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• W2345890567 abstract "•Lung adenocarcinoma rewires circadian transcription and metabolism in the liver•This rewiring involves the STAT3-Socs3 inflammatory signaling axis•Inhibition of hepatic insulin signaling and glucose intolerance are tumor driven•Lung adenocarcinoma drives deregulation of lipid metabolism in the liver The circadian clock controls metabolic and physiological processes through finely tuned molecular mechanisms. The clock is remarkably plastic and adapts to exogenous “zeitgebers,” such as light and nutrition. How a pathological condition in a given tissue influences systemic circadian homeostasis in other tissues remains an unanswered question of conceptual and biomedical importance. Here, we show that lung adenocarcinoma operates as an endogenous reorganizer of circadian metabolism. High-throughput transcriptomics and metabolomics revealed unique signatures of transcripts and metabolites cycling exclusively in livers of tumor-bearing mice. Remarkably, lung cancer has no effect on the core clock but rather reprograms hepatic metabolism through altered pro-inflammatory response via the STAT3-Socs3 pathway. This results in disruption of AKT, AMPK, and SREBP signaling, leading to altered insulin, glucose, and lipid metabolism. Thus, lung adenocarcinoma functions as a potent endogenous circadian organizer (ECO), which rewires the pathophysiological dimension of a distal tissue such as the liver.PaperClip/cms/asset/f3cf97ef-9e6d-4734-abf4-6c55a63cd182/mmc3.mp3Loading ...(mp3, 5.68 MB) Download audio The circadian clock controls metabolic and physiological processes through finely tuned molecular mechanisms. The clock is remarkably plastic and adapts to exogenous “zeitgebers,” such as light and nutrition. How a pathological condition in a given tissue influences systemic circadian homeostasis in other tissues remains an unanswered question of conceptual and biomedical importance. Here, we show that lung adenocarcinoma operates as an endogenous reorganizer of circadian metabolism. High-throughput transcriptomics and metabolomics revealed unique signatures of transcripts and metabolites cycling exclusively in livers of tumor-bearing mice. Remarkably, lung cancer has no effect on the core clock but rather reprograms hepatic metabolism through altered pro-inflammatory response via the STAT3-Socs3 pathway. This results in disruption of AKT, AMPK, and SREBP signaling, leading to altered insulin, glucose, and lipid metabolism. Thus, lung adenocarcinoma functions as a potent endogenous circadian organizer (ECO), which rewires the pathophysiological dimension of a distal tissue such as the liver. Metabolic, endocrine, and behavioral functions are largely circadian and their disruption is associated with a number of disorders and pathologies, including cancer (Asher and Sassone-Corsi, 2015Asher G. Sassone-Corsi P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock.Cell. 2015; 161: 84-92Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar, Bass, 2012Bass J. Circadian topology of metabolism.Nature. 2012; 491: 348-356Crossref PubMed Scopus (471) Google Scholar, Fu and Lee, 2003Fu L. Lee C.C. The circadian clock: pacemaker and tumour suppressor.Nat. Rev. Cancer. 2003; 3: 350-361Crossref PubMed Scopus (589) Google Scholar, Gamble et al., 2014Gamble K.L. Berry R. Frank S.J. Young M.E. Circadian clock control of endocrine factors.Nat. Rev. Endocrinol. 2014; 10: 466-475Crossref PubMed Scopus (265) Google Scholar, Masri et al., 2015Masri S. Kinouchi K. Sassone-Corsi P. Circadian clocks, epigenetics, and cancer.Curr. Opin. Oncol. 2015; 27: 50-56Crossref PubMed Scopus (92) Google Scholar, Partch et al., 2014Partch C.L. Green C.B. Takahashi J.S. Molecular architecture of the mammalian circadian clock.Trends Cell Biol. 2014; 24: 90-99Abstract Full Text Full Text PDF PubMed Scopus (837) Google Scholar). Circadian rhythms are governed by molecular machinery whose function is to maintain rhythmic precision within cells and synchrony between central and peripheral clocks. Importantly, circadian transcriptional circuits function in a defined tissue-specific manner by interplaying with specialized nuclear factors through poorly understood mechanisms (Masri and Sassone-Corsi, 2010Masri S. Sassone-Corsi P. Plasticity and specificity of the circadian epigenome.Nat. Neurosci. 2010; 13: 1324-1329Crossref PubMed Scopus (104) Google Scholar, Panda et al., 2002Panda S. Antoch M.P. Miller B.H. Su A.I. Schook A.B. Straume M. Schultz P.G. Kay S.A. Takahashi J.S. Hogenesch J.B. Coordinated transcription of key pathways in the mouse by the circadian clock.Cell. 2002; 109: 307-320Abstract Full Text Full Text PDF PubMed Scopus (1868) Google Scholar). Under standard physiological states, the core clock machinery is coupled to the metabolic cycles with which it operates in a coherent, concerted manner. However, the clock is also able to adapt to changing metabolic fluctuations as a compensatory mechanism and it does so by utilizing alternative transcriptional strategies. For instance, restricted feeding temporally phase shifts circadian gene expression in the liver (Damiola et al., 2000Damiola F. Le Minh N. Preitner N. Kornmann B. Fleury-Olela F. Schibler U. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus.Genes Dev. 2000; 14: 2950-2961Crossref PubMed Scopus (1741) Google Scholar, Stokkan et al., 2001Stokkan K.A. Yamazaki S. Tei H. Sakaki Y. Menaker M. Entrainment of the circadian clock in the liver by feeding.Science. 2001; 291: 490-493Crossref PubMed Scopus (1363) Google Scholar, Vollmers et al., 2009Vollmers C. Gill S. DiTacchio L. Pulivarthy S.R. Le H.D. Panda S. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression.Proc. Natl. Acad. Sci. USA. 2009; 106: 21453-21458Crossref PubMed Scopus (512) Google Scholar) and nutritional challenge is able to reprogram circadian transcription and subsequently alter cyclic metabolism (Eckel-Mahan et al., 2013Eckel-Mahan K.L. Patel V.R. de Mateo S. Orozco-Solis R. Ceglia N.J. Sahar S. Dilag-Penilla S.A. Dyar K.A. Baldi P. Sassone-Corsi P. Reprogramming of the circadian clock by nutritional challenge.Cell. 2013; 155: 1464-1478Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar, Hatori et al., 2012Hatori M. Vollmers C. Zarrinpar A. DiTacchio L. Bushong E.A. Gill S. Leblanc M. Chaix A. Joens M. Fitzpatrick J.A. et al.Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet.Cell Metab. 2012; 15: 848-860Abstract Full Text Full Text PDF PubMed Scopus (1181) Google Scholar, Kohsaka et al., 2007Kohsaka A. Laposky A.D. Ramsey K.M. Estrada C. Joshu C. Kobayashi Y. Turek F.W. Bass J. High-fat diet disrupts behavioral and molecular circadian rhythms in mice.Cell Metab. 2007; 6: 414-421Abstract Full Text Full Text PDF PubMed Scopus (1064) Google Scholar). Therefore, timing of food intake and nutritional challenge are able to uncouple the timekeeping of hepatic metabolic oscillations from the core clock machinery. Yet, aside from the consequences of nutritional challenge, the effects of other non-dietary factors that could uncouple and disrupt the hepatic clock remain largely unexplored. Cancer cells thrive based on a heightened metabolic rate that circumvents typical physiological means for energy production through the so-called Warburg effect (Hsu and Sabatini, 2008Hsu P.P. Sabatini D.M. Cancer cell metabolism: Warburg and beyond.Cell. 2008; 134: 703-707Abstract Full Text Full Text PDF PubMed Scopus (1723) Google Scholar, Vander Heiden et al., 2009Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (10142) Google Scholar). In addition, cancer cells excrete a number of factors systemically, including metabolic “waste” byproducts and/or inflammatory signals (Hanahan and Weinberg, 2011Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (42734) Google Scholar, Lin and Karin, 2007Lin W.W. Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer.J. Clin. Invest. 2007; 117: 1175-1183Crossref PubMed Scopus (1516) Google Scholar). For example, tumor-secreted lactate, a product of increased aerobic glycolysis of cancer cells, is associated with heightened metastatic incidence and increased angiogenesis, is responsible for metabolic reprogramming in adjacent tissues, and can induce a pro-inflammatory state (Colegio et al., 2014Colegio O.R. Chu N.Q. Szabo A.L. Chu T. Rhebergen A.M. Jairam V. Cyrus N. Brokowski C.E. Eisenbarth S.C. Phillips G.M. et al.Functional polarization of tumour-associated macrophages by tumour-derived lactic acid.Nature. 2014; 513: 559-563Crossref PubMed Scopus (1509) Google Scholar, Doherty and Cleveland, 2013Doherty J.R. Cleveland J.L. Targeting lactate metabolism for cancer therapeutics.J. Clin. Invest. 2013; 123: 3685-3692Crossref PubMed Scopus (696) Google Scholar). Similarly, the cooperative effects of the inflammatory response during tumorigenesis are well-documented (Gao et al., 2007Gao S.P. Mark K.G. Leslie K. Pao W. Motoi N. Gerald W.L. Travis W.D. Bornmann W. Veach D. Clarkson B. Bromberg J.F. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas.J. Clin. Invest. 2007; 117: 3846-3856Crossref PubMed Scopus (555) Google Scholar, Sansone et al., 2007Sansone P. Storci G. Tavolari S. Guarnieri T. Giovannini C. Taffurelli M. Ceccarelli C. Santini D. Paterini P. Marcu K.B. et al.IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland.J. Clin. Invest. 2007; 117: 3988-4002Crossref PubMed Scopus (647) Google Scholar). Tumor-secreted cytokines, such as Interleukin-6 (IL-6), can regulate metabolism in multiple tissues (Mauer et al., 2015Mauer J. Denson J.L. Brüning J.C. Versatile functions for IL-6 in metabolism and cancer.Trends Immunol. 2015; 36: 92-101Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar), suggesting a possible role in mediating tumor-induced metabolic changes systemically. Collectively, these tumor-derived metabolites and cytokines constitute the so-called tumor “macroenvironment” (Al-Zoughbi et al., 2014Al-Zoughbi W. Huang J. Paramasivan G.S. Till H. Pichler M. Guertl-Lackner B. Hoefler G. Tumor macroenvironment and metabolism.Semin. Oncol. 2014; 41: 281-295Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar), the systemic metabolic consequences of which remain elusive. Importantly, the effects of a tumor on organismal homeostasis are poorly understood, and given the unique ability of the clock in sensing metabolic discrepancies, a potential role of cancer in rewiring clock-controlled metabolism is intriguing (Sahar and Sassone-Corsi, 2009Sahar S. Sassone-Corsi P. Metabolism and cancer: the circadian clock connection.Nat. Rev. Cancer. 2009; 9: 886-896Crossref PubMed Scopus (410) Google Scholar). Indeed, our results demonstrate that lung adenocarcinoma rewires the circadian hepatic transcriptome and corresponding metabolome, yet the core clock machinery remains virtually unperturbed. The tumor imposes a profound metabolic reprogramming that implicates a number of signaling pathways, which operate within the framework of the tumor macroenvironment. As a paradigm, we reveal that the inflammatory STAT3-Socs3 signaling axis is induced in the liver of lung-tumor-bearing mice, resulting in inhibition of hepatic insulin signaling, glucose intolerance, and deregulated lipid metabolism. In conclusion, we illustrate a previously unappreciated role played by a distally located lung adenocarcinoma as an endogenous circadian organizer (ECO) in the rewiring of circadian homeostasis of the liver. The KrasLSL−G12D;p53fl/fl mice are a genetic model of lung adenocarcinoma that mimics human non-small cell lung cancer (NSCLC) (Jackson et al., 2005Jackson E.L. Olive K.P. Tuveson D.A. Bronson R. Crowley D. Brown M. Jacks T. The differential effects of mutant p53 alleles on advanced murine lung cancer.Cancer Res. 2005; 65: 10280-10288Crossref PubMed Scopus (408) Google Scholar, Jackson et al., 2001Jackson E.L. Willis N. Mercer K. Bronson R.T. Crowley D. Montoya R. Jacks T. Tuveson D.A. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras.Genes Dev. 2001; 15: 3243-3248Crossref PubMed Scopus (1427) Google Scholar). Upon intra-tracheal delivery of equivalent adenoviral titer of Cre recombinase, which induces the genetic rearrangement of the Lox-stop-Lox cassette to activate oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and to knock out the tumor suppressor p53, mice developed defined lung adenocarcinoma (Figure S1). This mouse model generates lung adenocarcinoma with 100% penetrance and uniform tumor burden among all mice (Jackson et al., 2001Jackson E.L. Willis N. Mercer K. Bronson R.T. Crowley D. Montoya R. Jacks T. Tuveson D.A. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras.Genes Dev. 2001; 15: 3243-3248Crossref PubMed Scopus (1427) Google Scholar). Equivalent adenoviral titer of FlpO recombinase was administered to p53fl/fl littermates of the same pure C57BL/6J background as a control that does not induce recombination. Upon sacrifice, lung-tumor-bearing (TB) mice exhibited wild-type (WT) expression of Kras in the liver, white adipose tissue (WAT), and muscle, and no metastatic lesions were observed in the liver (Figure S2).Figure S2KRAS Expression and Liver Histology, Related to Experimental ProceduresShow full captionA) Representative images of WT and TB mouse lungs.B) White adipose tissue (WAT), muscle and livers from WT (p53fl/fl) and TB (KrasLSL−G12D;p53fl/fl) mice were genotyped for KRASLSL−G12D expression to confirm that Cre expression in TB mice was confined only to the lung. Genotyping primers are located within the Lox-stop-lox cassette and within the KRAS allele, and the presence of a band indicates an intact Lox-stop-lox cassette and therefore no recombination.C) H&E stain of WT and TB mouse liver sections are shown. Also, Oil-Red-O stain for lipid accumulation in the liver was performed. Scale bars represent 200 μm distance.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A) Representative images of WT and TB mouse lungs. B) White adipose tissue (WAT), muscle and livers from WT (p53fl/fl) and TB (KrasLSL−G12D;p53fl/fl) mice were genotyped for KRASLSL−G12D expression to confirm that Cre expression in TB mice was confined only to the lung. Genotyping primers are located within the Lox-stop-lox cassette and within the KRAS allele, and the presence of a band indicates an intact Lox-stop-lox cassette and therefore no recombination. C) H&E stain of WT and TB mouse liver sections are shown. Also, Oil-Red-O stain for lipid accumulation in the liver was performed. Scale bars represent 200 μm distance. To investigate the distal effects of lung adenocarcinoma on circadian hepatic function, WT and TB mice were sacrificed every 4 hr over the circadian cycle (zeitgeber time [ZT] 0, 4, 8, 12, 16 and 20) and livers were subjected to transcriptomics and metabolomics analyses. Heat maps for oscillating genes based on transcriptomics, as determined by JTK_cycle, display striking differences in unique sets of oscillating genes from WT (left) and TB (right) mice (Figures 1A and 1B ). Gene ontology (GO) biological function was determined using DAVID pathway analysis for WT or TB oscillating genes. Pathway analysis revealed that WT-specific genes were enriched for a number of metabolic processes, including insulin response and regulation of cell cycle and proliferation, while TB-only oscillating genes were selectively enriched for endoplasmic reticulum (ER) signaling, unfolded protein response, cholesterol biosynthesis, and redox state (Figures 1C and S3). Phase analysis was performed for uniquely oscillating WT- and TB-specific genes to determine the relative phase of circadian gene expression. The peak in phase of expression was around ZT 8 in the WT category, whereas TB oscillating genes exhibited a bi-phasic profile that peaked around ZT 0 and again at ZT 12 (Figure 1D). Using the set of 505 genes that retain oscillation in both WT and TB mice, phase analysis was performed to determine if rhythmic genes retained their peak in expression. Strikingly, 46% of circadian genes exhibited a phase change, with 68% of these genes being phase advanced and 32% were phase delayed by at least 1 hr (Figure 1E). These results demonstrate that lung adenocarcinoma significantly reprograms the circadian hepatic transcriptome.Figure S3Redox-Related Genes and Metabolites in WT and TB Mice, Related to Figures 1 and 2Show full captionA) Gene expression profiles of Cyp51, Cyp3a25 and Fdft1 in WT and TB mice, were determined by real-time PCR.B) Abundance of NAD+ and NADH as determined by mass spectrometry in WT and TB mice.C) Abundance of oxidized and reduced glutathione in WT and TB mice over the circadian cycle. Error bars indicate SEM. Significance was calculated using Student’s t test and ∗ indicates a p value cutoff of 0.05.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A) Gene expression profiles of Cyp51, Cyp3a25 and Fdft1 in WT and TB mice, were determined by real-time PCR. B) Abundance of NAD+ and NADH as determined by mass spectrometry in WT and TB mice. C) Abundance of oxidized and reduced glutathione in WT and TB mice over the circadian cycle. Error bars indicate SEM. Significance was calculated using Student’s t test and ∗ indicates a p value cutoff of 0.05. Similar to the circadian transcriptome, metabolomics analysis revealed unique sets of oscillating metabolites in the livers of WT (left heat maps) or TB (right heat maps) mice (Figure 2A). Of ∼600 identified metabolites, two-way ANOVA analysis identified that 235 metabolites were differentially altered by the lung tumor and 328 metabolites were differentially expressed by time point (Figure 2B). Oscillating metabolites were further determined using JTK_cycle, and though the oscillation of 159 metabolites persisted, 90 were rhythmic exclusively in WT and 84 exclusively in TB mice (Figure 2B). Of these 159 metabolites that oscillate in WT and TB mice, 53% exhibited a change in phase, with 62% and 38% being phase advanced and delayed, respectively (Figure 2C). Classification of these metabolites into pathways demonstrated a clear reduction in oscillating lipids in TB versus WT mice (Figure 2D). In addition, a reduction in the levels of energetic metabolites NAD+, ATP and acetyl-CoA was seen (Figure 2E). This indicates altered usage or production of these molecules resulting in disruption of liver homeostasis in TB animals. Thus, the presence of lung tumors acts to distally rewire both transcriptional and metabolic programs in the liver. As further depicted below, this circadian reorganization appears to coordinately contribute to a TB-specific hepatic metabolic profile. A detailed analysis of the genes that were not altered between WT and TB mice was carried out, as shown in the heat map in Figure 3A. GO pathway analysis revealed this category is enriched in not only select metabolic genes, but also in rhythmic genes pertaining to the circadian clock (Figure 3B). The phosphorylation of the aryl hydrocarbon receptor nuclear-translocator-like (ARNTL or BMAL1) protein and expression of all core clock genes, including circadian locomotor output cycles kaput (Clock), Bmal1, Period (Per1-3), Cryptochrome (Cry1/2) and nuclear receptor subfamily 1, group D (Nr1d1 or Rev-Erbα), as well as the clock-controlled D site of albumin promoter binding protein (Dbp) gene, were unchanged in the livers of TB animals (Figures 3C and S4). In order to better characterize the effects of lung adenocarcinoma on the clock, locomotor behavior was analyzed, and no change in the free-running period was observed between WT and TB mice (Figure 3D). Similarly, behavioral actograms show that the circadian activity profile was equal during the light/dark cycles in WT and TB mice (Figure S4). Also, the feeding behavior remained rhythmic in TB mice while a non-significant decrease in food intake was observed (Figure 3E). The respiratory exchange ratio (RER) remained rhythmic, but TB mice displayed an elevated RER during the light phase and a dampened RER during the dark phase (Figure 3F), in keeping with a reduction in VO2, VCO2, and heat production (Figure S5). The altered circadian metabolites (Figures 2D and 2E) in conjunction with dampened RER levels (Figures 3F and S5) revealed a significant shift in the metabolic state of TB mice. Indeed, repressed energy expenditure might be a contributing factor to the uncoupling of the core clock and metabolic rhythms. Timing of food intake, which functions as a powerful zeitgeber (Damiola et al., 2000Damiola F. Le Minh N. Preitner N. Kornmann B. Fleury-Olela F. Schibler U. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus.Genes Dev. 2000; 14: 2950-2961Crossref PubMed Scopus (1741) Google Scholar, Eckel-Mahan et al., 2013Eckel-Mahan K.L. Patel V.R. de Mateo S. Orozco-Solis R. Ceglia N.J. Sahar S. Dilag-Penilla S.A. Dyar K.A. Baldi P. Sassone-Corsi P. Reprogramming of the circadian clock by nutritional challenge.Cell. 2013; 155: 1464-1478Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar, Vollmers et al., 2009Vollmers C. Gill S. DiTacchio L. Pulivarthy S.R. Le H.D. Panda S. Time of feeding and the intrinsic circadian clock drive rhythms in hepatic gene expression.Proc. Natl. Acad. Sci. USA. 2009; 106: 21453-21458Crossref PubMed Scopus (512) Google Scholar), also remains virtually unaltered in TB mice (Figure 3E).Figure S4Circadian Gene Expression and Locomotor Activity in WT and TB Mice, Related to Figure 3Show full captionA) Microarray profile plots of core clock genes, Per1, Per3, Rev-Erbβ and Cry2 in WT and TB mice over the circadian cycle.B) Representative western blots of BMAL1 phosphorylation in WT and TB mice, with nuclear p84 used as a loading control. Blots are representative of 3 sets of independent livers taken every 4 hr, for a total of 36 livers samples.C) WT and TB mice were individually housed in behavioral cages to assess locomoter activity. Activity during the light/dark (L/D) period is shown for 7 days.D) Representative actograms from WT and TB mice are shown for the circadian behavioral experiment. The red arrow indicates the beginning of the dark/dark (D/D) or free-running conditions for 2 weeks. White and black boxes indicate the light and dark periods, respectively.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure S5Indirect Calorimetry of WT and TB Mice, Related to Figure 3Show full caption(A–D) Indirect calorimetry was performed with 7 WT and 8 TB mice. Data for VO2 (A), VCO2 (B) and heat production (C) are shown for 48 hr (left panels). Right panels shown average data during the dark phase and light phase. D) Body weight of WT mice versus TB mice. Error bars indicate SEM. Significance was calculated using Student’s t test and ∗ indicates a p value cutoff of 0.05.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A) Microarray profile plots of core clock genes, Per1, Per3, Rev-Erbβ and Cry2 in WT and TB mice over the circadian cycle. B) Representative western blots of BMAL1 phosphorylation in WT and TB mice, with nuclear p84 used as a loading control. Blots are representative of 3 sets of independent livers taken every 4 hr, for a total of 36 livers samples. C) WT and TB mice were individually housed in behavioral cages to assess locomoter activity. Activity during the light/dark (L/D) period is shown for 7 days. D) Representative actograms from WT and TB mice are shown for the circadian behavioral experiment. The red arrow indicates the beginning of the dark/dark (D/D) or free-running conditions for 2 weeks. White and black boxes indicate the light and dark periods, respectively. (A–D) Indirect calorimetry was performed with 7 WT and 8 TB mice. Data for VO2 (A), VCO2 (B) and heat production (C) are shown for 48 hr (left panels). Right panels shown average data during the dark phase and light phase. D) Body weight of WT mice versus TB mice. Error bars indicate SEM. Significance was calculated using Student’s t test and ∗ indicates a p value cutoff of 0.05. Given the changes in energy expenditure as measured by RER (Figure 3F) and the dampened lipid profiles identified by metabolomics in TB mice (Figure 2D), the effect of lung adenocarcinoma on fatty acid synthesis, breakdown by beta-oxidation, and utilization for cholesterol production were further investigated. The sterol regulatory element binding protein (SREBP) pathway is known to control lipid metabolism in the liver in a circadian manner (Gilardi et al., 2014Gilardi F. Migliavacca E. Naldi A. Baruchet M. Canella D. Le Martelot G. Guex N. Desvergne B. CycliX ConsortiumGenome-wide analysis of SREBP1 activity around the clock reveals its combined dependency on nutrient and circadian signals.PLoS Genet. 2014; 10: e1004155Crossref PubMed Scopus (39) Google Scholar, Le Martelot et al., 2009Le Martelot G. Claudel T. Gatfield D. Schaad O. Kornmann B. Lo Sasso G. Moschetta A. Schibler U. REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis.PLoS Biol. 2009; 7: e1000181Crossref PubMed Scopus (322) Google Scholar), and its deregulation is in accordance with the observed alteration of lipid levels (Figure 2D). The SREBP pathway is known to be inhibited by the energy sensor AMP-activated protein kinase (AMPK) (Li et al., 2011Li Y. Xu S. Mihaylova M.M. Zheng B. Hou X. Jiang B. Park O. Luo Z. Lefai E. Shyy J.Y. et al.AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice.Cell Metab. 2011; 13: 376-388Abstract Full Text Full Text PDF PubMed Scopus (1133) Google Scholar, Vavvas et al., 1997Vavvas D. Apazidis A. Saha A.K. Gamble J. Patel A. Kemp B.E. Witters L.A. Ruderman N.B. Contraction-induced changes in acetyl-CoA carboxylase and 5′-AMP-activated kinase in skeletal muscle.J. Biol. Chem. 1997; 272: 13255-13261Crossref PubMed Scopus (348) Google Scholar). Indeed, activation of AMPKα by phosphorylation of threonine (Thr) 172 was markedly elevated in TB mice and peaked at ZT 16 (Figure 4A). Given the dampened ATP levels in TB mice (Figure 2E), these effects are aligned with the increased intracellular AMP/ATP ratios over the circadian cycle (Figure 4A). Accordingly, the SREBP1 pathway was suppressed, as both gene expression profiles and the levels of the mature form of nuclear SREBP1c protein were repressed at ZT 16 in TB mice (Figure 4B). Similarly, significant inhibition of SREBP1 target genes was observed, as seen with Fasn, Acaca, and Elovl6 expression (Figure 4C). The repression of SREBP1-dependent signaling in the livers of TB mice was further substantiated by the decreased levels of long-chain fatty acids and esterified fatty acids (Figure 4D), including myristate, linolenate, palmitoleate, and eicosapentaenoate (EPA). This suggests either a decrease in fatty acid biosynthesis or an increase in breakdown by beta-oxidation, the former case being most likely given the suppression of SREBP1 signaling and the unaltered peroxisome proliferator-activated receptor alpha (PPARα) and beta-oxidation gene expression profiles in livers of TB mice (Figure S6).Figure S6Metabolic Gene Expression in Liver, WAT, and Muscle of WT and TB Mice, Related to Figure 4Show full captionA) Gene expression of beta-oxidation related genes in WT and TB mouse livers over the circadian cycle. Pparα, Ehhadh, Acadm and Acadl are shown.B) Expression of mitochondrial and metabolic genes in white adipose tissue (WAT) in WT and TB mice. Expression profiles of Pgc1α, Cpt1α, Pparγ and Srebp1c were determined by real-time PCR.C) Expression profiles of Pgc1α, Cpt1α, Pparα and Glut4 in WT and TB mouse muscle. Error bars indicate SEM. Significance was calculated using Student’s t test and ∗ indicates a p value cutoff of 0.05.View Large Image Figure ViewerDownload Hi-res image Download (PPT) A) Gene expression of beta-oxidation related genes in WT and TB mouse livers over the circadian cycle. Pparα, Ehhadh, Acadm and Acadl are shown. B) Expression of mitochondrial and metabolic genes in white adipose tissue (WAT) in WT and TB mice. Expression profiles of Pgc1α, Cpt1α, Pparγ and Srebp1c were determined by real-time PCR. C) Expression profiles of Pgc1α, Cpt1α, Pparα and Glut4 in WT and TB mouse muscle. Error bars indicate SEM. Signific" @default.
• W2345890567 created "2016-06-24" @default.
• W2345890567 creator A5014151765 @default.
• W2345890567 creator A5034335838 @default.
• W2345890567 creator A5061887638 @default.
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• W2345890567 date "2016-05-01" @default.
• W2345890567 modified "2023-10-16" @default.
• W2345890567 title "Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis" @default.
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• W2345890567 doi "https://doi.org/10.1016/j.cell.2016.04.039" @default.
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