CX3CL1–CX3CR1 signalling deficiency exacerbates obesity-induced inflammation and insulin resistance in male mice

Endocrinology ◽  
2021 ◽  
Author(s):  
Mayumi Nagashimada ◽  
Kazuki Sawamoto ◽  
Yinhua Ni ◽  
Hironori Kitade ◽  
Naoto Nagata ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Tissue Macrophage ◽  
Epididymal White Adipose Tissue

Abstract The CX3CL1–CX3CR1 system plays an important role in disease progression by regulating inflammation both positively and negatively. We reported previously that C-C chemokine receptor 5, as well as CCR2, promotes obesity-associated adipose tissue inflammation and insulin resistance. Here, we demonstrate that CX3CL1–CX3CR1 signalling is involved in adipose tissue inflammation and insulin resistance in obese mice, via adipose tissue macrophage recruitment and M1/M2 polarization. CX3CL1 expression was persistently decreased in the epididymal white adipose tissue (eWAT) of high-fat diet-induced obese (DIO) mice, despite increased expression of other chemokines. Interestingly, in Cx3cr1  −/− mice, glucose tolerance, insulin resistance, and hepatic steatosis induced by DIO or leptin deficiency were exacerbated. CX3CL1–CX3CR1 signalling deficiency resulted in reduced M2-polarized macrophage migration and an M1-dominant shift of macrophages within eWAT. Furthermore, transplantation of Cx3cr1  −/− bone marrow was sufficient to impair glucose tolerance, insulin sensitivity, and regulation of M1/M2 status. Moreover, CX3CL1 administration in vivo led to the attenuation of glucose intolerance and insulin resistance. Thus, therapy targeting the CX3CL1–CX3CR1 system may be beneficial in the treatment of type 2 diabetes by regulating M1/M2 macrophages.

Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance

2013 ◽  
Vol 305 (3) ◽  
pp. E388-E395 ◽  
Author(s):  
Michael S. F. Wiedemann ◽  
Stephan Wueest ◽  
Flurin Item ◽  
Eugen J. Schoenle ◽  
Daniel Konrad
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Hepatic Insulin Resistance ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Hepatic Insulin Sensitivity ◽  
Tissue Inflammation

High-fat feeding for 3–4 days impairs glucose tolerance and hepatic insulin sensitivity. However, it remains unclear whether the evolving hepatic insulin resistance is due to acute lipid overload or the result of induced adipose tissue inflammation and consequent dysfunctional adipose tissue-liver cross-talk. In the present study, feeding C57Bl6/J mice a fat-enriched diet [high-fat diet (HFD)] for 4 days induced glucose intolerance, hepatic insulin resistance (as assessed by hyperinsulinemic euglycemic clamp studies), and hepatic steatosis as well as adipose tissue inflammation (i.e., TNFα expression) compared with standard chow-fed mice. Adipocyte-specific depletion of the antiapoptotic/anti-inflammatory factor Fas (CD95) attenuated adipose tissue inflammation and improved glucose tolerance as well as hepatic insulin sensitivity without altering the level of hepatic steatosis induced by HFD. In summary, our results identify adipose tissue inflammation and resulting dysfunctional adipose tissue-liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance.

scholarly journals Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

2013 ◽  
Vol 15 (1) ◽  
Author(s):  
Charmaine S. Tam ◽  
Leanne M. Redman
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Low Grade ◽  
Metabolic Dysfunction ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Proinflammatory Mediators ◽  
Low Grade Inflammation

AbstractObesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

scholarly journals Loss of Oncostatin M Signaling in Adipocytes Induces Insulin Resistance and Adipose Tissue Inflammation in Vivo

2016 ◽  
Vol 291 (33) ◽  
pp. 17066-17076 ◽  
Author(s):  
Carrie M. Elks ◽  
Peng Zhao ◽  
Ryan W. Grant ◽  
Hardy Hang ◽  
Jennifer L. Bailey ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Cell Types ◽  
Oncostatin M ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation ◽  
Fat Feeding

Oncostatin M (OSM) is a multifunctional gp130 cytokine. Although OSM is produced in adipose tissue, it is not produced by adipocytes. OSM expression is significantly induced in adipose tissue from obese mice and humans. The OSM-specific receptor, OSM receptor β (OSMR), is expressed in adipocytes, but its function remains largely unknown. To better understand the effects of OSM in adipose tissue, we knocked down Osmr expression in adipocytes in vitro using siRNA. In vivo, we generated a mouse line lacking Osmr in adiponectin-expressing cells (OSMRFKO mice). The effects of OSM on gene expression were also assessed in vitro and in vivo. OSM exerts proinflammatory effects on cultured adipocytes that are partially rescued by Osmr knockdown. Osm expression is significantly increased in adipose tissue T cells of high fat-fed mice. In addition, adipocyte Osmr expression is increased following high fat feeding. OSMRFKO mice exhibit increased insulin resistance and adipose tissue inflammation and have increased lean mass, femoral length, and bone volume. Also, OSMRFKO mice exhibit increased expression of Osm, the T cell markers Cd4 and Cd8, and the macrophage markers F4/80 and Cd11c. Interestingly, the same proinflammatory genes induced by OSM in adipocytes are induced in the adipose tissue of the OSMRFKO mouse, suggesting that increased expression of proinflammatory genes in adipose tissue arises both from adipocytes and other cell types. These findings suggest that adipocyte OSMR signaling is involved in the regulation of adipose tissue homeostasis and that, in obesity, OSMR ablation may exacerbate insulin resistance by promoting adipose tissue inflammation.

scholarly journals SMRT Regulates Metabolic Homeostasis and Adipose Tissue Macrophage Phenotypes in Tandem

Endocrinology ◽  
2020 ◽  
Vol 161 (10) ◽  
Author(s):  
Jonathan H Kahn ◽  
Anna Goddi ◽  
Aishwarya Sharma ◽  
Joshua Heiman ◽  
Alanis Carmona ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Hormone Receptors ◽  
Tissue Macrophage ◽  
Secreted Factors ◽  
Physiological Homeostasis

Abstract The Silencing Mediator of Retinoid and Thyroid Hormone Receptors (SMRT) is a nuclear corepressor, regulating the transcriptional activity of many transcription factors critical for metabolic processes. While the importance of the role of SMRT in the adipocyte has been well-established, our comprehensive understanding of its in vivo function in the context of homeostatic maintenance is limited due to contradictory phenotypes yielded by prior generalized knockout mouse models. Multiple such models agree that SMRT deficiency leads to increased adiposity, although the effects of SMRT loss on glucose tolerance and insulin sensitivity have been variable. We therefore generated an adipocyte-specific SMRT knockout (adSMRT-/-) mouse to more clearly define the metabolic contributions of SMRT. In doing so, we found that SMRT deletion in the adipocyte does not cause obesity—even when mice are challenged with a high-fat diet. This suggests that adiposity phenotypes of previously described models were due to effects of SMRT loss beyond the adipocyte. However, an adipocyte-specific SMRT deficiency still led to dramatic effects on systemic glucose tolerance and adipocyte insulin sensitivity, impairing both. This metabolically deleterious outcome was coupled with a surprising immune phenotype, wherein most genes differentially expressed in the adipose tissue of adSMRT-/- mice were upregulated in pro-inflammatory pathways. Flow cytometry and conditioned media experiments demonstrated that secreted factors from knockout adipose tissue strongly informed resident macrophages to develop a pro-inflammatory, MMe (metabolically activated) phenotype. Together, these studies suggest a novel role for SMRT as an integrator of metabolic and inflammatory signals to maintain physiological homeostasis.

scholarly journals Luteolin Improves Insulin Resistance in Postmenopausal Obese Mice by Altering Macrophage Polarization (FS12-01-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Yunjung Baek ◽  
Mi Nam Lee ◽  
Dayong Wu ◽  
Munkyong Pae
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Ovarian Function ◽  
Body Weight Gain ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation ◽  
Ovariectomized Mice

Abstract Objectives Previously, we showed that loss of ovarian function in mice fed high-fat diet exacerbated insulin resistance and adipose tissue inflammation. In the current study, we tested whether consumption of luteolin, an anti-inflammatory flavonoid, could mitigate adipose tissue inflammation and insulin resistance in obese ovariectomized mice. Methods Nine-week-old ovariectomized C57BL/6 mice were fed a low-fat diet (LFD), high-fat diet (HFD), or HFD supplemented with 0.005% luteolin (HFD + L) for 16 weeks. The anti-inflammatory drug salicylate was used as a positive control. Fasting blood glucose, insulin, and insulin resistance index HOMA-IR were measured every 4 weeks. Adipose tissue and spleen were characterized for tissue inflammation by real-time PCR and immune cell populations by flow cytometry after 16 weeks of feeding. Results HFD resulted in more body weight gain than LFD in ovariectomized mice and supplementing HFD with 0.005% luteolin did not affect the body weight gain. In addition, HFD elicited a significant elevation in fat mass, which were comparable between HFD and HFD + L groups. However, luteolin supplementation resulted in a significant decrease in CD11c+ macrophages in gonadal adipose tissue, as well as a trend of decrease in macrophage infiltration. Luteolin supplementation also significantly decreased mRNA expression of inflammatory and M1 markers MCP-1, CD11c, TNF-a, and IL-6, while maintaining expression of M2 marker MGL1. We further found that luteolin treatment protected mice from insulin resistance induced by HFD consumption; this improved insulin resistance was correlated with reductions in CD11c+ adipose tissue macrophages. Conclusions Our findings indicate that dietary luteolin supplementation attenuates adipose tissue inflammation and insulin resistance found in mice with loss of ovarian function coupled with a HFD intake, and this effect may be partly mediated through suppressing M1-like polarization of macrophages in adipose tissue. These results have clinical implication in implementing dietary intervention for prevention of metabolic syndrome associated with postmenopause and obesity. Funding Sources Supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2018R1A1A1A05078886).

scholarly journals Progression from High Insulin Resistance to Type 2 Diabetes Does Not Entail Additional Visceral Adipose Tissue Inflammation

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e48155 ◽  
Author(s):  
Nuria Barbarroja ◽  
Chary Lopez-Pedrera ◽  
Lourdes Garrido-Sanchez ◽  
Maria Dolores Mayas ◽  
Wilfredo Oliva-Olivera ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
High Insulin ◽  
Visceral Adipose

Role of brown adipose tissue in modulating adipose tissue inflammation and insulin resistance in high-fat diet fed mice

2019 ◽  
Vol 854 ◽  
pp. 354-364 ◽  
Author(s):  
Kripa Shankar ◽  
Durgesh Kumar ◽  
Sanchita Gupta ◽  
Salil Varshney ◽  
Sujith Rajan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
High Fat Diet ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation ◽  
Brown Adipose

Abstract 537: Dock2 Deficiency Mitigates High-Fat Diet-Induced Obesity by Reducing Adipose Tissue Inflammation While Increasing Energy Expenditure

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Xia Guo ◽  
Feifei Li ◽  
Zaiyan Xu ◽  
Shi-You Chen
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Inflammatory Diseases ◽  
Body Weight Gain ◽  
Public Health Problem ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation

Obesity is a public health problem as its association with type 2 diabetes, cardiovascular disorders and many other diseases. Adipose tissue inflammation is frequently observed and plays a vital role in obesity and insulin resistance. Dedicator of cytokinesis 2 (DOCK2) has shown proinflammatory effect in several inflammatory diseases, but its role in obesity remain unknown. To explore the function of DOCK2 in obesity and insulin resistance, wild-type (WT) and DOCK2 knockout (DOCK2-/-) mice were fed with chow or high-fat diet (HFD) for 12 weeks. Metabolic, biochemical and histologic analyses were performed. DOCK2 expression was robustly up-regulated in adipose tissue in WT mice given HFD. DOCK2-/- mice were protected against HFD-enhanced body weight gain with an improved metabolic homeostasis and insulin resistance. In addition, DOCK2 deficiency attenuated adipose tissue and systemic inflammation accompanied by a reduced macrophage infiltration. Moreover, DOCK2 deficiency induced the adipose tissue browning and increased energy expenditure as shown by the up-regulation of metabolic genes in DOCK2-/- mice. Our data indicated that DOCK2 deficiency can protect mice from HFD-induced obesity, metabolic disorders, and insulin resistance. Therefore, targeting DOCK2 may be a potential therapeutic strategy for treating obesity-associated diseases.

scholarly journals Nrf2 deficiency in myeloid cells is not sufficient to protect mice from high-fat diet-induced adipose tissue inflammation and insulin resistance

2012 ◽  
Vol 52 (9) ◽  
pp. 1708-1715 ◽  
Author(s):  
Akshaya K. Meher ◽  
Poonam R. Sharma ◽  
Vitor A. Lira ◽  
Masayuki Yamamoto ◽  
Thomas W. Kensler ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Myeloid Cells ◽  
Adipose Tissue Inflammation ◽  
High Fat ◽  
Tissue Inflammation
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