Although the adipose tissue (AT) is a central metabolic organ in the regulation of whole-body energy homeostasis, it is also an important endocrine and immunological organ. As an endocrine organ, AT ...secretes a variety of bioactive peptides known as adipokines - some of which have inflammatory and immunoregulatory properties. As an immunological organ, AT contains a broad spectrum of innate and adaptive immune cells that have mostly been studied in the context of obesity. However, overwhelming evidence supports the notion that AT is a genuine immunological effector site, which contains all cell subsets required to induce and generate specific and effective immune responses against pathogens. Indeed, AT was reported to be an immune reservoir in the host's response to infection, and a site of parasitic, bacterial and viral infections. In addition, besides AT's immune cells, preadipocytes and adipocytes were shown to express innate immune receptors, and adipocytes were reported as antigen-presenting cells to regulate T-cell-mediated adaptive immunity. Here we review the current knowledge on the role of AT and AT's immune system in host defense against pathogens. First, we will summarize the main characteristics of AT: type, distribution, function, and extraordinary plasticity. Second, we will describe the intimate contact AT has with lymph nodes and vessels, and AT immune cell composition. Finally, we will present a comprehensive and up-to-date overview of the current research on the contribution of AT to host defense against pathogens, including the respiratory viruses influenza and SARS-CoV-2.
Along with respiratory tract disease
, viral respiratory infections can also cause extrapulmonary complications with a potentially critical impact on health. In the present study, we used an ...experimental model of influenza A virus (IAV) infection to investigate the nature and outcome of the associated gut disorders. In IAV-infected mice, the signs of intestinal injury and inflammation, altered gene expression, and compromised intestinal barrier functions peaked on day 7 postinfection. As a likely result of bacterial component translocation, gene expression of inflammatory markers was upregulated in the liver. These changes occurred concomitantly with an alteration of the composition of the gut microbiota and with a decreased production of the fermentative, gut microbiota-derived products short-chain fatty acids (SCFAs). Gut inflammation and barrier dysfunction during influenza were not attributed to reduced food consumption, which caused in part gut dysbiosis. Treatment of IAV-infected mice with SCFAs was associated with an enhancement of intestinal barrier properties, as assessed by a reduction in the translocation of dextran and a decrease in inflammatory gene expression in the liver. Lastly, SCFA supplementation during influenza tended to reduce the translocation of the enteric pathogen Salmonella enterica serovar Typhimurium and to enhance the survival of doubly infected animals. Collectively, influenza virus infection can remotely impair the gut's barrier properties and trigger secondary enteric infections. The latter phenomenon can be partially countered by SCFA supplementation.
Coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)) is primarily a respiratory illness. However, various extrapulmonary manifestations have ...been reported in patients with severe forms of COVID-19. Notably, SARS-CoV-2 was shown to directly trigger white adipose tissue (WAT) dysfunction, which in turn drives insulin resistance, dyslipidemia, and other adverse outcomes in patients with COVID-19. Although advanced age is the greatest risk factor for COVID-19 severity, published data on the impact of SARS-CoV-2 infection on WAT in aged individuals are scarce. Here, we characterized the response of subcutaneous and visceral WAT depots to SARS-CoV-2 infection in young adult and aged golden hamsters. In both age groups, infection was associated with a decrease in adipocyte size in the two WAT depots; this effect was partly due to changes in tissue's lipid metabolism and persisted for longer in aged hamsters than in young-adult hamsters. In contrast, only the subcutaneous WAT depot contained crown-like structures (CLSs) in which dead adipocytes were surrounded by SARS-CoV-2-infected macrophages, some of them forming syncytial multinucleated cells. Importantly, older age predisposed to a unique manifestation of viral disease in the subcutaneous WAT depot during SARS-CoV-2 infection; the persistence of very large CLSs was indicative of an age-associated defect in the clearance of dead adipocytes by macrophages. Moreover, we uncovered age-related differences in plasma lipid profiles during SARS-CoV-2 infection. These data suggest that the WAT's abnormal response to SARS-CoV-2 infection may contribute to the greater severity of COVID-19 observed in elderly patients.
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•Critical lack of data for many replacement FRs ubiquitous and high tonnage.•TPhP and TDCIPP are probable EDCs with anti-AR, anti-PR, estrogenic activities.•Modulation of ER and AR ...repeatedly confirmed for PBP, ip-TPP or DBE-DBCH.•Replacement FRs share profiles of ED activities, such as anti-androgenicity, raising thus concerns for mixture effects.
Endocrine disrupting chemicals (EDCs) constitute a major public health concern because they can induce a large spectrum of adverse effects by interfering with the hormonal system. Rapid identification of potential EDCs using in vitro screenings is therefore critical, particularly for chemicals of emerging concerns such as replacement flame retardants (FRs). The review aimed at identifying (1) data gaps and research needs regarding endocrine disrupting (ED) properties of replacement FRs and (2) potential EDCs among these emerging chemicals.
A systematic search was performed from open literature and ToxCast/Tox21 programs, and results from in vitro tests on the activities of 52 replacement FRs towards five hormone nuclear receptors (NRs) associated with reproductive outcomes (estrogen, androgen, glucocorticoid, progesterone, and aryl hydrocarbon receptors) were compiled and organized into tables. Findings were complemented with information from structure-based in silico model predictions and in vivo information when relevant.
For the majority of the 52 replacement FRs, experimental in vitro data on activities towards these five NRs were either incomplete (15 FRs) or not found (24 FRs). Within the replacement FRs for which effect data were found, some appeared as candidate EDCs, such as triphenyl phosphate (TPhP) and tris(1,3-dichloropropyl)phosphate (TDCIPP). The search also revealed shared ED profiles. For example, anti-androgenic activity was reported for 19 FRs and predicted for another 21 FRs.
This comprehensive review points to critical gaps in knowledge on ED potential for many replacement FRs, including chemicals to which the general population is likely exposed. Although this review does not cover all possible characteristics of ED, it allowed the identification of potential EDCs associated with reproductive outcomes, calling for deeper evaluation and possibly future regulation of these chemicals. By identifying shared ED profiles, this work also raises concerns for mixture effects since the population is co-exposed to several FRs and other chemicals.
Obese patients with non-alcoholic steatohepatitis (NASH) are prone to severe forms of COVID-19. There is an urgent need for new treatments that lower the severity of COVID-19 in this vulnerable ...population. To better replicate the human context, we set up a diet-induced model of obesity associated with dyslipidemia and NASH in the golden hamster (known to be a relevant preclinical model of COVID-19). A 20-week, free-choice diet induces obesity, dyslipidemia, and NASH (liver inflammation and fibrosis) in golden hamsters. Obese NASH hamsters have higher blood and pulmonary levels of inflammatory cytokines. In the early stages of a SARS-CoV-2 infection, the lung viral load and inflammation levels were similar in lean hamsters and obese NASH hamsters. However, obese NASH hamsters showed worse recovery (i.e., less resolution of lung inflammation 10 days post-infection (dpi) and lower body weight recovery on dpi 25). Obese NASH hamsters also exhibited higher levels of pulmonary fibrosis on dpi 25. Unlike lean animals, obese NASH hamsters infected with SARS-CoV-2 presented long-lasting dyslipidemia and systemic inflammation. Relative to lean controls, obese NASH hamsters had lower serum levels of angiotensin-converting enzyme 2 activity and higher serum levels of angiotensin II—a component known to favor inflammation and fibrosis. Even though the SARS-CoV-2 infection resulted in early weight loss and incomplete body weight recovery, obese NASH hamsters showed sustained liver steatosis, inflammation, hepatocyte ballooning, and marked liver fibrosis on dpi 25. We conclude that diet-induced obesity and NASH impair disease recovery in SARS-CoV-2-infected hamsters. This model might be of value for characterizing the pathophysiologic mechanisms of COVID-19 and evaluating the efficacy of treatments for the severe forms of COVID-19 observed in obese patients with NASH.
Like all obligate intracellular pathogens, influenza A virus (IAV) reprograms host cell's glucose and lipid metabolism to promote its own replication. However, the impact of influenza infection on ...white adipose tissue (WAT), a key tissue in the control of systemic energy homeostasis, has not been yet characterized. Here, we show that influenza infection induces alterations in whole-body glucose metabolism that persist long after the virus has been cleared. We report depot-specific changes in the WAT of IAV-infected mice, notably characterized by the appearance of thermogenic brown-like adipocytes within the subcutaneous fat depot. Importantly, viral RNA- and viral antigen-harboring cells are detected in the WAT of infected mice. Using in vitro approaches, we find that IAV infection enhances the expression of brown-adipogenesis-related genes in preadipocytes. Overall, our findings shed light on the role that the white adipose tissue, which lies at the crossroads of nutrition, metabolism and immunity, may play in influenza infection.
Although the adipose tissue (AT) is a central metabolic organ in the regulation of whole-body energy homeostasis, it is also an important endocrine and immunological organ. As an endocrine organ, AT ...secretes a variety of bioactive peptides known as adipokines – some of which have inflammatory and immunoregulatory properties. As an immunological organ, AT contains a broad spectrum of innate and adaptive immune cells that have mostly been studied in the context of obesity. However, overwhelming evidence supports the notion that AT is a genuine immunological effector site, which contains all cell subsets required to induce and generate specific and effective immune responses against pathogens. Indeed, AT was reported to be an immune reservoir in the host’s response to infection, and a site of parasitic, bacterial and viral infections. In addition, besides AT’s immune cells, preadipocytes and adipocytes were shown to express innate immune receptors, and adipocytes were reported as antigen-presenting cells to regulate T-cell-mediated adaptive immunity. Here we review the current knowledge on the role of AT and AT’s immune system in host defense against pathogens. First, we will summarize the main characteristics of AT: type, distribution, function, and extraordinary plasticity. Second, we will describe the intimate contact AT has with lymph nodes and vessels, and AT immune cell composition. Finally, we will present a comprehensive and up-to-date overview of the current research on the contribution of AT to host defense against pathogens, including the respiratory viruses influenza and SARS-CoV-2.
Tributyltin (TBT) is an environmental contaminant commonly used in anti-fouling agents for boats, as well as a by-product from several industrial processes. It has been shown to accumulate in ...organisms living in areas with heavy maritime traffic thereby entering the food chain. Here, we determined the consequences of in utero exposure to TBT on the developing fetal gonads in the Sprague–Dawley rat. Timed pregnant rats were gavaged either with vehicle or TBT (0.25, 2.5, 10 or 20
mg/kg) from days 0 to 19 or 8 to 19 of gestation. On gestational day 20, dams were sacrificed; fetal testes and ovaries were processed for light (LM) or electron microscopic (EM) evaluation and RNA was prepared for gene expression profiling. At the highest doses of TBT the number of Sertoli cells and gonocytes was reduced, there were large intracellular spaces between Sertoli cells and gonocytes and there was an increased abundance of lipid droplets in the Sertoli cells; EM studies revealed abnormally dilated endoplasmic reticulum in Sertoli cells and gonocytes. In the intertubular region between adjacent interstitial cells, immunostaining for the gap junctional protein connexin 43 was strong in controls, whereas it was reduced or completely absent in treated rats. In the ovaries, TBT (20
mg/kg, days 0–19; 10
mg/kg, days 8–19) reduced the number of germ cells by 44% and 46%, respectively. On examining gene expression profiles in the testis, 40 genes out of 1176 tested were upregulated more than two-fold over control. While no genes were upregulated in the TBT exposed fetal ovary, eight genes were downregulated. In conclusion, in utero exposure to TBT resulted in gender-specific alterations in gonadal development and gene expression profiles suggesting that there may be different adaptive changes to toxicity in developing male and female rats.
Tributyltin, an organotin, is ubiquitous in the environment. The consumption of contaminated marine species leads to human dietary exposure to this compound. Tributyltin is an endocrine disruptor in ...many wildlife species and inhibits aromatase in mammalian placental and granulosa-like tumor cell lines. We investigated the effects of tributyltin chloride exposure on pregnancy outcome in the Sprague-Dawley rat. Timed pregnant rats were gavaged either with vehicle (olive oil) or tributyltin chloride (0.25, 2.5, 10, or 20 mg/kg) from days 0–19 or 8–19 of gestation. On gestational day 20, dams were sacrificed, and pregnancy outcome was determined. Tributyltin and its metabolites (dibutyltin, monobutyltin) were measured in maternal blood by gas chromatography. Both tributyltin and dibutyltin were present in maternal blood at approximately equal concentrations, whereas monobutyltin contributed minimally to total organotins. Organotin concentrations increased in a dose-dependent pattern in dams, independent of the window of exposure. Tributyltin chloride administration significantly reduced maternal weight gain only at the highest dose (20 mg/kg); a significant increase in post-implantation loss and decreased litter sizes, in addition to decreased fetal weights, was observed in this group. Tributyltin chloride exposure did not result in external malformations, nor was there a change in sex ratios. However, exposure to 0.25, 2.5, or 10 mg/kg tributyltin chloride from gestation days (GD) 0–19 resulted in a significant increase in normalized anogenital distances in male fetuses; exposure from days 8–19 had no effect. There was a dramatic increase in the incidence of low weight (≤0.75 of the mean) fetuses after exposure to 20 mg/kg tributyltin chloride. Delayed ossification of the fetal skeleton was observed after in utero exposure to either 10 mg/kg or 20 mg/kg tributyltin chloride. Serum thyroxine and triiodothyronine levels were reduced significantly in dams exposed to 10 and 20 mg/kg tributyltin chloride throughout gestation; in dams treated with tributyltin from GD 8–19, serum thyroxine concentrations, but not triiodothyronine, were significantly decreased at both the 2.5 and 10 mg/kg exposures. Thus, maternal thyroid hormone homeostasis may be important in mediating the developmental toxicity of organotins.
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