Role of adiponectin and proinflammatory gene expression in adipose tissue chronic inflammation in women with metabolic syndrome

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is implicated in the etiology of metabolic syndrome. We previously showed that pharmacological inhibition of 11β-HSD1 ameliorated multiple facets of metabolic syndrome and attenuated atherosclerosis in ApoE−/− mice. However, the molecular mechanism underlying the atheroprotective effect was not clear. In this study, we tested whether and how 11β-HSD1 inhibition affects vascular inflammation, a major culprit for atherosclerosis and its associated complications. ApoE−/− mice were treated with an 11β-HSD1 inhibitor for various periods of time. Plasma lipids and aortic cholesterol accumulation were quantified. Several microarray studies were carried out to examine the effect of 11β-HSD1 inhibition on gene expression in atherosclerotic tissues. Our data suggest 11β-HSD1 inhibition can directly modulate atherosclerotic plaques and attenuate atherosclerosis independently of lipid lowering effects. We identified immune response genes as the category of mRNA most significantly suppressed by 11β-HSD1 inhibition. This anti-inflammatory effect was further confirmed in plaque macrophages and smooth muscle cells procured by laser capture microdissection. These findings in the vascular wall were corroborated by reduction in circulating MCP1 levels after 11β-HSD1 inhibition. Taken together, our data suggest 11β-HSD1 inhibition regulates proinflammatory gene expression in atherosclerotic tissues of ApoE−/− mice, and this effect may contribute to the attenuation of atherosclerosis in these animals.

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Differences in Upper and Lower Body Adipose Tissue Oxygen Tension Contribute to the Adipose Tissue Phenotype in Humans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-00547 ◽

2018 ◽

Vol 103 (10) ◽

pp. 3688-3697 ◽

Cited By ~ 2

Author(s):

Max A A Vogel ◽

Johan W E Jocken ◽

Henrike Sell ◽

Nicole Hoebers ◽

Yvonne Essers ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Oxygen Consumption ◽

Glucose Uptake ◽

Oxygen Tension ◽

Prolonged Exposure ◽

Metabolic Phenotype ◽

Lower Body ◽

Proinflammatory Gene ◽

Proinflammatory Gene Expression

Abstract Context and Objectives Upper and lower body adipose tissue (AT) exhibits opposing associations with obesity-related cardiometabolic diseases. Recent studies have suggested that altered AT oxygen tension (pO2) may contribute to AT dysfunction. Here, we compared in vivo abdominal (ABD) and femoral (FEM) subcutaneous AT pO2 in women who are overweight and have obesity, and investigated the effects of physiological AT pO2 on human adipocyte function. Design ABD and FEM subcutaneous AT pO2 and AT blood flow (ATBF) were assessed in eight [BMI (body mass index) 34.4 ± 1.6 kg/m2] postmenopausal women who were overweight with obesity and impaired glucose metabolism. ABD and FEM AT biopsy specimens were collected to determine adipocyte morphology and AT gene expression. Moreover, the effects of prolonged exposure (14 days) to physiological AT pO2 on adipokine expression/secretion, mitochondrial respiration, and glucose uptake were investigated in differentiated human multipotent adipose-derived stem cells. Results AT pO2 was higher in ABD than FEM AT (62.7 ± 6.6 vs 50.0 ± 4.5 mm Hg, P = 0.013), whereas ATBF was comparable between depots. Maximal uncoupled oxygen consumption rates were substantially lower in ABD than FEM adipocytes for all pO2 conditions. Low physiological pO2 (5% O2) decreased proinflammatory gene expression, increased basal glucose uptake, and altered adipokine secretion in ABD and FEM adipocytes. Conclusions We demonstrated for the first time, to our knowledge, that AT pO2 is higher in ABD than FEM subcutaneous AT in women who are overweight/with obesity, partly due to a lower oxygen consumption rate in ABD adipocytes. Moreover, low physiological pO2 decreased proinflammatory gene expression and improved the metabolic phenotype in differentiated human adipocytes, whereas more heterogeneous effects on adipokine secretion were found.

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Deficiency of Myeloid Pfkfb3 Protects Mice From Lung Edema and Cardiac Dysfunction in LPS-Induced Endotoxemia

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.745810 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jiean Xu ◽

Lina Wang ◽

Qiuhua Yang ◽

Qian Ma ◽

Yaqi Zhou ◽

...

Keyword(s):

Gene Expression ◽

Cardiac Dysfunction ◽

Aerobic Glycolysis ◽

Interleukin 1 ◽

Critical Role ◽

Glycolytic Flux ◽

Lung Edema ◽

Proinflammatory Gene ◽

Proinflammatory Gene Expression

Sepsis, a pathology resulting from excessive inflammatory response that leads to multiple organ failure, is a major cause of mortality in intensive care units. Macrophages play an important role in the pathophysiology of sepsis. Accumulating evidence has suggested an upregulated rate of aerobic glycolysis as a key common feature of activated proinflammatory macrophages. Here, we identified a crucial role of myeloid 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3), a glycolytic activator in lipopolysaccharide (LPS)-induced endotoxemia in mice. Pfkfb3 expression is substantially increased in bone marrow derived macrophages (BMDMs) treated with LPS in vitro and in lung macrophages of mice challenged with LPS in vivo. Myeloid-specific knockout of Pfkfb3 in mice protects against LPS-induced lung edema, cardiac dysfunction and hypotension, which were associated with decreased expression of interleukin 1 beta (Il1b), interleukin 6 (Il6) and nitric oxide synthase 2 (Nos2), as well as reduced infiltration of neutrophils and macrophages in lung tissue. Pfkfb3 ablation in cultured macrophages attenuated LPS-induced glycolytic flux, resulting in a decrease in proinflammatory gene expression. Mechanistically, Pfkfb3 ablation or inhibition with a Pfkfb3 inhibitor AZ26 suppresses LPS-induced proinflammatory gene expression via the NF-κB signaling pathway. In summary, our study reveals the critical role of Pfkfb3 in LPS-induced sepsis via reprogramming macrophage metabolism and regulating proinflammatory gene expression. Therefore, PFKFB3 is a potential target for the prevention and treatment of inflammatory diseases such as sepsis.

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