Adipose-resident T-cells (ARTs) regulate metabolic and inflammatory responses in obesity, but ART activation signals are poorly understood. Here, we describe class II major histocompatibility complex (MHCII) as an important component of high-fat diet (HFD)-induced obesity. Microarray analysis of primary adipocytes revealed that multiple genes involved in MHCII antigen processing and presentation increased in obese women. In mice, adipocyte MHCII increased within two weeks HFD, paralleling increases in pro-inflammatory and decreases in anti-inflammatory ART markers, and preceding adipose tissue macrophage (ATM) accumulation and pro-inflammatory M1 polarization. Mouse 3T3-L1 and primary adipocytes activated T-cells in an antigen-specific, contact-dependent manner, indicating adipocyte MHCII is functional. HFD-fed MHCII−/− mice developed less adipose inflammation and insulin resistance than wild-type mice, despite developing similar adiposity. These investigations uncover a mechanism whereby a HFD-induced adipocyte/ART dialogue involving MHCII instigates adipose inflammation and, together with ATM MHCII, escalates its progression.

Highlights d CD8 + T cell exhaustion is correlated with a high cholesterol level d Tumor microenvironment is enriched with cholesterol d Cholesterol in the tumor microenvironment induces CD8 + T cell exhaustion d ER stress-XBP1 pathway is required for cholesterol-induced CD8 + T cell exhaustion

Clinical trials and animal studies have revealed that loss of circulating estrogen induces rapid changes in whole body metabolism, fat distribution, and insulin action. The metabolic effects of estrogen are mediated primarily by its receptor, estrogen receptor-α; however, the detailed understanding of its mechanisms is incomplete. Recent investigations suggest that estrogen receptor-α elicits the metabolic effects of estrogen by genomic, nongenomic, and mitochondrial mechanisms that regulate insulin signaling, substrate oxidation, and energetics. This paper reviews clinical and experimental studies on the mechanisms of estrogen and the current state of knowledge regarding physiological and pathobiological influences of estrogen on metabolism.

Epicardial fat is a unique adipose tissue located between the myocardium and the visceral layer of pericardium. This tissue is characterized by highly active fatty acid metabolism and highly expressed thermogenic genes. Epicardial fat and the underlying myocardium share the same microcirculation, suggesting a close and strong interaction between these two structures. Under physiological conditions, epicardial fat protects and supports the heart to exert its normal function. Many clinical studies have shown significant associations between increased amounts of epicardial fat and coronary artery disease (CAD). In patients with CAD, increased epicardial fat becomes inflammatory and may promote plaque development through secretion of proinflammatory cytokines and other mechanisms. Therefore, epicardial fat is a biomarker of cardiovascular risk and a potential therapeutic target for cardiovascular disease. Weight loss and pharmaceuticals can reduce epicardial fat and improve its protective physiological functions.

Adipose tissue inflammation increases with obesity, but adipocyte vs. immune cell contributions are unclear. In the present study, transcriptome analyses were performed on highly-purified subcutaneous adipocytes from lean and obese women, and differentially expressed genes/pathways were determined in both adipocyte and stromal vascular fraction (SVF) samples. Adipocyte but not SVF expression of NOD-like receptor pathway genes, including NLRP3 and PYCARD, which regulate caspase-1-mediated IL-1β secretion, correlated with adiposity phenotypes and adipocyte class II major histocompatibility complex (MHCII) gene expression, but only MHCII remained after adjusting for age and body mass index. IFNγ stimulated adipocyte MHCII, NLRP3 and caspase-1 expression, while adipocyte MHCII-mediated CD4+ T cell activation, an important factor in adipose inflammation, induced IFNγ-dependent adipocyte IL-1β secretion. These results uncover a dialogue regulated by interactions among T cell IFNγ and adipocyte MHCII and NLRP3 inflammasome activity that appears to initiate and escalate adipose tissue inflammation during obesity.

BackgroundLimited information exists on the role of B‐cell‐dependent mechanisms in the progression of heart failure (HF). However, in failing human myocardium, there is evidence of deposition of activated complement components as well as anticardiac antibodies. We aimed to determine the contribution of B‐cells in HF progression using a nonsurgical mouse model of nonischemic cardiomyopathy (CMP).Methods and Results CMP protocol involved the use of l‐NAME and NaCl in the drinking water and angiotensin‐II infusion for 35 days. At day 35, mice were analyzed by cardiac magnetic resonance imaging, gene expression, and histology. Mice (12 weeks old) were divided into 4 groups, all in C57BL/6 background: wild‐type (WT) CMP; severe combined immunodeficiency (SCID) CMP (T‐ and B‐cell deficient); CD22− CMP (B‐cell depleted); and Nude CMP (T‐cell deficient), with their respective controls. We performed B‐cell depletion and reconstitution protocols. The protective effect of B‐cell depletion was demonstrated by a significant reduction of cell hypertrophy and collagen deposition and a preserved ejection fraction in the CD22− CMP group compared to WT CMP. Once SCID mice underwent B‐cell reconstitution with isolated CMP B‐cells, the CMP phenotype was restored. Furthermore, deposition of IgG3 and apoptosis in the myocardium follows the development of CMP; in addition, in vitro studies demonstrated that activated B‐cells stimulate collagen production by cardiac fibroblasts.ConclusionsThe absence of B‐cells in this model of HF resulted in less hypertrophy and collagen deposition, preservation of left ventricular function, and, in association with these changes, a reduction in expression of proinflammatory cytokines, immunoglobulin G deposition, and apoptosis in the myocardium. Taken together, these data suggest that B‐cells play a contributory role in an angiotensin‐II‐induced HF model.

Background Impaired bioenergetics is a prominent feature of the failing heart, but the underlying metabolic perturbations are poorly understood. Methods and Results We compared metabolomic, gene transcript, and protein data from six paired failing human left ventricular (LV) tissue samples obtained during left ventricular assist device (LVAD) insertion (heart failure (HF) samples) and at heart transplant (post-LVAD samples). Non-failing left ventricular (NFLV) wall samples procured from explanted hearts of patients with right HF served as novel comparison samples. Metabolomic analyses uncovered a distinct pattern in HF tissue: 2.6 fold increased pyruvate concentrations coupled with reduced Krebs cycle intermediates and short-chain acylcarnitines, suggesting a global reduction in substrate oxidation. These findings were associated with decreased transcript levels for enzymes that catalyze fatty acid oxidation and pyruvate metabolism and for key transcriptional regulators of mitochondrial metabolism and biogenesis, peroxisome proliferator-activated receptor gamma co-activator1α (PGC1A, 1.3 fold) and estrogen-related receptor α (ERRA, 1.2 fold) and γ (ERRG, 2.2 fold). Thus, parallel decreases in key transcription factors and their target metabolic enzyme genes can explain the decreases in associated metabolic intermediates. Mechanical support with LVAD improved all of these metabolic and transcriptional defects. Conclusions These observations underscore an important pathophysiologic role for severely defective metabolism in HF, while the reversibility of these defects by LVAD suggests metabolic resilience of the human heart.

No abstract