Identification of adipocyte plasma membrane-associated protein as a novel modulator of human cytomegalovirus infection.

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that can cause disability in newborns and serious clinical diseases in immunocompromised patients. HCMV has a large genome with enormous coding potential; its viral particles are equipped with complicated glycoprotein complexes and can infect a wide range of human cells. Although multiple host cellular receptors interacting with viral glycoproteins have been reported, the mechanism of HCMV infection remains a mystery. Here we report identification of adipocyte plasma membrane-associated protein (APMAP) as a novel modulator active in the early stage of HCMV infection. APMAP is necessary for HCMV infection in both epithelial cells and fibroblasts; knockdown of APMAP expression significantly reduced HCMV infection of these cells. Interestingly, ectopic expression of human APMAP in cells refractory to HCMV infection, such as canine MDCK and murine NIH/3T3 cells, promoted HCMV infection. Furthermore, reduction in viral immediate early (IE) gene transcription at 6 h post infection and delayed nucleus translocation of tegument delivered pp65 at 4 h post infection were detected in APMAP-deficient cells but not in the wildtype cells. These results suggest that APMAP plays a role in the early stage of HCMV infection. Results from biochemical studies of APMAP and HCMV proteins suggest that APMAP could participate in HCMV infection through interaction with gH/gL containing glycoprotein complexes at low pH and mediate nucleus translocation of tegument pp65. Taken together, our results suggest that APMAP functions as a modulator promoting HCMV infection in multiple cell types and is an important player in the complex HCMV infection mechanism.

What we know and what we need to know about adenovirus 36-induced obesity.

BACKGROUND: Many internal and external factors are related to obesity. Pathogens that can induce obesity are the most interesting external factors. While the relationship between pathogenic human intestinal microbiota and obesity has been extensively studied, viruses have received relatively little attention. Among the human obesity-related viruses, adenovirus 36 (Ad36) is most commonly associated with obesity. METHODS: A literature search was conducted using the articles in the PubMed database published from April 1982 to April 2019. The following main keywords were used: ('adenovirus 36') and ('obesity') and ('cellular mechanism' or 'genetic factor' or 'immune response' or 'inflammation'). RESULTS: In this review, we have discussed the known facts and what requires to be understood regarding Ad36-induced obesity. In particular, we have summarized the cellular mechanism of Ad36-induced obesity, as well as the genetic and immunological factors affected by Ad36 infection. Ad36 infection increases adipogenesis in animals and humans. Ad36-induced inflammation contributes to angiogenesis in adipose tissues, thereby maintaining proper glycemic control and metabolic robustness. The E4orf1 protein derived from Ad36 is responsible for increasing glucose uptake due to the translocation of GLUT4 via the Ras-PI3K pathway, which is involved in 'distal' insulin signaling. CONCLUSIONS: We expect that this review will assist in guiding future investigations regarding Ad36-induced obesity. (1) Identification of the direct and indirect factors affecting Ad36-induced obesity and understanding their mechanism of action and (2) utilization of the Ad36-induced improvement in glycemic control for clinical applications, with efforts toward developing E4orf1-based drugs.

Obesity and Fat Metabolism in Human Immunodeficiency Virus-Infected Individuals: Immunopathogenic Mechanisms and Clinical Implications.

Metabolic complications relating to complex effects of viral and immune-mediated mechanisms are now a focus of clinical care among persons living with human immunodeficiency virus (PLHIV), and obesity is emerging as a critical problem. To address knowledge gaps, the US National Institutes of Health sponsored a symposium in May 2018 entitled "Obesity and Fat Metabolism in HIV-infected Individuals." Mechanisms relating to adipose dysfunction and fibrosis, immune function, inflammation, and gastrointestinal integrity were highlighted as contributors to obesity among PLHIV. Fibrotic subcutaneous adipose tissue is metabolically dysfunctional and loses its capacity to expand, leading to fat redistribution, including visceral obesity and ectopic fat accumulation, promoting insulin resistance. Viral proteins, including viral protein R and negative regulatory factor, have effects on adipogenic pathways and cellular metabolism in resident macrophages and T cells. HIV also affects immune cell trafficking into the adipose compartments, with effects on adipogenesis, lipolysis, and ectopic fat accumulation. Key cellular metabolic functions are likely to be affected in PLHIV by gut-derived cytokines and altered microbiota. There are limited strategies to reduce obesity specifically in PLHIV. Enhancing our understanding of critical pathogenic mechanisms will enable the development of novel therapeutics that may normalize adipose tissue function and distribution, reduce inflammation, and improve insulin sensitivity in PLHIV.

Adenovirus type 36 regulates adipose stem cell differentiation and glucolipid metabolism through the PI3K/Akt/FoxO1/PPARγ signaling pathway.

BACKGROUND: This study aims to investigate the molecular mechanism of Adenovirus type 36 (Ad36) in adipocyte differentiation and glucolipid metabolism. METHODS: Rat obesity model was established by Ad36 infection and high-fat diet, respectively. Comparison of the body weight, clinical biochemical indicators, insulin sensitivity and lipid heterotopic deposition between these two models was performed. Ad36-induced adipocyte in vitro model was also established. The binding rate of FoxO1, PPARγ and its target gene promoter was detected using ChIP. The mRNA and protein expression levels of PPARγ and downstream target genes were detected by RT-PCR and Western blot, respectively. Oil red O staining was used to measure differentiation into adipocyte. Wortmannin (WM), inhibitor of PI3K, was used to act on Ad36-induced hADSCs. RESULTS: Ad36-induced obese rats did not exhibit disorders in blood glucose and blood TG, insulin resistance and lipid ectopic deposition. The expression of Adipoq, Lpin1 and Glut4 in the adipose tissue increased. Oil red O staining showed that Ad36 induced the differentiation of hAMSCs into human adipocytes in vitro. During this process, the binding rate of FoxO1 and PPARγ promoter regions was weakened. However, the binding rate of the transcription factor PPARγ to its target genes Acc, Adipoq, Lpin1 and Glut4 was enhanced, and thus increased the protein expression of P-FoxO1, PPARγ2, ACC, LPIN1, GLUT4 and ADIPOQ. The PI3K inhibitor Wortmannin reduced the expression of P-Akt, P-FoxO1 and PPARγ2, thereby inhibiting adipogenesis of hADSC. CONCLUSION: Ad36 may promote fatty acid and triglyceride synthesis, and improve insulin sensitivity by affecting the PI3K/Akt/FoxO1/PPARγ signaling pathway.

HIV Persistence in Adipose Tissue Reservoirs.

PURPOSE OF REVIEW: The purpose of this review is to examine the evidence describing adipose tissue as a reservoir for HIV-1 and how this often expansive anatomic compartment contributes to HIV persistence. RECENT FINDINGS: Memory CD4 T cells and macrophages, the major host cells for HIV, accumulate in adipose tissue during HIV/SIV infection of humans and rhesus macaques. Whereas HIV and SIV proviral DNA is detectable in CD4 T cells of multiple fat depots in virtually all infected humans and monkeys examined, viral RNA is less frequently detected, and infected macrophages may be less prevalent in adipose tissue. However, based on viral outgrowth assays, adipose-resident CD4 T cells are latently infected with virus that is replication-competent and infectious. Additionally, adipocytes interact with CD4 T cells and macrophages to promote immune cell activation and inflammation which may be supportive for HIV persistence. Antiviral effector cells, such as CD8 T cells and NK/NKT cells, are abundant in adipose tissue during HIV/SIV infection and typically exceed CD4 T cells, whereas B cells are largely absent from adipose tissue of humans and monkeys. Additionally, CD8 T cells in adipose tissue of HIV patients are activated and have a late differentiated phenotype, with unique TCR clonotypes of less diversity relative to blood CD8 T cells. With respect to the distribution of antiretroviral drugs in adipose tissue, data is limited, but there may be class-specific penetration of fat depots. The trafficking of infected immune cells within adipose tissues is a common event during HIV/SIV infection of humans and monkeys, but the virus may be mostly transcriptionally dormant. Viral replication may occur less in adipose tissue compared to other major reservoirs, such as lymphoid tissue, but replication competence and infectiousness of adipose latent virus are comparable to other tissues. Due to the ubiquitous nature of adipose tissue, inflammatory interactions among adipocytes and CD4 T cells and macrophages, and selective distribution of antiretroviral drugs, the sequestration of infected immune cells within fat depots likely represents a major challenge for cure efforts.

Regulation of PPARγ and CIDEC expression by adenovirus 36 in adipocyte differentiation.

This study is to investigate the role of adenovirus 36 (Ad36) in regulating expression of peroxisome proliferator-activated receptor γ (PPARγ) and cell death-inducing DFFA-like effector c (CIDEC) in Ad36-induced adipocyte differentiation. Human adipose-derived mesenchymal stem cells (hAMSCs) were isolated and cultured, and then infected with Ad36. Ad36-induced adipocytes were identified using quantitative real-time PCR and Oil red O staining. The expression levels of PPARγ and CIDEC in Ad36-induced adipocytes were determined by quantitative real-time PCR and Western blot analysis. Glucose uptake and intracellular triglyceride content were also determined in these induced cells. Our results from the Oil red O staining showed that Ad36 induced the differentiation of hAMSCs into human adipocytes in vitro. Moreover, the medium glucose concentration was significantly decreased, while the intracellular triglyceride content was significantly increased, in the Ad36-induced adipocytes, compared with the control group. Furthermore, our results showed that, the mRNA and protein expression levels of PPARγ and CIDEC were significantly upregulated in Ad36-induced adipocytes, in a time-dependent manner. On the other hand, compared with the control group, the CIDEC expression was downregulated when the Ad36-induced adipocytes were treated with the PPARγ inhibitor, GW9662. Ad36 could upregulate the expression level of CIDEC through increasing PPARγ expression during the adipocyte differentiation process.

Cell therapy could be a potential way to improve lipoprotein lipase deficiency.

BACKGROUND: Lipoprotein lipase (LPL) deficiency is an autosomal recessive genetic disorder characterized by extreme hypertriglyceridemia, with no cure presently available. The purpose of this study was to test the possibility of using cell therapy to alleviate LPL deficiency. METHODS: The LPL coding sequence was cloned into the MSCV retrovirus vector, after which MSCV-hLPL and MSCV (empty construct without LPL coding sequence) virion suspensions were made using the calcium chloride method. A muscle cell line (C2C12), kidney cell line (HEK293T) and pre-adipocyte cell line (3 T3-L1) were transfected with the virus in order to express recombinant LPL in vitro. Finally, each transfected cell line was injected subcutaneously into nude mice to identify the cell type which could secret recombinant LPL in vivo. Control cells were transfected with the MSCV empty vector. LPL activity was analyzed using a radioimmunoassay. RESULTS: After virus infection, the LPL activity at the cell surface of each cell type was significantly higher than in the control cells, which indicates that all three cell types can be used to generate functional LPL. The transfected cells were injected subcutaneously into nude mice, and the LPL activity of the nearby muscle tissue at the injection site in mice injected with 3 T3-L1 cells was more than 5 times higher at the injection sites than at non-injected control sites. The other two types of cells did not show this trend. CONCLUSION: The subcutaneous injection of adipocytes overexpressing LPL can improve the LPL activity of the adjacent tissue of nude mice. This is a ground-breaking preliminary study for the treatment of LPL deficiency, and lays a good foundation for using cell therapy to correct LPL deficiency.

An infection of human adenovirus 31 affects the differentiation of preadipocytes into fat cells, its metabolic profile and fat accumulation.

The primary issue undertaken in this study was to test the hypothesis that preadipocytes would have intrinsically elevated propensity to differentiate into mature adipocytes due to HAdV31 infection. To prove that, the metabolic and molecular mechanisms responsible for HAdV31-induced adipogenesis were examined. 3T3L1 cells (mouse embryonic fibroblast, adipose like cell line) were used as a surrogate model to analyze an increased proliferation, differentiation, and maturation of preadipocytes infected with human adenovirus. An expression of E4orf1, C/EBP-ß, PPAR-γ, GAPDH, aP2, LEP, and fatty acid synthase genes, intracellular lipid accumulation as well as cytokine release from the fat cells were assessed. Data showed that HAdV31 increased an expression of C/EBP-ß and PPAR-γ genes leading to an enhanced differentiation of preadipocytes into fat cells. Besides, overexpression of GAPDH and fatty acid synthase, and decreased expression of leptin caused an increased accumulation of intracellular lipids. Secretion of TNF-α and IL-6 from HAdV31-infected cells was strongly decreased, leading to unlimited virus replication. The results obtained from this study provided the evidences that HAdV31, likewise previously documented HAdV36, is a subsequent human adenovirus affecting the differentiation and lipid accumulation of 3T3L1 cells.

Different origin of adipogenic stem cells influences the response to antiretroviral drugs.

Lipodystrophy (LD) is a main side effect of antiretroviral therapy for HIV infection, and can be provoked by nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs). LD exists in different forms, characterized by fat loss, accumulation, or both, but its pathogenesis is still unclear. In particular, few data exist concerning the effects of antiretroviral drugs on adipocyte differentiation. Adipose tissue can arise either from mesenchymal stem cells (MSCs), that include bone marrow-derived MSCs (hBM-MSCs), or from ectodermal stem cells, that include dental pulp stem cells (hDPSCs). To analyze whether the embryonal origin of adipocytes might impact the occurrence of different phenotypes in LD, we quantified the effects of several antiretroviral drugs on the adipogenic differentiation of hBM-MSCs and hDPSCs. hBM-MSCs and hDPSCs were isolated from healthy donors. Cells were treated with 10 and 50 µM stavudine (d4T), efavirenz (EFV), atazanavir (ATV), ritonavir (RTV), and ATV-boosted RTV. Viability and adipogenesis were evaluated by staining with propidium iodide, oil red, and adipoRed; mRNA levels of genes involved in adipocyte differentiation, i.e. CCAAT/enhancer-binding protein alpha (CEBPα) and peroxisome proliferator-activated receptor gamma (PPARγ), and in adipocyte functions, i.e. fatty acid synthase (FASN), fatty acid binding protein-4 (FABP4), perilipin-1 (PLIN1) and 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2), were quantified by real time PCR. We found that ATV, RTV, EFV, and ATV-boosted RTV, but not d4T, caused massive cell death in both cell types. EFV and d4T affected the accumulation of lipid droplets and induced changes in mRNA levels of genes involved in adipocyte functions in hBM-MSCs, while RTV and ATV had little effects. All drugs stimulated the accumulation of lipid droplets in hDPSCs. Thus, the adipogenic differentiation of human stem cells can be influenced by antiretroviral drugs, and depends, at least in part, on their embryonal origin.

p204-Mediated innate antiviral responses in mouse adipose cells and their effects on cell functions.

Viruses can infect adipose tissues. However, innate antiviral responses in adipose cells and their effects on adipocyte function have not yet been intensively investigated. In this study, p204-initiated innate antiviral responses in mouse adipose cells were examined. Cytosolic DNA sensor p204 and its signaling adaptor stimulator of interferon (IFN) genes (STING) were constitutively expressed in primary preadipocytes. Synthetic herpes simplex viral DNA (HSV60), a p204 ligand, induced type I IFN expression by activating IFN regulatory factor 3. Major antiviral proteins, including IFN-stimulating gene 15, 2',5'-oligoadenylate synthetase and Mx GTPase 1, in preadipocytes were upregulated by HSV60. HSV60-triggered innate antiviral responses were significantly reduced by inhibition of p204 signaling with specific small interfering RNA targeting p204 or STING. HSV60 inhibited the differentiation of preadipocytes to mature adipocytes and enhanced the proliferation of adipose cells. Moreover, HSV60 induced innate antiviral responses in mature adipocytes and inhibited expressions of several adipokines, including leptin, adiponectin and resistin. These results indicated that p204 initiated innate antiviral responses in adipose cells, thereby modulating adipocyte function.

Adenovirus type 9 enhances differentiation and decreases cytokine release from preadipocytes.

The hypothesis was that preadipocytes would have intrinsically elevated propensity to differentiate into mature adipocytes due to AdV9 infection. To test this hypothesis, the metabolic and molecular mechanisms responsible for AdV9-induced adipogenesis were examined. An association between anti-AdV9 antibodies and human obesity was also identified. 3T3L1 cells were used as a surrogate model to analyze the preadipocyte proliferation, differentiation, and maturation. An expression of E4orf1, C/EBP-ß, PPAR-γ, GAPDH, aP2, LEP and fatty acid synthase gene, intracellular lipid accumulation and cytokine release were assessed. The presence of anti-AdV antibodies, serum lipids, plasma leptin, and CRP was evaluated in 204 obese and non-obese patients. AdV9-infected cells accumulated more intracellular lipids in comparison to uninfected controls. AdV9 enhanced an expression of C/EBP-ß and PPAR-γ leading to an increased differentiation of preadipocytes. Overexpression of aP2 and fatty acid synthase, and decreased expression of leptin confirmed an increased accumulation of intracellular lipids due to AdV infection. Secretion of TNF-α and IL-6 from AdV9-inoculated cells was decreased strongly. About 24.5% of prevalence of anti-AdV9 antibodies was reported in the study group. AdV9-infected subjects presented higher body weights, BMIs, WHR, and central obesity. The presence of anti-AdV9 antibodies was associated with changes in serum lipids level but neither elevated CRP nor decreased leptin levels were related to obesity due to AdV infection. Data obtained from this study provide the evidences that AdV9 is a second adenovirus, which has an influence on differentiation and lipid accumulation of 3T3L1 cells.

Pattern recognition receptor-initiated innate antiviral response in mouse adipose cells.

Although wide range of viruses can infect adipose tissues, innate antiviral response of adipose cells has not been investigated. This study focused on innate antiviral system in mouse adipose cells. Major virus sensors including Toll-like receptor 3 (TLR3), melanoma differentiation-associated antigen 5 (MDA5) and retinoic acid-inducible gene I (RIG-I) are constitutively expressed in preadipocytes and adipocytes. Poly(I:C), a common agonist of TLR3, MDA5 and RIG-I, induced the expression of type I interferons (IFN-α/ß) in the two types of adipose cells through the activation of IFN-regulatory factor 3 and upregulated pro-inflammatory factors such as TNF-α and IL-6 through the activation nuclear factor kappa B. Moreover, poly(I:C) induced multiple antiviral proteins including IFN-stimulating gene 15, 2'5'-oligoadenylate synthetase and Mx GTPase 1 in preadipocytes and adipocytes. The poly(I:C)-induced innate antiviral response was reduced by TLR3 deficiency and knockdown of MDA5 or RIG-I. Poly(I:C) also inhibited the differentiation of preadipocytes to adipocytes and suppressed the expression of leptin, adiponectin and resistin in mature adipocytes. The results demonstrated that adipose cells are equipped with innate antiviral system, which may modulate the function of adipocytes.

Proof-of-concept for a virus-induced obesity vaccine; vaccination against the obesity agent adenovirus 36.

Human adenovirus 36 (Ad36) is positively associated with obesity in humans and animals. Ad36 infection is characterized by increased adiposity and inflammation. To investigate the possibility that a prophylactic vaccine candidate might protect against Ad36-induced obesity and inflammation, we purified Ad36 and ultraviolet-irradiated virus to obtain a vaccine candidate. After immunizing the mice with the vaccine candidate (vaccinated group), live Ad36 was injected into mice as a challenge test. Unvaccinated mice (control group) were immunized with phosphate-buffered saline and then challenged with live Ad36. Fourteen weeks after challenge, we compared adiposity and inflammation in vaccinated and control mice. The control group showed 17% greater body weight and 20% more epididymal fats compared with the vaccinated group. In addition, the vaccinated group had decreased serum levels of pro-inflammatory cytokines, and infiltrated immune cells, especially M1 macrophages, in fat tissue. Therefore, the vaccine candidate for Ad36 was able to protect against Ad36-increased body weight and fat as well as inflammatory states after challenge. These results provide proof-of-concept for prophylactic vaccination against virus-induced adiposity.

Adenovirus 36 as an obesity agent maintains the obesity state by increasing MCP-1 and inducing inflammation.

BACKGROUND: Although it is well known that adenovirus 36 (Ad36) is associated with obesity in humans as well as in animals, the detailed cellular mechanism is unclear. METHODS: Wild-type (WT) mice and monocyte chemoattractant protein-1 knockout (MCP-1(-/-)) mice were infected with Ad36, and their weights and inflammatory status were measured. Macrophage infiltration was examined in their reproductive fat pads and in a coculture system. The correlation between Ad36 antibody presence and MCP-1 levels was tested in human samples. RESULTS: We have shown that Ad36 infection stimulated an inflammatory state by increasing the level of MCP-1 through the activation of nuclear factor κB, which in turn induced the infiltration of macrophages into adipocytes. This induced inflammation resulted in viral obesity, which caused chronic inflammation and affected lipid metabolism. In contrast to WT mice, MCP-1(-/-) mice were protected from Ad36-induced inflammation and obesity. The MCP-1 levels in Ad36-antibody-positive human group were higher than those in the antibody-negative group. CONCLUSIONS: These findings support the proposition that virus-induced inflammation is the cellular mechanism underlying Ad36-induced obesity. These results also suggest that MCP-1 plays a critical role in Ad36-induced obesity and that MCP-1 may be a therapeutic target in preventing virus-induced obesity.

Nef inhibits glucose uptake in adipocytes and contributes to insulin resistance in human immunodeficiency virus type I infection.

Human immunodeficiency virus (HIV) infection is associated with insulin resistance. HIV type 1 Nef downregulates cell surface protein expression, alters signal transduction, and interacts with the cytoskeleton and proteins involved in actin polymerization. These functions are required for glucose uptake by insulin-stimulated adipocytes. We sought to determine whether Nef alters adipocyte glucose homeostasis. Using radiolabeled glucose, we found that adipocytes exposed to recombinant Nef took in 42% less glucose after insulin stimulation than did control cells. This reduction resulted from a Nef-dependent inhibition of glucose transporter 4 (GLUT4) trafficking, as assessed by means of immunofluorescence microscopy. Immunoblot analysis revealed a decrease in phosphorylation of signal transducing proteins after Nef treatment, and fluorescence microscopy showed a dramatic alteration in cortical actin organization. We conclude that Nef interferes with insulin-stimulated processes in adipocytes. We have identified HIV Nef, which is detectable and antigenic in serum samples from HIV-infected people, as a novel contributor to the development of insulin resistance.

[Production of purified human recombinant alpha2b-interferon].

Technology for producing biologically active recombinant alpha2b-interferon is based on creating a bacterial producer strain containing the cDNA of human interferon alpha. The authors have obtained two producers of recombinant alpha2b-interferon, the synthesis of the target protein in them occurs in the inclusion bodies. The schemes of isolation and purification of biologically active recombinant alpha2b-interferon have been developed. The drug purity was approximately 97-98%. Biological activity in the culture of sensory cells in the cytopathic test was 4.2*10(8)ME/mg.

Epstein-Barr Virus Induces Adipocyte Dedifferentiation to Modulate the Tumor Microenvironment.

The most frequent location of metastatic EBV+ nasopharyngeal carcinoma (NPC) is the bone marrow, an adipocyte-dominant region. Several EBV-associated lymphoepithelioma-like carcinoma (LELC) types also grow in the anatomical vicinity of fat tissues. Here we show that in an adipose tissue-rich tumor setting, EBV targets adipocytes and remodels the tumor microenvironment. Positive immunoreactivity for EBV-encoded early antigen D was detected in adipose tissue near tumor beds of bone marrow metastatic NPC. EBV was capable of infecting primary human adipocytes in vitro, triggering expression of multiple EBV-encoded mRNA and proteins. In infected adipocytes, lipolysis was stimulated through enhanced expression of lipases and the AMPK metabolic pathway. The EBV-mediated imbalance in energy homeostasis was further confirmed by increased release of free fatty acids, glycerol, and expression of proinflammatory adipokines. Clinically, enhanced serum levels of free fatty acids in patients with NPC correlated with poorer recurrence-free survival. EBV-induced delipidation stimulated dedifferentiation of adipocytes into fibroblast-like cells expressing higher levels of S100A4, a marker protein of cancer-associated fibroblasts (CAF). IHC analyses of bone marrow metastatic NPC and salivary LELC revealed similar structural changes of dedifferentiated adipocytes located at the boundaries of EBV+ tumors. S100A4 expression in adipose tissues near tumor beds correlated with fibrotic response, implying that CAFs in the tumor microenvironment are partially derived from EBV-induced dedifferentiated adipocytes. Our data suggest that adipose tissue serves as an EBV reservoir, where EBV orchestrates the interactions between adipose tissues and tumor cells by rearranging metabolic pathways to benefit virus persistence and to promote a protumorigenic microenvironment. SIGNIFICANCE: This study suggests that Epstein-Barr virus hijacks adipocyte lipid metabolism to create a tumor-promoting microenvironment from which reactivation and relapse of infection could potentially occur.

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.

The Role of Adipocytes and Adipocyte-Like Cells in the Severity of COVID-19 Infections.

Coronavirus disease-2019 (COVID-19), caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrates high morbidity and mortality caused by development of a severe acute respiratory syndrome connected with extensive pulmonary fibrosis. In this Perspective, we argue that adipocytes and adipocyte-like cells, such as pulmonary lipofibroblasts, may play an important role in the pathogenic response to SARS-CoV-2. Expression of angiotensin-converting enzyme 2 (the functional receptor for SARS-CoV) is upregulated in adipocytes of patients with obesity and diabetes, which turns adipose tissue into a potential target and viral reservoir. This may explain why obesity and diabetes are potential comorbidities for COVID-19 infections. Similar to the recently established adipocyte-myofibroblast transition, pulmonary lipofibroblasts located in the alveolar interstitium and closely related to classical adipocytes demonstrate the ability to transdifferentiate into myofibroblasts that play an integral part of pulmonary fibrosis. This may significantly increase the severity of the local response to SARS-CoV-2 in the lung. To reduce the severity and mortality associated with COVID-19, we propose to probe for the clinical response to thiazolidinediones, peroxisome proliferator activated receptor γ agonists that are well-known antidiabetic drugs. Thiazolidinediones are able to stabilize lipofibroblasts in their "inactive" state, preventing the transition to myofibroblasts and thereby reducing the development of pulmonary fibrosis and stimulating its resolution.

SIV Infection and the HIV Proteins Tat and Nef Induce Senescence in Adipose Tissue and Human Adipose Stem Cells, Resulting in Adipocyte Dysfunction.

BACKGROUND: Aging is characterized by adipose tissue senescence, inflammation, and fibrosis, with trunk fat accumulation. Aging HIV-infected patients have a higher risk of trunk fat accumulation than uninfected individuals-suggesting that viral infection has a role in adipose tissue aging. We previously demonstrated that HIV/SIV infection and the Tat and Nef viral proteins were responsible for adipose tissue fibrosis and impaired adipogenesis. We hypothesized that SIV/HIV infection and viral proteins could induce adipose tissue senescence and thus lead to adipocyte dysfunctions. METHODS: Features of tissue senescence were evaluated in subcutaneous and visceral adipose tissues of SIV-infected macaques and in human adipose stem cells (ASCs) exposed to Tat or Nef for up to 30 days. RESULTS: p16 expression and p53 activation were higher in adipose tissue of SIV-infected macaques than in control macaques, indicating adipose tissue senescence. Tat and Nef induced higher senescence in ASCs, characterized by higher levels of senescence-associated beta-galactosidase activity, p16 expression, and p53 activation vs. control cells. Treatment with Tat and Nef also induced oxidative stress and mitochondrial dysfunction. Prevention of oxidative stress (using N-acetyl-cysteine) reduced senescence in ASCs. Adipocytes having differentiated from Nef-treated ASCs displayed alterations in adipogenesis with lower levels of triglyceride accumulation and adipocyte marker expression and secretion, and insulin resistance. CONCLUSION: HIV/SIV promotes adipose tissue senescence, which in turn may alter adipocyte function and contribute to insulin resistance.