Adipocyte inflammation and pathogenesis of viral pneumonias: an overlooked contribution

Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to viral respiratory pneumonias associated with H1N1 influenza and SARS-CoV-2 pandemics. Given the global obesity prevalence, a better understanding of the mechanisms behind obese susceptibility to infection is imperative. Altered immune cell metabolism and function are often perceived as a key causative factor of dysregulated inflammation. However, the contribution of adipocytes, the dominantly altered cell type in obesity with broad inflammatory properties, to infectious disease pathogenesis remains largely ignored. Thus, skewing of adipocyte-intrinsic cellular metabolism may lead to the development of pathogenic inflammatory adipocytes, which shape the overall immune responses by contributing to either premature immunosenescence, delayed hyperinflammation, or cytokine storm in infections. In this review, we discuss the underappreciated contribution of adipocyte cellular metabolism and adipocyte-produced mediators on immune system modulation and how such interplay may modify disease susceptibility and pathogenesis of influenza and SARS-CoV-2 infections in obese individuals.     

Characterization of regulatory T cells in obese omental adipose tissue in humans

Obesity‐associated visceral adipose tissue (AT) inflammation promotes insulin resistance and type 2 diabetes (T2D). In mice, lean visceral AT is populated with anti‐inflammatory cells, notably regulatory T cells (Tregs) expressing the IL‐33 receptor ST2. Conversely, obese AT contains fewer Tregs and more proinflammatory cells. In humans, however, there is limited evidence for a similar pattern of obesity‐associated immunomodulation. We used flow cytometry and mRNA quantification to characterize human omental AT in 29 obese subjects, 18 of whom had T2D. Patients with T2D had increased proportions of inflammatory cells, including M1 macrophages, with positive correlations to body mass index. In contrast, Treg frequencies negatively correlated to body mass index but were comparable between T2D and non‐T2D individuals. Compared to human thymic Tregs, omental AT Tregs expressed similar levels of FOXP3, CD25, IKZF2, and CTLA4, but higher levels of PPARG, CCR4, PRDM1, and CXCL2. ST2, however, was not detectable on omental AT Tregs from lean or obese subjects. This is the first comprehensive investigation into how omental AT immunity changes with obesity and T2D in humans, revealing important similarities and differences to paradigms in mice. These data increase our understanding of how pathways of immune regulation could be targeted to ameliorate AT inflammation in humans.     

Obesity and dysregulated central and peripheral macrophage–neuron cross‐talk

The involvement of macrophages in the pathogenesis of obesity has been recognized since 2003. Early studies mostly focused on the role of macrophages in adipose tissue (AT) and in obesity‐associated chronic low‐grade inflammation. Lately, AT macrophages were shown to undergo intrinsic metabolic changes that affect their immune function (i.e., immunometabolism), corresponding to their unique properties along the range of pro‐ versus anti‐inflammatory activity. In parallel, recent studies in mice revealed critical neuronal–macrophage interactions, both in the CNS and in peripheral tissues, including in white and brown AT. These intercellular activities impinge on energy and metabolic homeostasis, partially by also engaging adipocytes in a neuronal–macrophage–adipocyte ménage à trois. Finally, neuropeptides (NP), such as NPY and appetite‐reducing NPFF, may prove as mediators in such intercellular network. In this concise review, we highlight some of these recent insights on adipose macrophage immunometabolism, as well as central and peripheral neuronal–macrophage interactions with emphasis on their impact on adipocyte biology and whole‐body metabolism. We also discuss the expanding view on the role of the NP, NPY and NPFF, in obesity.     

Endogenous lipid antigens for invariant natural killer T cells hold the reins in adipose tissue homeostasis

The global obesity epidemic and its associated co‐morbidities, including type 2 diabetes, cardiovascular disease and certain types of cancers, have drawn attention to the pivotal role of adipocytes in health and disease. Besides their ‘classical’ function in energy storage and release, adipocytes interact with adipose‐tissue‐resident immune cells, among which are lipid‐responsive invariant natural killer T (iNKT) cells. The iNKT cells are activated by lipid antigens presented by antigen‐presenting cells as CD1d/lipid complexes. Upon activation, iNKT cells can rapidly secrete soluble mediators that either promote or oppose inflammation. In lean adipose tissue, iNKT cells elicit a predominantly anti‐inflammatory immune response, whereas obesity is associated with declining iNKT cell numbers. Recent work showed that adipocytes act as non‐professional antigen‐presenting cells for lipid antigens. Here, we discuss endogenous lipid antigen processing and presentation by adipocytes, and speculate on how these lipid antigens, together with ‘environmental factors’ such as tissue/organ environment and co‐stimulatory signals, are able to influence the fate of adipose‐tissue‐resident iNKT cells, and thereby the role of these cells in obesity and its associated pathologies.     

Sarcopenic obesity or obese sarcopenia: A cross talk between age-associated adipose tissue and skeletal muscle inflammation as a main mechanism of the pathogenesis

Sarcopenia, an age-associated decline in skeletal muscle mass coupled with functional deterioration, may be exacerbated by obesity leading to higher disability, frailty, morbidity and mortality rates. In the combination of sarcopenia and obesity, the state called sarcopenic obesity (SOB), some key age- and obesity-mediated factors and pathways may aggravate sarcopenia. This review will analyze the mechanisms underlying the pathogenesis of SOB. In obese adipose tissue (AT), adipocytes undergo hypertrophy, hyperplasia and activation resulted in accumulation of pro-inflammatory macrophages and other immune cells as well as dysregulated production of various adipokines that together with senescent cells and the immune cell-released cytokines and chemokines create a local pro-inflammatory status. In addition, obese AT is characterized by excessive production and disturbed capacity to store lipids, which accumulate ectopically in skeletal muscle. These intramuscular lipids and their derivatives induce mitochondrial dysfunction characterized by impaired β-oxidation capacity and increased reactive oxygen species formation providing lipotoxic environment and insulin resistance as well as enhanced secretion of some pro-inflammatory myokines capable of inducing muscle dysfunction by auto/paracrine manner. In turn, by endocrine manner, these myokines may exacerbate AT inflammation and also support chronic low grade systemic inflammation (inflammaging), overall establishing a detrimental vicious circle maintaining AT and skeletal muscle inflammation, thus triggering and supporting SOB development. Under these circumstances, we believe that AT inflammation dominates over skeletal muscle inflammation. Thus, in essence, it redirects the vector of processes from “sarcopenia → obesity” to “obesity → sarcopenia”. We therefore propose that this condition be defined as “obese sarcopenia”, to reflect the direction of the pathological pathway.     

A decade of progress in adipose tissue macrophage biology

One decade has passed since seminal publications described macrophage infiltration into adipose tissue (AT) as a key contributor to inflammation and obesity-related insulin resistance. Currently, a PubMed search for ‘adipose tissue inflammation’ reveals over 3500 entries since these original reports. We now know that resident macrophages in lean AT are alternatively activated, M2-like, and play a role in AT homeostasis. In contrast, the macrophages in obese AT are dramatically increased in number and are predominantly classically activated, M1-like, and promote inflammation and insulin resistance. Mediators of AT macrophage (ATM) phenotype include adipokines and fatty acids secreted from adipocytes as well as cytokines secreted from other immune cells in AT. There are several mechanisms that could explain the large increase in ATMs in obesity. These include recruitment-dependent mechanisms such as adipocyte death, chemokine release, and lipolysis of fatty acids. Newer evidence also points to recruitment-independent mechanisms such as impaired apoptosis, increased proliferation, and decreased egress. Although less is known about the homeostatic function of M2-like resident ATMs, recent evidence suggests roles in AT expansion, thermoregulation, antigen presentation, and iron homeostasis. The field of immunometabolism has come a long way in the past decade, and many exciting new discoveries are bound to be made in the coming years that will expand our understanding of how AT stands at the junction of immune and metabolic co-regulation.     

Obesity promotes prolonged ovalbumin‐induced airway inflammation modulating T helper type 1 (Th1), Th2 and Th17 immune responses in BALB/c mice

Clinical and epidemiological studies indicate that obesity affects the development and phenotype of asthma by inducing inflammatory mechanisms in addition to eosinophilic inflammation. The aim of this study was to assess the effect of obesity on allergic airway inflammation and T helper type 2 (Th2) immune responses using an experimental model of asthma in BALB/c mice. Mice fed a high‐fat diet (HFD) for 10 weeks were sensitized and challenged with ovalbumin (OVA), and analyses were performed at 24 and 48 h after the last OVA challenge. Obesity induced an increase of inducible nitric oxide synthase (iNOS)‐expressing macrophages and neutrophils which peaked at 48 h after the last OVA challenge, and was associated with higher levels of interleukin (IL)‐4, IL‐9, IL‐17A, leptin and interferon (IFN)‐γ in the lungs. Higher goblet cell hyperplasia was associated with elevated mast cell influx into the lungs and trachea in the obese allergic mice. In contrast, early eosinophil influx and lower levels of IL‐25, thymic stromal lymphopoietin (TSLP), CCL11 and OVA‐specific immunoglobulin (IgE) were observed in the obese allergic mice in comparison to non‐obese allergic mice. Moreover, obese mice showed higher numbers of mast cells regardless of OVA challenge. These results indicate that obesity affects allergic airway inflammation through mechanisms involving mast cell influx and the release of TSLP and IL‐25, which favoured a delayed immune response with an exacerbated Th1, Th2 and Th17 profile. In this scenario, an intense mixed inflammatory granulocyte influx, classically activated macrophage accumulation and intense mucus production may contribute to a refractory therapeutic response and exacerbate asthma severity.     

Adipose invariant natural killer T cells

Adipose tissue is a dynamic organ that makes up a substantial proportion of the body; in severe obesity it can account for 50% of body mass. Details of the unique immune system resident in human and murine adipose tissue are only recently emerging, and so it has remained a largely unexplored and unappreciated immune site until now. Adipose tissue harbours a unique collection of immune cells, which often display unusual functions compared with their counterparts elsewhere in the body. These resident immune cells are key to maintaining tissue and immune homeostasis, yet in obesity their chronic aberrant stimulation can contribute to the inflammation and pathogenesis associated with obesity. Anti‐inflammatory adipose‐resident lymphocytes are often depleted in obesity, whereas pro‐inflammatory immune cells accumulate, leading to an overall inflammatory state, which is a key step in the development of obesity‐induced metabolic disease. A good example is invariant natural killer T (iNKT) cells, which make up a large proportion of lymphocytes in human and murine adipose tissue. Here, they are unusually poised to produce anti‐inflammatory or regulatory cytokines, however in obesity, iNKT cells are greatly reduced. As iNKT cells are potent transactivaors of other immune cells, and can act as a bridge between innate and adaptive immunity, their loss in obesity represents the loss of a major regulatory population. Restoring iNKT cells, or activating them in obese mice leads to improved glucose handling, insulin sensitivity, and even weight loss, and hence represents an exciting therapeutic avenue to be explored for restoring homeostasis in obese adipose tissue.     

Lipopolysaccharide‐binding protein and leptin are associated with stress‐induced interleukin‐6 cytokine expression ex vivo in obesity

Obesity is associated with enhanced inflammation and mental stress, but limited information has addressed the potential additive effect of psychological stress on obesity‐associated inflammation. This study examined whether obese subjects would elicit a greater host immune response (IL‐6 mRNA and cytokine) to lipopolysaccharide (LPS) in response to mental stress. Blood samples for LPS‐stimulated IL‐6 mRNA and cytokine were collected prior to and following mental stress. Results showed that obese subjects elicited a greater LPS‐induced IL‐6 along with its mRNA expression following mental stress compared to normal‐weight subjects. Stress‐induced IL‐6 cytokine response to LPS was correlated with the baseline levels of plasma LPS binding protein (LBP) and leptin. These findings are consistent with the idea that endogenous inflammatory agents (e.g., LBP and leptin), often elevated with obesity, enhance inflammatory responses to psychological stress.     

Regulation of metabolic health and adipose tissue function by group 2 innate lymphoid cells

Adipose tissue (AT) is home to an abundance of immune cells. With chronic obesity, inflammatory immune cells accumulate and promote insulin resistance and the progression to type 2 diabetes mellitus. In contrast, recent studies have highlighted the regulation and function of immune cells in lean, healthy AT, including those associated with type 2 or “allergic” immunity. Although traditionally activated by infection with multicellular helminthes, AT type 2 immunity is active independently of infection, and promotes tissue homeostasis, AT “browning,” and systemic insulin sensitivity, protecting against obesity‐induced metabolic dysfunction and type 2 diabetes mellitus. In particular, group 2 innate lymphoid cells (ILC2s) are integral regulators of AT type 2 immunity, producing the cytokines interleukin‐5 and IL‐13, promoting eosinophils and alternatively activated macrophages, and cooperating with and promoting AT regulatory T (Treg) cells. In this review, we focus on the recent developments in our understanding of group 2 innate lymphoid cell cells and type 2 immunity in AT metabolism and homeostasis.     

Adipocitokines, adipose tissue and its relationship with immune system cells

Adipokines or adipocytokines are the proteins secreted by the adipose tissue. These bioactive molecules include proteins that modify insulin sensitivity (acylation-stimulating protein (ASP), TNF-alpha IL-6, resistin, leptin and adiponectin), and proteins that have known effects on vascularity (angiotensinogen and the plasminogen inhibitor protein PAI-I). Several studies have found a close relationship between adipocytes and immune cells as a consequence of evolutionary mechanisms that favor metabolic adaptation and survival under adverse conditions. It is known that adipokines contribute to the inflammation and insulin resistance present in obese individuals. The aim of this review is to analyze current information related to the physiology of the adipose tissue, with a special emphasis on the secretion of adipokines and their role in inflammation. We recommend that therapies addressing the treatment of obesity related disorders should focus on modifying the inflammatory process that originates in the adipose tissue.     

The effect of maternal Inflammation on foetal programming of metabolic disease

Maternal obesity during pregnancy increases the child's risk of developing obesity and obesity‐related diseases later in life. Key components in foetal programming of metabolic risk remain to be identified; however, chronic low‐grade inflammation associated with obesity might be responsible for metabolic imprinting in the offspring. We have therefore surveyed the literature to evaluate the role of maternal obesity‐induced inflammation in foetal programming of obesity and related diseases. The literature on this topic is limited, so this review also includes animal models where maternal inflammation is mimicked by single injections with lipopolysaccharide (LPS). An LPS challenge results in an immunological response that resembles the obesity‐induced immune profile, although LPS injections provoke a stronger response than the subclinical obesity‐associated response. Maternal LPS or cytokine exposures result in increased adiposity and impaired metabolic homeostasis in the offspring, similar to the phenotype observed after exposure to maternal obesity. The cytokine levels might be specifically important for the metabolic imprinting, as cytokines are both transferable from maternal to foetal circulation and have the capability to modulate placental nutrient transfer. However, the immune response associated with obesity is moderate and therefore potentially weakened by the pregnancy‐driven immune modulation, dominated by anti‐inflammatory Treg and Th2 cells. We know from other low‐grade inflammatory diseases, such as rheumatoid arthritis, that pregnancy can improve disease state. If pregnancy is also capable of suppressing the obesity‐associated inflammation, the immunological markers might be less likely to affect metabolic programming in the developing foetus than otherwise implied.     

Does Inflammation Mediate the Association Between Obesity and Insulin Resistance?

In adult obesity, low-grade systemic inflammation is considered an important step in the pathogenesis of insulin resistance (IR). The association between obesity and inflammation is less well established in adolescents. Here, we ascertain the importance of inflammation in IR among obese adolescents by utilizing either random forest (RF) classification or mediation analysis approaches. The inflammation balance score, composed of eight pro- and anti-inflammatory makers, as well as most of the individual inflammatory markers differed significantly between lean and overweight/obese. In contrast, adiponectin was the only individual marker selected as a predictor of IR by RF, and the balance score only revealed a medium-to-low importance score. Neither adiponectin nor the inflammation balance score was found to mediate the relationship between obesity and IR. These findings do not support the premise that low-grade systemic inflammation is a key for the expression of IR in the human. Prospective longitudinal studies should confirm these findings.     

Free fatty acids sensitize dendritic cells to amplify TH1/TH17‐immune responses

Obesity is associated with body fat gain and impaired glucose metabolism. Here, we identified both body fat gain in obesity and impaired glucose metabolism as two independent risk factors for increased serum levels of free fatty acids (FFAs). Since obesity is associated with increased and/or delayed resolution of inflammation observed in various chronic inflammatory diseases such as psoriasis, we investigated the impact of FFAs on human monocyte‐derived and mouse bone marrow‐derived dendritic cell (DCs) functions relevant for the pathogenesis of chronic inflammation. FFAs such as palmitic acid (PA) and oleic acid (OA) did not affect the pro‐inflammatory immune response of DCs. In contrast, PA and OA sensitize DCs resulting in augmented secretion of TH1/TH17‐instructive cytokines upon pro‐inflammatory stimulation. Interestingly, obesity in mice worsened a TH1/TH17‐driven psoriasis‐like skin inflammation. Strong correlation of the amount of total FFA, PA, and OA in serum with the severity of skin inflammation points to a critical role of FFA in obesity‐mediated exacerbation of skin inflammation. Our data suggest that increased levels of FFAs might be a predisposing factor promoting a TH1/TH17‐mediated inflammation such as psoriasis in response to an inflammatory danger signal.     

The “Big Bang” in obese fat: Events initiating obesity‐induced adipose tissue inflammation

Obesity is associated with the accumulation of pro‐inflammatory cells in visceral adipose tissue (VAT), which is an important underlying cause of insulin resistance and progression to diabetes mellitus type 2 (DM2). Although the role of pro‐inflammatory cytokines in disease development is established, the initiating events leading to immune cell activation remain elusive. Lean adipose tissue is predominantly populated with regulatory cells, such as eosinophils and type 2 innate lymphocytes. These cells maintain tissue homeostasis through the excretion of type 2 cytokines, such as IL‐4, IL‐5, and IL‐13, which keep adipose tissue macrophages (ATMs) in an anti‐inflammatory, M2‐like state. Diet‐induced obesity is associated with the loss of tissue homeostasis and development of type 1 inflammatory responses in VAT, characterized by IFN‐γ. A key event is a shift of ATMs toward an M1 phenotype. Recent studies show that obesity‐induced adipocyte hypertrophy results in upregulated surface expression of stress markers. Adipose stress is detected by local sentinels, such as NK cells and CD8⁺ T cells, which produce IFN‐γ, driving M1 ATM polarization. A rapid accumulation of pro‐inflammatory cells in VAT follows, leading to inflammation. In this review, we provide an overview of events leading to adipose tissue inflammation, with a special focus on adipose homeostasis and the obesity‐induced loss of homeostasis which marks the initiation of VAT inflammation.     

Morphological and Inflammatory Changes in Visceral Adipose Tissue During Obesity

Obesity is a major health burden worldwide and is a major factor in the development of insulin resistance and metabolic complications such as type II diabetes. Chronic nutrient excess leads to visceral adipose tissue (VAT) expansion and dysfunction in an active process that involves the adipocytes, their supporting matrix, and immune cell infiltrates. These changes contribute to adipose tissue hypoxia, adipocyte cell stress, and ultimately cell death. Accumulation of lymphocytes, macrophages, and other immune cells around dying adipocytes forms the so-called “crown-like structure”, a histological hallmark of VAT in obesity. Cross talk between immune cells in adipose tissue dictates the overall inflammatory response, ultimately leading to the production of pro-inflammatory mediators which directly induce insulin resistance in VAT. In this review, we summarize recent studies demonstrating the dramatic changes that occur in visceral adipose tissue during obesity leading to low-grade chronic inflammation and metabolic disease.