Resolvins, Specialized Proresolving Lipid Mediators, and Their Potential Roles in Metabolic Diseases

Spite, Matthew; Clària, Joan; Serhan, Charles N.

doi:10.1016/j.cmet.2013.10.006

Cited by 375 publications

(333 citation statements)

References 125 publications

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“…Additionally, AICAR treatment reduced HFD-induced CD8 + T cell infiltration, which may have contributed to the attenuated inflammation since CD8 + T cells facilitate WAT accumulation of inflammatory CD11c + M1 macrophages [39]. Hepatic steatosis is associated with obesity and diabetes and enhances susceptibility to liver disease [40,41]. AICAR inhibited hepatic steatosis, reducing HFD-induced hepatic triacylglycerol accumulation in both wild-type and Adipoq −/− mice.…”

Section: Discussionmentioning

confidence: 99%

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

et al. 2017

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Aims/hypothesis In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo. Methods Six-week-old male C57BL/6J wild-type and Adipoq −/− mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12 weeks and given vehicle or AICAR (500 μg/g) three times/week from weeks 4-12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35-50 kg/m 2 ) individuals were incubated with vehicle or AICAR (1 mmol/l) for 6 h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry. Results AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8 + T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p < 0.05), urinary H 2 O 2 (p < 0.05) and renal superoxide levels (p < 0.01) in both wild-type and Adipoq −/− mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq −/− mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients. Conclusions/interpretation AICAR may promote metabolic health and protect against obesity-induced systemic diseases Catherine Godson and Kumar Sharma are joint senior authors.Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 99%

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

et al. 2017

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“…LTB 4 , in addition to being a potent chemoattractant for leukocytes, enhances the release of proinflammatory adipokines, such as MCP-1 and interleukin (IL)-6, from obese adipose tissue (10,11). LTB 4 levels are elevated in adipose tissue during obesity (11)(12)(13), and LTB 4 has been described to play a role in the development of insulin resistance and to directly decrease insulin signaling in myocytes and hepatocytes in vitro (5,14,15). In addition, although the activation of the ALOX5/ALOX5AP complex is key to leukotriene synthesis, it can alternatively lead to the biosynthesis of other compounds, such as lipoxins (16).…”

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confidence: 99%

“…Obesity is associated with low-grade chronic inflammation of adipose tissue, which has been causally linked to the development of insulin resistance, type 2 diabetes, arthritis, cancer, cardiovascular diseases, asthma, and Alzheimer disease (1,2). In contrast to acute inflammation, in chronic inflammation the initiation phase is not followed by a resolution, and failure of resolution may be responsible for low-grade inflammation in obesity (3)(4)(5). During the unresolved inflammation, proinflammatory cytokines released by the adipose tissue act in a paracrine and systemic manner, promoting the development of insulin resistance in metabolic tissues (6,7).…”

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confidence: 99%

“…Lipoxins, which belong to the specialized proresolving mediator (SPM) family, exert anti-inflammatory effects and are involved in the resolution of inflammation (5). Treatment with LXA 4 of adipose tissue explants from aging mice-a model of adipose inflammation-leads to a decrease in IL-6 and restoration of GLUT4 and insulin receptor substrate (IRS)1 expression, indicating less inflammation and improved insulin sensitivity (21).…”

mentioning

confidence: 99%

“…Lipid mediators, such as eicosanoids produced from arachidonic acid, play critical roles in inflammation and its resolution (5,6,8). Among them, leukotrienes are wellknown proinflammatory molecules (9).…”

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confidence: 99%

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ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

et al. 2016

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Eicosanoids, such as leukotriene B4 (LTB4) and lipoxin A4 (LXA4), may play a key role during obesity. While LTB4 is involved in adipose tissue inflammation and insulin resistance, LXA4 may exert anti-inflammatory effects and alleviate hepatic steatosis. Both lipid mediators derive from the same pathway, in which arachidonate 5-lipoxygenase (ALOX5) and its partner, arachidonate 5-lipoxygenase–activating protein (ALOX5AP), are involved. ALOX5 and ALOX5AP expression is increased in humans and rodents with obesity and insulin resistance. We found that transgenic mice overexpressing ALOX5AP in adipose tissue had higher LXA4 rather than higher LTB4 levels, were leaner, and showed increased energy expenditure, partly due to browning of white adipose tissue (WAT). Upregulation of hepatic LXR and Cyp7a1 led to higher bile acid synthesis, which may have contributed to increased thermogenesis. In addition, transgenic mice were protected against diet-induced obesity, insulin resistance, and inflammation. Finally, treatment of C57BL/6J mice with LXA4, which showed browning of WAT, strongly suggests that LXA4 is responsible for the transgenic mice phenotype. Thus, our data support that LXA4 may hold great potential for the future development of therapeutic strategies for obesity and related diseases.

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Diagnostics and Therapy in Veterinary Dermatology

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Resolvins, Specialized Proresolving Lipid Mediators, and Their Potential Roles in Metabolic Diseases

Cited by 375 publications

References 125 publications

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

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