NK cells in human visceral adipose tissue contribute to obesity‐associated insulin resistance through low‐grade inflammation

Central obesity is associated with low-grade inflammation that promotes type 2 diabetes and cardiovascular disease in obese individuals. The 12- and 5-lipoxygenase (12-LO and 5-LO) enzymes have been linked to inflammatory changes, leading to the development of atherosclerosis. 12-LO has also been linked recently to inflammation and insulin resistance in adipocytes. We analyzed the expression of LO and proinflammatory cytokines in adipose tissue and adipocytes in obese Zucker rats, a widely studied genetic model of obesity, insulin resistance, and the metabolic syndrome. mRNA expression of 12-LO, 5-LO, and 5-LO-activating protein (FLAP) was upregulated in adipocytes and adipose tissue from obese Zucker rats compared with those from lean rats. Concomitant with increased LO gene expression, the 12-LO product 12-HETE and the 5-LO products 5-HETE and leukotriene B4 (LTB4) were also increased in adipocytes. Furthermore, upregulation of key proinflammatory markers interleukin (IL)-6, TNFα, and monocyte chemoattractant protein-1 were observed in adipocytes isolated from obese Zucker rats. Immunohistochemistry indicated that the positive 12-LO staining in adipose tissue represents cells in addition to adipocytes. This was confirmed by Western blotting in stromal vascular fractions. These changes were in part reversed by the novel anti-inflammatory drug lisofylline (LSF). LSF also reduced p-STAT4 in visceral adipose tissue from obese Zucker rats and improved the metabolic profile, reducing fasting plasma glucose and increasing insulin sensitivity in obese Zucker rats. In 3T3-L1 adipocytes, LSF abrogated the inflammatory response induced by LO products. Thus, therapeutic agents reducing LO or STAT4 activation may provide novel tools to reduce obesity-induced inflammation.

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Early postprandial low-grade inflammation after high-fat meal in healthy rats: possible involvement of visceral adipose tissue

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2009.03.004 ◽

2010 ◽

Vol 21 (6) ◽

pp. 550-555 ◽

Cited By ~ 31

Author(s):

Joëlle Magné ◽

François Mariotti ◽

Romy Fischer ◽

Véronique Mathé ◽

Daniel Tomé ◽

...

Keyword(s):

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Low Grade ◽

High Fat ◽

Visceral Adipose ◽

Low Grade Inflammation ◽

Fat Meal

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Adipose tissue inflammation and insulin resistance: all obese humans are not created equal

Biochemical Journal ◽

10.1042/bj20101062 ◽

2010 ◽

Vol 430 (2) ◽

pp. e1-e4 ◽

Cited By ~ 20

Author(s):

Marie-Soleil Gauthier ◽

Neil B. Ruderman

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Obese Individual ◽

Low Grade ◽

Key Factors ◽

Insulin Resistant ◽

The Metabolic Syndrome ◽

Biochemical Journal ◽

Visceral Adipose ◽

Low Grade Inflammation

In recent years, it has become widely accepted that obesity is characterized by a chronic low-grade inflammation of adipose tissue that predisposes affected individuals to insulin resistance, Type 2 diabetes and other disorders associated with the metabolic syndrome. On the other hand, a subset of obese individuals appears to be protected against insulin resistance and the disorders to which it predisposes. The comparison between such insulin-sensitive and insulin-resistant obese individuals offers a unique opportunity to identify key factors that either contribute to or prevent the development of insulin resistance in humans, without the confounding effect of a major difference in fat mass. In the previous issue of the Biochemical Journal, Barbarroja et al. reported that insulin-sensitive obese individuals show less inflammation in their visceral adipose tissue than a group of insulin-resistant subjects matched for BMI (body mass index). This finding reinforces the concept that inflammation in adipose tissue may be a cause of insulin resistance in most obese individuals, although it does not prove it. Further studies will be required for this purpose, as well as to identify the pathogenetic factors that determine whether or not adipose tissue of an obese individual becomes inflamed.

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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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Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0032 ◽

2013 ◽

Vol 15 (1) ◽

Cited By ~ 2

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).

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Adipose Tissue Macrophages, Low Grade Inflammation and Insulin Resistance in Human Obesity

Current Pharmaceutical Design ◽

10.2174/138161208784246153 ◽

2008 ◽

Vol 14 (12) ◽

pp. 1225-1230 ◽

Cited By ~ 310

Author(s):

Leonie Heilbronn ◽

Lesley Campbell

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Low Grade ◽

Human Obesity ◽

Adipose Tissue Macrophages ◽

Low Grade Inflammation

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Multinucleated giant cells in adipose tissue are specialized in adipocyte degradation

10.2337/figshare.13168862 ◽

2020 ◽

Author(s):

Ada Admin ◽

Julia Braune ◽

Andreas Lindhorst ◽

Janine Fröba ◽

Constance Hobusch ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Ex Vivo ◽

Giant Cells ◽

Low Grade ◽

Adipose Tissue Macrophages ◽

Visceral Adipose ◽

Low Grade Inflammation

Obesity is associated with a chronic low-grade inflammation in visceral adipose tissue (AT) characterized by an increasing number of adipose tissue macrophages (ATMs) and linked to type 2 diabetes. AT inflammation is histologically indicated by the formation of so-called crown-like structures (CLS), as accumulation of ATMs around dying adipocytes, and the occurrence of multi-nucleated giant cells (MGCs). However to date, the function of MGCs in obesity is unknown. Hence, the aim of this study was to characterize MGCs in AT and unravel the function of these cells. We demonstrate that MGCs occur in obese patients and after 24 weeks of high fat diet (HFD) in mice, accompanying signs of AT inflammation and then represent ~3% of ATMs in mice. Mechanistically, we found evidence that adipocyte death triggers MGC formation. Most importantly, MGCs in obese AT have a higher capacity to phagocytose oversized particles, such as adipocytes, as shown by live-imaging of AT, 45 µm bead uptake ex vivo and a higher lipid content in vivo. Finally, we show that IL-4 treatment is sufficient to increase the number of MGCs in AT, whereas other factors maybe more important for endogenous MGC formation in vivo.

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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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