Loss of toll-like receptor 3 function improves glucose tolerance and reduces liver steatosis in obese mice

Wu, Linda; Huang, Chuican; Adhikarakunnathu, Sree; Mateo, Lani R. San; Duffy, Karen E.; Rafferty, Patricia; Bugelski, Peter J.; Raymond, Holly; Deutsch, Heather; Picha, Kristen; Ward, Christine K.; Alexoupolou, Lena; Flavell, Richard A.; Mbow, Moustapha; Susulic, Vedrana S.

doi:10.1016/j.metabol.2012.04.015

Cited by 34 publications

(26 citation statements)

References 56 publications

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“…TLR3 may also act distally in other metabolic tissues and initiate processes that lead to changes in the islets. This notion is supported by the observation that TLR3 increases hepatic production of VLDL and is also in line with published data indicating a role for TLR3 in liver regeneration and hepatocyte proliferation (47,51).…”

Section: Discussionsupporting

confidence: 91%

Toll-Like Receptor 3 Influences Glucose Homeostasis and β-Cell Insulin Secretion

Strodthoff

Wirström

et al. 2015

Diabetes

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Toll-like receptors (TLRs) have been implicated in the pathogenesis of type 2 diabetes. We examined the function of TLR3 in glucose metabolism and type 2 diabetes-related phenotypes in animals and humans. TLR3 is highly expressed in the pancreas, suggesting that it can influence metabolism. Using a diet-induced obesity model, we show that TLR3-deficient mice had enhanced glycemic control, facilitated by elevated insulin secretion. Despite having high insulin levels, Tlr3 2/2 mice did not experience disturbances in whole-body insulin sensitivity, suggesting that they have a robust metabolic system that manages increased insulin secretion. Increase in insulin secretion was associated with upregulation of islet glucose phosphorylation as well as exocytotic protein VAMP-2 in Tlr3 2/2 islets. TLR3 deficiency also modified the plasma lipid profile, decreasing VLDL levels due to decreased triglyceride biosynthesis. Moreover, a meta-analysis of two healthy human populations showed that a missense single nucleotide polymorphism in TLR3 (encoding L412F) was linked to elevated insulin levels, consistent with our experimental findings. In conclusion, our results increase the understanding of the function of innate receptors in metabolic disorders and implicate TLR3 as a key control system in metabolic regulation.

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Section: Discussionsupporting

confidence: 91%

Toll-Like Receptor 3 Influences Glucose Homeostasis and β-Cell Insulin Secretion

Strodthoff

Wirström

et al. 2015

Diabetes

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“…Along with inflammatory mediators, TLR3 was recently reported to affect glucose and lipid metabolism (Wu and L.H., 2012), which agrees with emerging evidence suggesting that a link exists between innate immunity and metabolic diseases such as type 2 DM (Dasu et al, 2010;Ehses et al, 2010;Shi et al, 2006;Kim et al, 2013). The current study implicates a pivotal role of TLR3 in type 2 DM based on observations in vivo and in vitro of TLR3 upregulation in islet b-cell models of glucolipotoxicity ( Fig.…”

Section: Discussionsupporting

confidence: 90%

Elevated toll-like receptor 3 inhibits pancreatic β-cell proliferation through G1 phase cell cycle arrest

Wang

Gao

et al. 2013

Molecular and Cellular Endocrinology

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“…However, the Tlr4 KO mice had lower activation of the NF-kB pathway and reduced cellular insulin resistance compared with the wild-type mice, suggesting the importance of the innate immune pathway in inducing insulin resistance (Kim et al 2007). The effects shown in the Tlr4 KO mice have also been observed in Tlr3 KO mice; again these mice were fed a high-fat diet yet showed improved insulin sensitivity, lipid profile and reduced hepatic steatosis compared with wild-type mice (Wu et al 2012b). …”

Section: The Effect Of Lipids On Adipokine Inflammationmentioning

confidence: 74%

Adipokine inflammation and insulin resistance: the role of glucose, lipids and endotoxin

Piya¹,

McTernan²,

Kumar³

2012

Journal of Endocrinology

227

165

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Adipose tissue is an active endocrine organ, and our knowledge of this secretory tissue, in recent years, has led us to completely rethink how our body functions and becomes dysregulated with weight gain. Human adipose tissue appears to act as a multifunctional secretory organ with the capacity to control energy homoeostasis through peripheral and central regulation of energy homoeostasis. It also plays an important role in innate immunity. However, the capability to more than double its original mass to cope with positive energy balance in obesity leads to many pathogenic changes. These changes arise within the adipose tissue as well as inducing secondary detrimental effects on other organs like muscle and liver, including chronic low-grade inflammation mediated by adipocytokines (adipokine inflammation). This inflammation is modulated by dietary factors and nutrients including glucose and lipids, as well as gut bacteria in the form of endotoxin or LPS. The aim of this current review is to consider the impact of nutrients such as glucose and lipids on inflammatory pathways, specifically within adipose tissue. Furthermore, how nutrients such as these can influence adipokine inflammation and consequently insulin resistance directly through their effects on secretion of adipocytokines (TNFa, IL6 and resistin) as well as indirectly through increases in endotoxin is discussed.

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Loss of toll-like receptor 3 function improves glucose tolerance and reduces liver steatosis in obese mice

Cited by 34 publications

References 56 publications

Toll-Like Receptor 3 Influences Glucose Homeostasis and β-Cell Insulin Secretion

Toll-Like Receptor 3 Influences Glucose Homeostasis and β-Cell Insulin Secretion

Elevated toll-like receptor 3 inhibits pancreatic β-cell proliferation through G1 phase cell cycle arrest

Adipokine inflammation and insulin resistance: the role of glucose, lipids and endotoxin

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