Influenza infection rewires energy metabolism and induces browning features in adipose cells and tissues
ABSTRACT: Influenza A viruses cause epidemics and pandemics with damaging health and economic impacts. Alike any obligate intracellular pathogen, IAVs hijack host cell machinery and energetic resources to multiply within, and eventually exit, the host. Increased fatty acid and cholesterol synthesis, as well as increased glucose metabolism have been identified as the major metabolic changes induced by infection. Besides these effects on metabolism, IAV infection also triggers a variety of innate defense mechanisms within the host cell. Although mainly defined as a virus of the respiratory tract, with airway epithelial cells being its prime cellular habitat, complications outside the site of infection have also been reported. However, whether influenza on its own may impact on endocrine tissues and, thereby, lead to metabolic complications, has never been investigated. Here, we compared the response of preadipocytes and adipocytes to IAV infection, in terms of transcriptomic profiles and bioenergetics. The results showed that IAV triggers a browning adipogenesis process, leading to metabolic reprogramming of the adipose tissue resulting in long-lasting alterations of body metabolism. We conclude that the adipose tissue might be an undervalued organ in influenza pathophysiology.
Project description:Adipogenesis involves the regulation of hundreds of genes by several well-studied proteins, but the role of long, noncoding RNAs in this process has not been defined. We track the regulation of hundreds of lncRNAs during adipocyte differentiation, and find several that are essential for this process. We extractedbrown and white primary adipocytes and pre-adipocytes and profiled lncRNA expresssion via mRNA-Seq. We also profiled cultured, differentiated adipocytes to verify that we could recapitulate the adipocyte expression profile in preparation for a loss-of-function screen for essential adipogenic lincRNAs.
Project description:C57BL/6 mice were intranasally inoculated with a sublethal dose of H3N2 Influenza A virus (IAV) or with PBS (mock). At 7 days post-infection (7 dpi, corresponding to the peak inflammatory response in the lungs), IAV-infected and non-infected mice were sacrified and inguinal (SCAT) and visceral (i.e. epididymal) white adipose tissues (EWAT), without associated lymph nodes, were collected. Total RNA were extracted from these tissues and genes differential expression was determined using whole genome oligonucleotide microarrays (G4858A, 8x60k chips SurePrint G3 unrestricted GE, Agilent Technologies).
Project description:Insulin and IGF-1 promote adipocyte differentiation via complex and overlapping signalling networks. Here we used microarray analysis of brown preadipocytes derived from wild-type and insulin receptor substrate (IRS) knockout (KO) animals, which exhibited progressively impaired differentiation, to define the set of genes that predict adipogenic potential in these cells. 374 genes/ESTs were identified whose expression in preadipocytes correlated with their ultimate ability to differentiate. Many of these genes were related to early adipogenic events, including genes involved in extracellular matrix, cytoskeletal organization, growth arrest, post-mitotic clonal expansion, and inhibitors of adipogenesis, including preadipocyte factor-1 and multiple members of the Wnt-signalling pathway. Reconstitution of IRS-1 KO cells with IRS-1 reversed these changes and restored the ability to differentiate. Several of these genes showed concordant changes in brown adipose tissue in vivo. Necdin was markedly increased in IRS-1 KO cells that could not differentiate, and knockdown of necdin restored brown adipogenesis with down-regulation of Pref-1 and Wnt10a expression. We demonstrated a necdin-E2F4 interaction repressing PPARg transcription. IRS proteins regulated necdin via a CREB dependent pathway, defining a signalling network involved in brown preadipocyte determination.
Project description:Obesity is a major risk factor for the development of insulin resistance and type II diabetes. The nuclear receptors PPAR delta and PPAR gamma play a central role in regulating metabolism in adipose tissue, as well as being targets for the treatment of insulin resistance. The metabolic effects of PPAR delta and PPAR gamma activation have been examined both in vivo in white adipose tissue from ob/ob mice and in vitro in cultured 3T3-L1 adipocytes using a combined 1H NMR spectroscopy and mass spectrometry metabolomic methodology to understand the contrasting roles of these receptors. These steady state measurements were supplemented with 13C-stable isotope substrate labeling to assess fluxes, respirometry and transcriptomic microarray analysis. The metabolic effects of the two receptors were readily distinguished, with PPAR gamma activation characterised by increased fat storage and fat synthesis/elongation, while activation of PPAR delta caused increased fatty acid beta-oxidation, TCA cycle rate and oxidation of extracellular branch chain amino acids. Stimulated glycolysis and increased desaturation of fatty acids were the only common pathways. PPAR delta has a role as an anti-obesity target as well as an anti-diabetic. Total RNA obtained from cultured 3T3-L1 cells treated for 48 hours with either DMSO control, GW610742 PPARd agonist or GW347845 PPARg agonist and compared.
Project description:Blnc1 is a novel nuclear lncRNA that promotes brown and beige adipocyte differentiation and function. Blnc1 forms a ribonucleoprotein complex with transcription factor EBF2 to stimulate the thermogenic gene program. Further, Blnc1 itself is a target of EBF2, thereby forming a feedforward regulatory loop to drive adipogenesis toward thermogenic phenotype. We used microarrays to elucidate the role of Blnc1 on brown adipocyte differentiation and the induction of the thermogenic gene program. Brown adipocytes expressing vector or brown fat lncRNA 1 (blnc1) were differentiated for 6 days and harvested for RNA isolation and microarray using Affymetrix Mouse MG-430 PM Strip arrays. Two replicated samples were included in this study.
Project description:Influenza A virus (IAV) lacks the enzyme for adding 5’ caps to its RNAs, and thus snatches the 5’ ends of host capped RNAs to prime transcription. Neither the preference of the host RNA sequences snatched, nor the effect of “cap-snatching” on host processes has been completely defined. Previous studies of influenza cap-snatching used poly(A)-selected RNA from infected cells or relied solely on annotated host protein-coding genes to define host mRNAs selected by the virus. To examine the substrate-product relationship between all host RNAs, including non-coding RNAs, and viral RNAs, we used an unbiased approach to identify the host and viral capped RNAs from IAV-infected cells. We demonstrate that IAV predominantly snatches caps from non-coding host RNAs, particularly U1 and U2 small nuclear RNAs (snRNAs). Because snRNAs regulate host mRNA processing, cap-snatching of snRNAs may constitute a means by which IAV hijacks host cell metabolism. examine caps snatched by influenza virus A
Project description:Background: Exposure to the endocrine-disrupting chemical bisphenol A (BPA) is correlated with obesity and promotes adipogenesis of human preadipocytes into mature adipocytes. However, the mechanism of action of BPA-induced human adipogenesis in vitro remains to be fully characterized. Methods: In this study, potential mechanisms of BPA-induced adipogenesis in primary human preadipocytes were evaluated using gene expression microarray analysis. Preadipocytes from donors with normal body mass indexes were differentiated in the presence of 50 µM BPA or 1 µM dexamethasone (DEX) for 48 hours. Results: Microarray analysis revealed 235 up-regulated and 138 down-regulated genes following BPA treatment, including sterol regulatory element binding factor 1 (SREBF1), a key transcription factor known to regulate many components of lipid metabolism and adipogenesis. For DEX treated preadipocytes, 1136 genes were up-regulated, including the adipogenic marker lipoprotein lipase, while 1031 genes were down-regulated. Ingenuity Pathway Analysis was used to identify functional annotations of the gene expression changes associated with response to BPA and DEX treatments. BPA exposure was associated with expression changes in the genes involved in the accumulation of triacylglycerol while DEX was linked to metabolism of triacylglycerol and cleavage of fatty acids. The analysis also revealed enrichment of genes in pathways known to be associated with BPA exposure including thyroid-receptor/retinoic X receptor (TR/RXR) activation, mammalian target of rapamycin (mTOR) signaling and cholesterol biosynthesis, whereas DEX treatment was linked to cholesterol biosynthesis and ethanol degradation. Interestingly, alterations in the mTOR pathway in response to BPA did not occur in DEX-treated preadipocytes. Conclusions: Our data suggest that potential mechanisms of action of BPA-induced adipogenesis involve SREBF1, the TR/RXR and the mTOR pathways. The study used 40 samples in total which included 5 replicates (cells from 5 unique donors) of 8 different treatments. The 8 treatments were as follows: 1) untreated (negative) control for 48 hours, 2) 25 uM BPA treated for 48 hours, 3) 50 uM BPA treated for 48 hours, 4) untreated (negative) control + insulin for 48 hours, 5) 25 uM BPA + insulin treated for 48 hours, 6) 50 uM BPA + insulin treated for 48 hours, 7) 1uM Dexamethasone + insulin treated for 48 hours, 8) 1uM Dexamethasone + insulin treated for 96 hours.
Project description:Miao2010 - Innate and adaptive immune
responses to primary Influenza A Virus infection
This model is described in the article:
Quantifying the early immune
response and adaptive immune response kinetics in mice infected
with influenza A virus.
Miao H, Hollenbaugh JA, Zand MS,
Holden-Wiltse J, Mosmann TR, Perelson AS, Wu H, Topham DJ.
J. Virol. 2010 Jul; 84(13):
Seasonal and pandemic influenza A virus (IAV) continues to
be a public health threat. However, we lack a detailed and
quantitative understanding of the immune response kinetics to
IAV infection and which biological parameters most strongly
influence infection outcomes. To address these issues, we use
modeling approaches combined with experimental data to
quantitatively investigate the innate and adaptive immune
responses to primary IAV infection. Mathematical models were
developed to describe the dynamic interactions between target
(epithelial) cells, influenza virus, cytotoxic T lymphocytes
(CTLs), and virus-specific IgG and IgM. IAV and immune kinetic
parameters were estimated by fitting models to a large data set
obtained from primary H3N2 IAV infection of 340 mice. Prior to
a detectable virus-specific immune response (before day 5), the
estimated half-life of infected epithelial cells is
approximately 1.2 days, and the half-life of free infectious
IAV is approximately 4 h. During the adaptive immune response
(after day 5), the average half-life of infected epithelial
cells is approximately 0.5 days, and the average half-life of
free infectious virus is approximately 1.8 min. During the
adaptive phase, model fitting confirms that CD8(+) CTLs are
crucial for limiting infected cells, while virus-specific IgM
regulates free IAV levels. This may imply that CD4 T cells and
class-switched IgG antibodies are more relevant for generating
IAV-specific memory and preventing future infection via a more
rapid secondary immune response. Also, simulation studies were
performed to understand the relative contributions of
biological parameters to IAV clearance. This study provides a
basis to better understand and predict influenza virus
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