Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism

Lancaster, Graeme I.; Langley, Katherine G.; Berglund, Nils; Kammoun, Hélène L.; Reibe, Saskia; Estévez, Emma; Weir, Jacquelyn M.; Mellett, Natalie A.; Pernes, Gerard; Conway, James R. W.; Lee, Man K.S.; Timpson, Paul; Murphy, Andrew; Masters, Seth L.; Gerondakis, Steve; Bartoniček, Nenad; Kaczorowski, Dominik C.; Dinger, Marcel E.; Meikle, Peter J.; Bond, Peter J.; Febbraio, Mark A.

doi:10.1016/j.cmet.2018.03.014

Cited by 354 publications

(309 citation statements)

References 78 publications

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“…It has been suggested that fatty acids activate macrophages by binding to TLR4 (339, 423). However, other evidence indicates that long chain saturated fatty acids are not direct ligands of TLR4 but rather that saturated fatty acid-induced inflammation requires an initial priming event of TLR4 (110, 258). Intriguingly, mice lacking TLR4 (a) are protected from the ability of a systemic lipid infusion to trigger insulin resistance, and (b) become obese when fed a HFD but remain relatively insulin sensitive with lower levels of inflammation in liver and adipose tissue (423).…”

Section: Adipose Tissue Inflammation In Obesitymentioning

confidence: 99%

Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus

Burhans

Hagman

Kuzma

et al. 2018

Comprehensive Physiology

279

241

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The objective of this comprehensive review is to summarize and discuss the available evidence of how adipose tissue inflammation affects insulin sensitivity and glucose tolerance. Low-grade, chronic adipose tissue inflammation is characterized by infiltration of macrophages and other immune cell populations into adipose tissue, and a shift towards more pro-inflammatory subtypes of leukocytes. The infiltration of pro-inflammatory cells in adipose tissue is associated with an increased production of key chemokines such as C-C motif chemokine ligand 2, pro-inflammatory cytokines including tumor necrosis factor α and interleukins 1β and 6, as well as reduced expression of the key insulin sensitizing adipokine, adiponectin. In both rodent models and humans, adipose tissue inflammation is consistently associated with excess fat mass and insulin resistance. In humans, associations with insulin resistance are stronger and more consistent for inflammation in visceral as opposed to subcutaneous fat. Further, genetic alterations in mouse models of obesity that reduce adipose tissue inflammation are – almost without exception - associated with improved insulin sensitivity. However, a dissociation between adipose tissue inflammation and insulin resistance can be observed in very few rodent models of obesity as well as in humans following bariatric surgery- or low-calorie diet-induced weight loss, illustrating that the etiology of insulin resistance is multifactorial. Taken together, adipose tissue inflammation is a key factor in the development of insulin resistance and type 2 diabetes in obesity, along with other factors that likely include inflammation and fat accumulation in other metabolically active tissues.

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Section: Adipose Tissue Inflammation In Obesitymentioning

confidence: 99%

Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus

Burhans

Hagman

Kuzma

et al. 2018

Comprehensive Physiology

279

241

View full text Add to dashboard Cite

show abstract

“…Recent data show that pro-inflammatory activation of macrophages by saturated fatty acids (SFA) is independent of Toll-like receptor 4, yet the receptor that is responsible is still not known (7). 20 Recently, we have shown that in vitro activation of the phagocytic receptor, macrophage scavenger receptor 1 (MSR1, also known as SR-A or CD204), results in pro-inflammatory macrophage polarisation through JNK activation (8).…”

Section: Main Textmentioning

confidence: 99%

Macrophage Scavenger Receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

Govaere

Martínez–López

Petersen

et al. 2020

Preprint

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Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), however the exact mechanisms remain incompletely understood. Here we demonstrate that macrophage scavenger receptor 1 (MSR1) is associated with the occurrence of hepatic lipid-laden foamy macrophages and correlates with the degree of steatosis and steatohepatitis in a large cohort of NAFLD patients. Mice lacking Msr1 are protected against high fat diet-induced metabolic disorder, showing less hepatic inflammation and fibrosis, reduced circulating fatty acids, increased lipid storage in the adipocytes and improved glucose tolerance. Moreover, MSR1 triggers diet-induced JNK-mediated inflammatory activation of macrophages independent of lipopolysaccharide. Taken together, our data suggest a critical role for MSR1 in lipid homeostasis and a potential therapeutic target for the treatment of NAFLD.One Sentence SummaryThe immunometabolic role of MSR1 in human NAFLD.

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“…However, some PRRs protect against metabolic inflammation and insulin resistance during obesity (Denou et al 2015;Cavallari et al 2017). It has now been shown that PRRs can reprogram cellular metabolism and propagate inflammation as opposed to being direct sensors for obesity-associated inflammatory "ligands", such as saturated fatty acids (Lancaster et al 2018). There is still much to learn about how obesity-related triggers of inflammation engage elements of the immune system to alter cellular and systemic metabolism.…”

Section: Introductionmentioning

confidence: 99%

Targeting macrophage scavenger receptor 1 promotes insulin resistance in obese male mice

Cavallari¹,

Anhê²,

Foley³

et al. 2018

Physiol Rep

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Immune components can bridge inflammatory triggers to metabolic dysfunction. Scavenger receptors sense lipoproteins, but it is not clear how different scavenger receptors alter carbohydrate metabolism during obesity. Macrophage scavenger receptor 1 (MSR1) and macrophage receptor with collagenous structure (MARCO) are scavenger receptors that have been implicated in lipoprotein metabolism and cardiovascular disease. We assessed glucose control, tissue‐specific insulin sensitivity, and inflammation in Msr1‐ and Marco‐deficient mice fed with obesogenic diets. Compared to wild‐type (WT) mice, Msr1 −/− mice had worse blood glucose control that was only revealed after diet‐induced obesity, not in lean mice. Obese Msr1 −/− mice had worse insulin‐stimulated glucose uptake in the adipose tissue, which occurred in the absence of overt differences in adipose inflammation compared to obese WT mice. Msr1 deletion worsened dysglycemia independently from bacterial cell wall insulin sensitizers, such as muramyl dipeptide. MARCO was dispensable for glycemic control in obese mice. Oral administration of the polysaccharide fucoidan worsened glucose control in obese WT mice, but fucoidan had no effect on glycemia in obese Msr1 −/− mice. Therefore, MSR1 is a scavenger receptor responsible for changes in glucose control in response to the environmental ligand fucoidan. Given the interest in dietary supplements and natural products reducing inflammation or insulin resistance in metabolic disease during obesity, our results highlight the importance of understanding which ligand–receptor relationships promote versus those that protect against metabolic disease factors. Our results show that ligand or gene targeting of MSR1 exacerbates insulin resistance in obese mice.

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Evidence that TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism

Cited by 354 publications

References 78 publications

Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus

Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus

Macrophage Scavenger Receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

Targeting macrophage scavenger receptor 1 promotes insulin resistance in obese male mice

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