Lower plasma PCSK9 in normocholesterolemic subjects is associated with upregulated adipose tissue surface‐expression of LDLR and CD36 and NLRP3 inflammasome

Obesity-associated activation of the renin-angiotensin-aldosterone system is implicated in the pathogenesis of insulin resistance; however, influences of mineralocorticoid receptor (MR) inhibition remain unclear. Therefore, we aimed to clarify the anti-inflammatory mechanisms of MR inhibition using eplerenone, a selective MR antagonist, in C57BL/6 mice fed a high-fat diet (HFD) for 12 weeks. Eplerenone prevented excessive body weight gain and fat accumulation, ameliorated glucose intolerance and insulin resistance and enhanced energy metabolism. In the epididymal white adipose tissue (eWAT), eplerenone prevented obesity-induced accumulation of F4/80+CD11c+CD206−-M1-adipose tissue macrophage (ATM) and reduction of F4/80+CD11c−CD206+-M2-ATM. Interestingly, M1-macrophage exhibited lower expression levels of MR, compared with M2-macrophage, in the ATM of eWAT and in vitro-polarized bone marrow-derived macrophages (BMDM). Importantly, eplerenone and MR knockdown attenuated the increase in the expression levels of proIl1b, Il6 and Tnfa, in the eWAT and liver of HFD-fed mice and LPS-stimulated BMDM. Moreover, eplerenone suppressed IL1b secretion from eWAT of HFD-fed mice. To reveal the anti-inflammatory mechanism, we investigated the involvement of NLRP3-inflammasome activation, a key process of IL1b overproduction. Eplerenone suppressed the expression of the inflammasome components, Nlrp3 and Caspase1, in the eWAT and liver. Concerning the second triggering factors, ROS production and ATP- and nigericin-induced IL1b secretion were suppressed by eplerenone in the LPS-primed BMDM. These results indicate that eplerenone inhibited both the priming and triggering signals that promote NLRP3-inflammasome activation. Therefore, we consider MR to be a crucial target to prevent metabolic disorders by suppressing inflammasome-mediated chronic inflammation in the adipose tissue and liver under obese conditions.

Download Full-text

Depot- and gender-specific expression of NLRP3 inflammasome and toll-like receptors in adipose tissue of cancer patients

BioFactors ◽

10.1002/biof.1287 ◽

2016 ◽

Vol 42 (4) ◽

pp. 397-406 ◽

Cited By ~ 5

Author(s):

Michio Shimabukuro ◽

Hiromi Sato ◽

Hirofumi Izaki ◽

Daiju Fukuda ◽

Etsuko Uematsu ◽

...

Keyword(s):

Adipose Tissue ◽

Cancer Patients ◽

Nlrp3 Inflammasome ◽

Toll Like Receptors ◽

Specific Expression ◽

And Gender ◽

Gender Specific

Download Full-text

Statins activate the NLRP3 inflammasome and impair insulin signaling via p38 and mTOR

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00125.2020 ◽

2020 ◽

Vol 319 (1) ◽

pp. E110-E116 ◽

Cited By ~ 2

Author(s):

Brandyn D. Henriksbo ◽

Akhilesh K. Tamrakar ◽

Jobanjit S. Phulka ◽

Nicole G. Barra ◽

Jonathan D. Schertzer

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Signaling ◽

Nlrp3 Inflammasome ◽

Protein Prenylation ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Pyrin Domain ◽

Opposing Effects ◽

20 Nm

Statins lower cholesterol and risk of cardiovascular disease. Statins can increase blood glucose and risk of new-onset diabetes. It is unclear why statins can have opposing effects on lipids versus glucose. Statins have cholesterol-independent pleiotropic effects that influence both insulin and glucose control. Statin lowering of isoprenoids required for protein prenylation promotes pancreatic β-cell dysfunction and adipose tissue insulin resistance. Protein prenylation influences immune function and statin-mediated adipose tissue insulin resistance involves the NLR family pyrin domain-containing 3 (NLRP3) inflammasome and IL-1β. However, the intracellular cues that statins engage to activate the NLRP3 inflammasome and those responsible for IL-1β-mediated insulin resistance in adipose tissue have not been identified. We hypothesized that stress kinases or components of the insulin signaling pathway mediated statin-induced insulin resistance. We tested the associations of p38, ERK, JNK, phosphatase, and tensin homolog (PTEN), and mTOR in statin-exposed adipose tissue from WT and IL-1β−/− mice. We found that statins increased phosphorylation of p38 in WT and IL-1β−/− mice. Statin activation of p38 upstream of IL-1β led to priming of this NLRP3 inflammasome effector in macrophages. We found that mTORC1 inhibition with low doses of rapamycin (2 or 20 nM) lowered macrophage priming of IL-1β mRNA and secretion of IL-1β caused by multiple statins. Rapamycin (20 nM) or the rapalog everolimus (20 nM) prevented atorvastatin-induced lowering of insulin-mediated phosphorylation of Akt in mouse adipose tissue. These results position p38 and mTOR as mediators of statin-induced insulin resistance in adipose tissue and highlight rapalogs as candidates to mitigate the insulin resistance and glycemic side effects of statins.

Download Full-text

NLRP3 Inflammasome Activation in Adipose Tissues and Its Implications on Metabolic Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21114184 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4184 ◽

Cited By ~ 1

Author(s):

Kelvin Ka-Lok Wu ◽

Samson Wing-Ming Cheung ◽

Kenneth King-Yip Cheng

Keyword(s):

Adipose Tissue ◽

Nlrp3 Inflammasome ◽

Metabolic Disorders ◽

Immune Cell ◽

Diabetic Patients ◽

Inflammasome Activation ◽

Low Grade ◽

Adipose Tissues ◽

Adipose Tissue Dysfunction ◽

Nlrp3 Inflammasome Activation

Adipose tissue is an active endocrine and immune organ that controls systemic immunometabolism via multiple pathways. Diverse immune cell populations reside in adipose tissue, and their composition and immune responses vary with nutritional and environmental conditions. Adipose tissue dysfunction, characterized by sterile low-grade chronic inflammation and excessive immune cell infiltration, is a hallmark of obesity, as well as an important link to cardiometabolic diseases. Amongst the pro-inflammatory factors secreted by the dysfunctional adipose tissue, interleukin (IL)-1β, induced by the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, not only impairs peripheral insulin sensitivity, but it also interferes with the endocrine and immune functions of adipose tissue in a paracrine manner. Human studies indicated that NLRP3 activity in adipose tissues positively correlates with obesity and its metabolic complications, and treatment with the IL-1β antibody improves glycaemia control in type 2 diabetic patients. In mouse models, genetic or pharmacological inhibition of NLRP3 activation pathways or IL-1β prevents adipose tissue dysfunction, including inflammation, fibrosis, defective lipid handling and adipogenesis, which in turn alleviates obesity and its related metabolic disorders. In this review, we summarize both the negative and positive regulators of NLRP3 inflammasome activation, and its pathophysiological consequences on immunometabolism. We also discuss the potential therapeutic approaches to targeting adipose tissue inflammasome for the treatment of obesity and its related metabolic disorders.

Download Full-text

The combination of mucus-degrading gram-negative bacteria and reduced antimicrobial peptides drives adipose tissue inflammation and NAFLD progression in mice lacking NLRP3-inflammasome

Digestive and Liver Disease ◽

10.1016/j.dld.2017.01.008 ◽

2017 ◽

Vol 49 (1) ◽

pp. e2-e3

Author(s):

I. Pierantonelli ◽

C. Rychlicki ◽

D. Giordano ◽

A. Giordano ◽

S. Uzzau ◽

...

Keyword(s):

Adipose Tissue ◽

Antimicrobial Peptides ◽

Nlrp3 Inflammasome ◽

Gram Negative Bacteria ◽

Adipose Tissue Inflammation ◽

Gram Negative ◽

Tissue Inflammation

Download Full-text

Macrophage-derived apolipoprotein E ameliorates dyslipidemia and atherosclerosis in obese apolipoprotein E-deficient mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00601.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. E284-E290 ◽

Cited By ~ 13

Author(s):

Robin D. Atkinson ◽

Kimberly R. Coenen ◽

Michelle R. Plummer ◽

Marnie L. Gruen ◽

Alyssa H. Hasty

Keyword(s):

Adipose Tissue ◽

Apolipoprotein E ◽

Plasma Lipids ◽

Atherosclerotic Lesion ◽

Density Lipoprotein ◽

Tissue Expansion ◽

Lower Plasma ◽

Lesion Area ◽

Lesion Formation ◽

Atherosclerotic Lesion Formation

Previous studies have demonstrated that macrophage-derived apolipoprotein E (apoE) reduces atherosclerotic lesion formation in lean apoE-deficient (−/−) mice. apoE has also been demonstrated to play a role in adipocyte differentiation and lipid accumulation. Because the prevalence of obesity has grown to epidemic proportions, we sought to determine whether macrophage-derived apoE could impact atherosclerotic lesion formation or adipose tissue expansion and inflammation in obese apoE−/− mice. To this end, we transplanted obese leptin-deficient ( ob/ ob) apoE−/− mice with bone marrow from either ob/ ob;apoE−/− or ob/ ob;apoE+/+ donors. There were no differences in body weight, total body adipose tissue, or visceral fat pad mass between recipient groups. The presence of macrophage-apoE had no impact on adipose tissue macrophage content or inflammatory cytokine expression. Recipients of apoE+/+ marrow demonstrated 3.7-fold lower plasma cholesterol ( P < 0.001) and 1.7-fold lower plasma triglyceride levels ( P < 0.01) by 12 wk after transplantation even though apoE was present in plasma at concentrations <10% of wild-type levels. The reduced plasma lipids reflected a dramatic decrease in very low density lipoprotein and a mild increase in high-density lipoprotein levels. Atherosclerotic lesion area was >10-fold lower in recipients of ob/ ob;apoE+/+ marrow ( P < 0.005). Similar results were seen in leptin receptor-deficient ( db/ db) apoE−/− mice. Finally, when bone marrow transplantation was performed in 4-mo-old ob/ ob;apoE−/− and db/ db;apoE−/− mice with preexisting lesions, recipients of apoE+/+ marrow had a 2.8-fold lower lesion area than controls ( P = 0.0002). These results demonstrate that macrophage-derived apoE does not impact adipose tissue expansion or inflammatory status; however, even very low levels of macrophage-derived apoE are capable of reducing plasma lipids and atherosclerotic lesion area in obese mice.

Download Full-text