Mechanism of protection from insulin resistance by toll-like receptor 2 deficiency in high-fat diet fed mice: involvement in macrophage polarization

AbstractKdm2a catalyzes H3K36me2 demethylation to play an intriguing epigenetic regulatory role in cell proliferation, differentiation, and apoptosis. Herein we found that myeloid-specific knockout of Kdm2a (LysM-Cre-Kdm2af/f, Kdm2a−/−) promoted macrophage M2 program by reprograming metabolic homeostasis through enhancing fatty acid uptake and lipolysis. Kdm2a−/− increased H3K36me2 levels at the Pparg locus along with augmented chromatin accessibility and Stat6 recruitment, which rendered macrophages with preferential M2 polarization. Therefore, the Kdm2a−/− mice were highly protected from high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis, and featured by the reduced accumulation of adipose tissue macrophages and repressed chronic inflammation following HFD challenge. Particularly, Kdm2a−/− macrophages provided a microenvironment in favor of thermogenesis. Upon HFD or cold challenge, the Kdm2a−/− mice manifested higher capacity for inducing adipose browning and beiging to promote energy expenditure. Collectively, our findings demonstrate the importance of Kdm2a-mediated H3K36 demethylation in orchestrating macrophage polarization, providing novel insight that targeting Kdm2a in macrophages could be a viable therapeutic approach against obesity and insulin resistance.

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C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

Diabetologia ◽

10.1007/s00125-007-0654-8 ◽

2007 ◽

Vol 50 (6) ◽

pp. 1267-1276 ◽

Cited By ~ 241

Author(s):

M. Poggi ◽

D. Bastelica ◽

P. Gual ◽

M. A. Iglesias ◽

T. Gremeaux ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

White Adipose Tissue ◽

High Fat Diet ◽

Toll Like Receptor ◽

High Fat ◽

Toll Like Receptor 4

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Down-regulation of miR-144 elicits proinflammatory cytokine production by targeting toll-like receptor 2 in nonalcoholic steatohepatitis of high-fat-diet-induced metabolic syndrome E3 rats

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2014.12.007 ◽

2015 ◽

Vol 402 ◽

pp. 1-12 ◽

Cited By ~ 27

Author(s):

Dongmin Li ◽

Xuan Wang ◽

Xi Lan ◽

Yue Li ◽

Li Liu ◽

...

Keyword(s):

Metabolic Syndrome ◽

Nonalcoholic Steatohepatitis ◽

High Fat Diet ◽

Proinflammatory Cytokine ◽

Cytokine Production ◽

Proinflammatory Cytokine Production ◽

Toll Like Receptor ◽

High Fat ◽

Down Regulation ◽

Toll Like Receptor 2

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Abstract 15813: Loss-of-Function Mutation in Toll-Like Receptor 4 Partially Protects Against Peripheral and Cardiac Insulin Resistance During a Long-Term High-Fat Diet

Circulation ◽

10.1161/circ.130.suppl_2.15813 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Ellen Jackson ◽

Elizabeth Rendina-Ruedy ◽

Matt Priest ◽

Brenda Smith ◽

Veronique Lacombe

Keyword(s):

Insulin Resistance ◽

Protein Content ◽

Glucose Transport ◽

High Fat Diet ◽

Whole Body ◽

Toll Like Receptor ◽

Loss Of Function ◽

High Fat ◽

The Face ◽

Tlr4 Activation

Diabetes mellitus is an epidemic disease characterized by alterations in glucose transport, which is tightly regulated by a family of specialized proteins called the glucose transporters (GLUTs). Although diabetic cardiomyopathy is a common complication in diabetic patients, its pathogenesis is still not well understood. Toll-like receptor (TLR) 4, which plays a central role in pathogen recognition by the innate immune system, may also play a critical role in linking inflammation and metabolic disease. We hypothesized that TLR4 activation triggers cardiac insulin resistance. We used mice with a loss-of function mutation in TLR4 (C3H/HeJ) and age-matched wild-type (WT, C57BL/6N) mice (n=8/group) to investigate how feeding a high-fat diet (HFD, 60% kcal from fat) for 16 weeks affected whole-body and cardiac glucose metabolism. After 16 weeks, WT mice fed a HFD were obese and developed hyperglycemia and insulin resistance compared to WT mice on a control diet (10% kcal from fat). The C3H/HeJ mice were partially protected against HFD-induced obesity and insulin resistance. In the heart, WT mice fed a HFD had a 30% decrease (P<0.05) in GLUT4 protein content as measured by Western Blot of cardiac crude membrane protein extracts. In contrast, the loss-of-function point mutation in TLR4 partially rescued cardiac GLUT4 content in the face of a HFD. Interestingly, there was a 40% increase (P<0.05) in the novel GLUT isoform, GLUT8, in the heart when mice of either genotype were fed a HFD. Additionally, GLUT4 protein content was negatively (P<0.05) correlated with GLUT8 content in the myocardium, suggesting that GLUT8 may act as a compensatory mechanism in the face of HFD-induced GLUT4 downregulation. Phosphorylated Akt, a key protein of the insulin signaling pathway, was positively (P<0.05) correlated with GLUT4 content, while the basal/inactive form was negatively correlated. In conclusion, these data suggest that activation of TLR4 activation during diabetes and obesity alters glucose transport by an Akt mechanism, and as such is a pathogenic factor during peripheral and cardiac insulin resistance. Overall, TLR4 appears to be a key modulator in the cross-talk between inflammatory and metabolic pathways, as well as a potential therapeutic target for diabetes.

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One-week high-fat diet leads to reduced toll-like receptor 2 expression and function in young healthy men

Nutrition Research ◽

10.1016/j.nutres.2014.08.012 ◽

2014 ◽

Vol 34 (12) ◽

pp. 1045-1051 ◽

Cited By ~ 10

Author(s):

Zhongxiao Wan ◽

Cody Durrer ◽

Dorrian Mah ◽

Svetlana Simtchouk ◽

Jonathan P. Little

Keyword(s):

High Fat Diet ◽

Toll Like Receptor ◽

High Fat ◽

Healthy Men ◽

Toll Like Receptor 2 ◽

And Function

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Cinchonine Prevents High-Fat-Diet-Induced Obesity through Downregulation of Adipogenesis and Adipose Inflammation

PPAR Research ◽

10.1155/2012/541204 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Sung A. Jung ◽

Miseon Choi ◽

Sohee Kim ◽

Rina Yu ◽

Taesun Park

Keyword(s):

High Fat Diet ◽

Body Weight Gain ◽

Signaling Cascades ◽

Toll Like Receptor ◽

High Fat ◽

Reduced Body ◽

Diet Induced Obesity ◽

Toll Like Receptor 2 ◽

Underlying Mechanisms ◽

Adipose Inflammation

Cinchonine (C19H22N2O) is a natural compound of Cinchona bark. Although cinchonine's antiplatelet effect has been reported in the previous study, antiobesity effect of cinchonine has never been studied. The main objective of this study was to investigate whether cinchonine reduces high-fat-diet- (HFD-) induced adipogenesis and inflammation in the epididymal fat tissues of mice and to explore the underlying mechanisms involved in these reductions. HFD-fed mice treated with 0.05% dietary cinchonine for 10 weeks had reduced body weight gain (−38%), visceral fat-pad weights (−26%), and plasma levels of triglyceride, free fatty acids, total cholesterol, and glucose compared with mice fed with the HFD. Moreover, cinchonine significantly reversed HFD-induced downregulations of WNT10b and galanin-mediated signaling molecules and key adipogenic genes in the epididymal adipose tissues of mice. Cinchonine also attenuated the HFD-induced upregulation of proinflammatory cytokines by inhibiting toll-like-receptor-2- (TLR2-) and TLR4-mediated signaling cascades in the adipose tissue of mice. Our findings suggest that dietary cinchonine with its effects on adipogenesis and inflammation may have a potential benefit in preventing obesity.

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