Myeloid Differentiation Factor 88 (MyD88)-Deficiency Increases Risk of Diabetes in Mice

Hosoi, Toru; Yokoyama, Shota; Matsuo, Suguru; Akira, Shizuo; Ozawa, Koichiro

doi:10.1371/journal.pone.0012537

Cited by 102 publications

(84 citation statements)

References 34 publications

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“…43 However this is not always the case, as there is evidence to suggest MyD88 null mice have an exaggerated response to high fat diet-induced increases in leptin, insulin, cholesterol and indices of liver inflammation. 44 To our knowledge, there is no other report of the effects of physical activity or exercise on the protein content of MyD88 in adipose tissue, and therefore the physiological relevance of the increased MyD88 in both iWAT and eWAT with VWR warrants future investigation. As a secondary assessment, we considered the role of FST as a potential molecular mediator as others have shown that FST increases in circulation after LPS exposure and can act to reduce inflammation.…”

Section: Discussionmentioning

confidence: 85%

Habitual physical activity protects against lipopolysaccharide-induced inflammation in mouse adipose tissue

et al. 2016

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Sepsis is a systemic inflammatory response to infection, with no preventative strategies. In this study, we identify a role for habitual physical activity in the prevention of adipose tissue inflammation induced by a model of sepsis, lipopolysaccharide (LPS). Male C57BL/6J mice (8 weeks old) were housed with access to voluntary wheel running (VWR) or sedentary (SED) for 10 weeks. Mice were then injected with LPS (2 mg/kg) or saline (SAL), and tissues were removed 6 hours postinjection. VWR attenuated body, epididymal adipose tissue (eWAT), and subcutaneous inguinal adipose tissue (iWAT) mass gain, improved glucose tolerance, increased markers of mitochondrial biogenesis in iWAT and eWAT, and increased UCP-1 protein content in iWAT. In iWAT, VWR attenuated the LPS induced increase in mRNA expression of TNF-a, MCP-1, and follistatin, along with phosphorylation of STAT3. In addition, VWR had a main effect for reducing iWAT mRNA expression of IL-1b, IL-6, and SOCS3. In eWAT, VWR had a main effect for reducing mRNA expression of IL-1b, MCP-1, IL-6, and follistatin. Further, VWR increased SOCS3 mRNA expression and phosphorylation of STAT3 in SAL mice, thus the relative change in response to LPS for these markers was attenuated. The protective effect of prior physical activity occurred in conjunction with increases in the protein content of a component of the LPS binding complex, MyD88. Overall, the results from this study demonstrate that habitual physical activity can attenuate the LPS induced inflammatory response in adipose tissue and this occurs to a greater extent in iWAT compare with eWAT.

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Section: Discussionmentioning

confidence: 85%

Habitual physical activity protects against lipopolysaccharide-induced inflammation in mouse adipose tissue

et al. 2016

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“…The intracellular signals downstream of TLR activation occur via multiple pathways, which may be dependent on, or independent of, the adaptor protein MyD88. While MyD88-dependent signaling contributes to hypothalamic inflammation with obesity (61), its role in other metabolic tissues is unclear, as Myd88 -/-mice are more susceptible to insulin resistance with DIO (91). Activation of IκB kinase-β (IKKβ) occurs downstream of MyD88 and plays critical roles in inflammation in the liver, myeloid cells, and the hypothalamus in the obese state (92,93).…”

Section: How Does Inflammation Cause Metabolic Dysfunction?mentioning

confidence: 99%

Inflammatory links between obesity and metabolic disease

Lumeng¹,

Saltiel²

2011

J. Clin. Invest.

1,890

1,519

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The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity. This has led to a convergence of the fields of immunology and nutrient physiology and the understanding that they are inextricably linked. The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases. In this Review, we highlight the cellular and molecular mechanisms at play in the generation of obesity-induced inflammation. We also emphasize how defining the immune regulation in metabolic tissues has broadened the understanding of the diversity of inflammatory responses. IntroductionThe burden of obesity on health extends across multiple organ systems and diseases. While its impact on tissues involved in nutrient regulation is manifest in the development of insulin resistance and type 2 diabetes, there are also unexpected connections between obesity and the risk of cancer and pulmonary diseases. Over the past decade, the search for a potential unifying mechanism behind the pathogenesis of obesity-associated diseases has revealed a close relationship between nutrient excess and derangements in the cellular and molecular mediators of immunity and inflammation. This has given birth to the concept of "metainflammation" (1) to describe the chronic low-grade inflammatory response to obesity. We present here a broad overview of the links between obesity and immune responses with a focus on metabolic disease and argue that the intersection between the pathways that control nutrient metabolism and inflammatory responses may be broadly applicable to our understanding of inflammation and the immune system.

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“…In addition to the MyD88-dependent pathway, TLR4 recruits TRIF to activate downstream signaling cascades and the activation of IRF3 (Figure 1). Myd88 -/-mice fed a HFD exhibited increased circulating levels of insulin, leptin, and cholesterol, which is associated with insulin and leptin resistance and development of severe T2DM 58 . Myd88 -/-mice also had smaller islets and abnormal glucose tolerance after treatment with low-dose streptozotocin-a naturally occurring chemical that has toxic effects on insulin-producing β cells 59 .…”

Section: [H3] Tlr Adaptor Moleculesmentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich oligomerization domain (NOD)-like receptors (NLRs).These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL1β, and IL18 and thus initiate an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

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Myeloid Differentiation Factor 88 (MyD88)-Deficiency Increases Risk of Diabetes in Mice

Cited by 102 publications

References 34 publications

Habitual physical activity protects against lipopolysaccharide-induced inflammation in mouse adipose tissue

Habitual physical activity protects against lipopolysaccharide-induced inflammation in mouse adipose tissue

Inflammatory links between obesity and metabolic disease

Innate immunity in diabetes and diabetic nephropathy

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