced by adipose tissue contribute to the development of insulin resistance and increased risk of cardiovascular disease. On the other hand, the molecules with anti-inflammatory action, that have been associated with the improvement of insulin sensitivity, have your decreased production. Imbalance of these substances contributes significantly to metabolic disorders found in obese individuals. The current review aims to provide updated information regarding the activity of biomolecules produced by WAT.

Download Full-text

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

PLoS ONE ◽

10.1371/journal.pone.0252547 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0252547

Author(s):

Xiaoxiang Yan ◽

Natsumi Imano ◽

Kayoko Tamaki ◽

Motoaki Sano ◽

Ken Shinmura

Keyword(s):

Insulin Resistance ◽

T Cells ◽

Adipose Tissue ◽

T Cell ◽

Caloric Restriction ◽

Visceral Adipose Tissue ◽

Aged Mice ◽

Age Related ◽

Visceral Adipose

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.

Download Full-text

Natural killer T cells in adipose tissue prevent insulin resistance

Journal of Clinical Investigation ◽

10.1172/jci62739 ◽

2012 ◽

Vol 122 (9) ◽

pp. 3343-3354 ◽

Cited By ~ 137

Author(s):

Henk S. Schipper ◽

Maryam Rakhshandehroo ◽

Stan F.J. van de Graaf ◽

Koen Venken ◽

Arjen Koppen ◽

...

Keyword(s):

Insulin Resistance ◽

T Cells ◽

Adipose Tissue ◽

Natural Killer ◽

Natural Killer T Cells ◽

Killer T Cells ◽

Natural Killer T

Download Full-text

Overexpression of PTPN2 in Visceral Adipose Tissue Ameliorated Atherosclerosis via T Cells Polarization Shift in Diabetic Apoe-/- Mice

Cellular Physiology and Biochemistry ◽

10.1159/000488415 ◽

2018 ◽

Vol 46 (1) ◽

pp. 118-132 ◽

Cited By ~ 4

Author(s):

Ya Li ◽

Huimin Zhou ◽

Feng Wang ◽

Lu Han ◽

Minghao Liu ◽

...

Keyword(s):

Insulin Resistance ◽

T Cells ◽

Adipose Tissue ◽

T Cell ◽

Molecular Mechanisms ◽

Recombinant Adenovirus ◽

Tyrosine Phosphatase ◽

Vulnerability Index ◽

Diabetic Mice ◽

Cell Accumulation

Background/Aims: Dysregulated inflammation in adipose tissue, marked by increased pro-inflammatory T-cell accumulation and reduced regulatory T cells (Treg), contributes to diabetes-associated insulin resistance and atherosclerosis. However, the molecular mechanisms underlying T-cell-mediated inflammation in adipose tissue remain largely unknown. Methods: Sixty apolipoprotein E (ApoE-/-) mice were randomly divided into chow and diabetes groups. Diabetes was induced by a high-fat and high-sugar diet combined with low-dose streptozotocin. Then we transferred a recombinant adenovirus carrying the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene into epididymal white adipose tissue (EWAT) of ApoE-/- mice. After transfection, all mice were euthanized to evaluate the effects of PTPN2 on T cells polarization and atherosclerosis. Results: PTPN2 was downregulated in EWAT of diabetic ApoE-/- mice. PTPN2 overexpression in EWAT reversed the high Th1/Treg and Th17/Treg ratios in EWAT of diabetic mice. In addition, PTPN2 overexpression in EWAT could significantly reduce macrophages infiltration, the ratio of M1/M2 macrophages and the expression of pro-inflammatory cytokines in EWAT, improving insulin resistance. In aortic root lesions, the vulnerability index were significantly decreased by overexpression of PTPN2 in EWAT. Conclusion: These data suggested that PTPN2 overexpression in EWAT would inhibit systemic inflammation and increase the plaque stability via T cells polarization shift in diabetic mice.

Download Full-text