INFLAMMATION, BUT NOT RECRUITMENT, OF ADIPOSE TISSUE MACROPHAGES REQUIRES SIGNALING THROUGH MAC-1 IN DIET-INDUCED OBESITY (DIO)

AbstractPro-inflammatory activation of adipose tissue macrophages (ATMs) is causally linked to obesity and obesity-associated disorders. A number of studies have demonstrated the crucial role of mitochondrial metabolism in macrophage activation. However, there is a lack of pharmaceutical agents to target the mitochondrial metabolism of ATMs for the treatment of obesity-related diseases. Here, we characterize a near-infrared fluorophore (IR-61) that preferentially accumulates in the mitochondria of ATMs and has a therapeutic effect on diet-induced obesity as well as obesity-associated insulin resistance and fatty liver. IR-61 inhibits the classical activation of ATMs by increasing mitochondrial complex levels and oxidative phosphorylation via the ROS/Akt/Acly pathway. Taken together, our findings indicate that specific enhancement of ATMs oxidative phosphorylation improves chronic inflammation and obesity-related disorders. IR-61 might be an anti-inflammatory agent useful for the treatment of obesity-related diseases by targeting the mitochondria of ATMs.

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Metabolically Activated Adipose Tissue Macrophages Perform Detrimental and Beneficial Functions during Diet-Induced Obesity

Cell Reports ◽

10.1016/j.celrep.2017.08.096 ◽

2017 ◽

Vol 20 (13) ◽

pp. 3149-3161 ◽

Cited By ~ 84

Author(s):

Brittney R. Coats ◽

Kelly Q. Schoenfelt ◽

Valéria C. Barbosa-Lorenzi ◽

Eduard Peris ◽

Chang Cui ◽

...

Keyword(s):

Adipose Tissue ◽

Diet Induced Obesity ◽

Adipose Tissue Macrophages

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Inflammation, but not recruitment, of adipose tissue macrophages requires signalling through Mac-1 (CD11b/CD18) in diet-induced obesity (DIO)

Thrombosis and Haemostasis ◽

10.1160/th16-07-0553 ◽

2017 ◽

Vol 117 (02) ◽

pp. 325-338 ◽

Cited By ~ 11

Author(s):

Dennis Wolf ◽

Nora Bukosza ◽

David Engel ◽

Marjorie Poggi ◽

Felix Jehle ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Adipose Tissue Inflammation ◽

Inflammatory Gene Expression ◽

Tissue Inflammation ◽

Inflammatory Gene ◽

Diet Induced Obesity ◽

Adipose Tissue Macrophages ◽

Cell Accumulation

SummaryCell accumulation is a prerequisite for adipose tissue inflammation. The leukocyte integrin Mac-1 (CD11b/CD18, αMβ2) is a classic adhesion receptor critically regulating inflammatory cell recruitment. Here, we tested the hypothesis that a genetic deficiency and a therapeutic modulation of Mac-1 regulate adipose tissue inflammation in a mouse model of diet-induced obesity (DIO). C57Bl6/J mice genetically deficient (Mac-1-/-) or competent for Mac-1 (WT) consumed a high fat diet for 20 weeks. Surprisingly, Mac-1-/- mice presented with increased diet-induced weight gain, decreased insulin sensitivity in skeletal muscle and in the liver in insulin-clamps, insulin secretion deficiency and elevated glucose levels in fasting animals, and dyslipidaemia. Unexpectedly, accumulation of adipose tissue macrophages (ATMs) was unaffected, while gene expression indicated less inflamed adipose tissue and macrophages in Mac-1-/- mice. In contrast, inflammatory gene expression at distant locations, such as in skeletal muscle, was not changed. Treatment of ATMs with an agonistic anti-Mac-1 antibody, M1/70, induced pro-inflammatory genes in cell culture. In vivo, treatment with M1/70 induced a hyper-inflammatory phenotype with increased expression of IL-6 and MCP-1, whereas accumulation of ATMs did not change. Finally, inhibition of Mac-1’s adhesive interaction to CD40L by the peptide inhibitor cM7 did not affect myeloid cell accumulation in adipose tissue. We present the surprising finding that adhesive properties of the leukocyte integrin Mac-1 are not required for macrophage accumulation in adipose tissue. Instead, Mac-1 modulates inflammatory gene expression in macrophages. These findings question the net effect of integrin blockade in cardio-metabolic disease.D. W., N. B., and D. E. equally contributed to this work.K. P., E. L., and A. Z. share senior authorship.Note: The review process for this manuscript was fully handled by Gregory Y. H. Lip, Editor in Chief.Supplementary Material to this article is available online at www.thrombosis-online.com.

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MGL1 promotes adipose tissue inflammation and insulin resistance by regulating 7/4hi monocytes in obesity

Journal of Experimental Medicine ◽

10.1084/jem.20091333 ◽

2009 ◽

Vol 206 (13) ◽

pp. 3143-3156 ◽

Cited By ~ 83

Author(s):

Daniel J. Westcott ◽

Jennifer B. DelProposto ◽

Lynn M. Geletka ◽

Tianyi Wang ◽

Kanakadurga Singer ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Critical Role ◽

Alternatively Activated Macrophages ◽

Inflammatory Monocytes ◽

Diet Induced Obesity ◽

Adipose Tissue Macrophages ◽

Visceral Adipose

Adipose tissue macrophages (ATMs) play a critical role in obesity-induced inflammation and insulin resistance. Distinct subtypes of ATMs have been identified that differentially express macrophage galactose-type C-type lectin 1 (MGL1/CD301), a marker of alternatively activated macrophages. To evaluate if MGL1 is required for the anti-inflammatory function of resident (type 2) MGL1+ ATMs, we examined the effects of diet-induced obesity (DIO) on inflammation and metabolism in Mgl1−/− mice. We found that Mgl1 is not required for the trafficking of type 2 ATMs to adipose tissue. Surprisingly, obese Mgl1−/− mice were protected from glucose intolerance, insulin resistance, and steatosis despite having more visceral fat. This protection was caused by a significant decrease in inflammatory (type 1) CD11c+ ATMs in the visceral adipose tissue of Mgl1−/− mice. MGL1 was expressed specifically in 7/4hi inflammatory monocytes in the blood and obese Mgl1−/− mice had lower levels of 7/4hi monocytes. Mgl1−/− monocytes had decreased half-life after adoptive transfer and demonstrated decreased adhesion to adipocytes indicating a role for MGL1 in the regulation of monocyte function. This study identifies MGL1 as a novel regulator of inflammatory monocyte trafficking to adipose tissue in response to DIO.

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Increased Inflammatory Properties of Adipose Tissue Macrophages Recruited During Diet-Induced Obesity

Diabetes ◽

10.2337/db06-1076 ◽

2006 ◽

Vol 56 (1) ◽

pp. 16-23 ◽

Cited By ~ 668

Author(s):

C. N. Lumeng ◽

S. M. DeYoung ◽

J. L. Bodzin ◽

A. R. Saltiel

Keyword(s):

Adipose Tissue ◽

Diet Induced Obesity ◽

Adipose Tissue Macrophages

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Abstract 597: Diet-induced Obesity Requires Signalling Through Tumor Necrosis Factor Receptor-associated Factor 1 (TRAF-1) in Adipocytes

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.597 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Dennis Wolf ◽

Nathaly Anto Michel ◽

Ingo Hilgendorf ◽

Christoph Bode ◽

Andreas Zirlik

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Hormone Sensitive Lipase ◽

Obese Mouse ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Diet Induced Obesity ◽

The Metabolic Syndrome ◽

Adipose Tissue Macrophages ◽

Genetic Deficiency

Background: Accumulation of inflammatory leukocytes is a prerequisite of adipose tissue inflammation during cardio-metabolic disease. We recently reported that a genetic deficiency of the intracellular signalling adaptor TRAF-1 attenuates inflammatory cell recruitment and vascular inflammation in atherosclerosis. Here, we tested the contribution of TRAF-1 to diet-induced obesity (DIO) in mice. Methods and Results: To test the association of TRAFs and obesity we screened for expression of different TRAFs in adipose tissue. We found an up-regulation of TRAF-1 mRNA in obese mouse and human adipose tissue, resulting from higher gene expression in adipocytes, but not in adipose tissue macrophages. To test a functional relevance of TRAF-1 signalling in obesity, WT or TRAF-1 -/- mice consumed a high fat diet HFD for 20 weeks. Surprisingly, genetic deficiency of TRAF-1 abolished diet-induced weight gain by supressing peripheral fat depositions. Consequently, TRAF-1 -/- mice demonstrated ameliorated glucose levels after glucose and insulin tolerance tests and dampened insulin signalling. Consistently, we also found reduced accumulation of adipose tissue macrophages. Mechanistically, TRAF-1 -/- mice demonstrated no differences in basic energy metabolism, such as in energy expenditure. However, TRAF-1 -/- adipocytes had higher expression of Adipose Triglyceride Lipase (ATGL) and Hormone-sensitive Lipase (HSL), suggesting increased lipid breakdown in adipocytes. In accord, plasma levels of free fatty acids were higher, while leptin levels were reduced in TRAF-1 -/- mice. Finally, in a collective of patients with a high prevalence of the metabolic syndrome, TRAF-1 expression correlated with the metabolic syndrome, suggesting clinical relevance of our findings. Conclusion: We present the novel finding that the signalling adapter TRAF-1 correlates with obesity in mice and humans. Genetic deficiency of TRAF-1 attenuates diet-induced obesity by increasing lipolysis in adipocytes. These findings identify TRAF-1 as a novel therapeutic target in obesity and adipose-tissue inflammation.

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