Clinical trials revealed limited response duration of glioblastomas to VEGF-neutralizing antibody bevacizumab. Thriving in the devascularized microenvironment occurring after antiangiogenic therapy requires tumor cell adaptation to decreased glucose, with 50% less glucose identified in bevacizumab-treated xenografts. Compared with bevacizumab-responsive xenograft cells, resistant cells exhibited increased glucose uptake, glycolysis, 13C NMR pyruvate to lactate conversion, and survival in low glucose. Glucose transporter 3 (GLUT3) was upregulated in bevacizumab-resistant versus sensitive xenografts and patient specimens in a HIF-1α–dependent manner. Resistant versus sensitive cell mitochondria in oxidative phosphorylation–selective conditions produced less ATP. Despite unchanged mitochondrial numbers, normoxic resistant cells had lower mitochondrial membrane potential than sensitive cells, confirming poorer mitochondrial health, but avoided the mitochondrial dysfunction of hypoxic sensitive cells. Thin-layer chromatography revealed increased triglycerides in bevacizumab-resistant versus sensitive xenografts, a change driven by mitochondrial stress. A glycogen synthase kinase-3β inhibitor suppressing GLUT3 transcription caused greater cell death in bevacizumab-resistant than -responsive cells. Overexpressing GLUT3 in tumor cells recapitulated bevacizumab-resistant cell features: survival and proliferation in low glucose, increased glycolysis, impaired oxidative phosphorylation, and rapid in vivo proliferation only slowed by bevacizumab to that of untreated bevacizumab-responsive tumors. Targeting GLUT3 or the increased glycolysis reliance in resistant tumors could unlock the potential of antiangiogenic treatments.
Ruby Kuang, Arman Jahangiri, Smita Mascharak, Alan Nguyen, Ankush Chandra, Patrick M. Flanigan, Garima Yagnik, Jeffrey R. Wagner, Michael De Lay, Diego Carrera, Brandyn A. Castro, Josie Hayes, Maxim Sidorov, Jose Luiz Izquierdo Garcia, Pia Eriksson, Sabrina Ronen, Joanna Phillips, Annette Molinaro, Suneil Koliwad, Manish K. Aghi
Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.
Øystein Fluge, Olav Mella, Ove Bruland, Kristin Risa, Sissel E. Dyrstad, Kine Alme, Ingrid G. Rekeland, Dipak Sapkota, Gro V. Røsland, Alexander Fosså, Irini Ktoridou-Valen, Sigrid Lunde, Kari Sørland, Katarina Lien, Ingrid Herder, Hanne Thürmer, Merete E. Gotaas, Katarzyna A. Baranowska, Louis M.L.J. Bohnen, Christoph Schäfer, Adrian McCann, Kristian Sommerfelt, Lars Helgeland, Per M. Ueland, Olav Dahl, Karl J. Tronstad
The molecular determinants of lung cancer risk remain largely unknown. Airway epithelial cells are prone to assault by risk factors and are considered to be the primary cell type involved in the field of cancerization. To investigate risk-associated changes in the bronchial epithelium proteome that may offer new insights into the molecular pathogenesis of lung cancer, proteins were identified in the airway epithelial cells of bronchial brushing specimens from risk-stratified individuals by shotgun proteomics. Differential expression of selected proteins was validated by parallel reaction monitoring mass spectrometry in an independent set of individual bronchial brushings. We identified 2,869 proteins, of which 312 proteins demonstrated a trend in expression. Pathway analysis revealed enrichment of carbohydrate metabolic enzymes in high-risk individuals. Glucose consumption and lactate production were increased in human bronchial epithelial BEAS2B cells treated with cigarette smoke condensate for 7 months. Increased lipid biosynthetic capacity and net reductive carboxylation were revealed by metabolic flux analyses of [U-13C5] glutamine in this in vitro model, suggesting profound metabolic reprogramming in the airway epithelium of high-risk individuals. These results provide a rationale for the development of potentially new chemopreventive strategies and selection of patients for surveillance programs.
S.M. Jamshedur Rahman, Xiangming Ji, Lisa J. Zimmerman, Ming Li, Bradford K. Harris, Megan D. Hoeksema, Irina A. Trenary, Yong Zou, Jun Qian, Robbert J.C. Slebos, Jennifer Beane, Avrum Spira, Yu Shyr, Rosana Eisenberg, Daniel C. Liebler, Jamey D. Young, Pierre P. Massion
The small intestine has an underappreciated role as a lipid storage organ. Under conditions of high dietary fat intake, enterocytes can minimize the extent of postprandial lipemia by storing newly absorbed dietary fat in cytoplasmic lipid droplets. Lipid droplets can be subsequently mobilized for the production of chylomicrons. The mechanisms that regulate this process are poorly understood. We report here that the milk protein Mfge8 regulates hydrolysis of cytoplasmic lipid droplets in enterocytes after interacting with the αvβ3 and αvβ5 integrins. Mice deficient in Mfge8 or the αvβ3 and αvβ5 integrins accumulate excess cytoplasmic lipid droplets after a fat challenge. Mechanistically, interruption of the Mfge8-integrin axis leads to impaired enterocyte intracellular triglyceride hydrolase activity in vitro and in vivo. Furthermore, Mfge8 increases triglyceride hydrolase activity through a PI3 kinase/mTORC2–dependent signaling pathway. These data identify a key role for Mfge8 and the αvβ3 and αvβ5 integrins in regulating enterocyte lipid processing.
Amin Khalifeh-Soltani, Deepti Gupta, Arnold Ha, Jahangir Iqbal, Mahmood Hussain, Michael J. Podolsky, Kamran Atabai
Systemic mitochondrial energy deficiency is implicated in the pathophysiology of many age-related human diseases. Currently available tools to estimate mitochondrial oxidative phosphorylation (OXPHOS) capacity in skeletal muscle in vivo lack high anatomic resolution. Muscle groups vary with respect to their contractile and metabolic properties. Therefore, muscle group–specific estimates of OXPHOS would be advantageous. To address this need, a noninvasive creatine chemical exchange saturation transfer (CrCEST) MRI technique has recently been developed, which provides a measure of free creatine. After exercise, skeletal muscle can be imaged with CrCEST in order to make muscle group–specific measurements of OXPHOS capacity, reflected in the recovery rate (τCr) of free Cr. In this study, we found that individuals with genetic mitochondrial diseases had significantly (
Catherine DeBrosse, Ravi Prakash Reddy Nanga, Neil Wilson, Kevin D’Aquilla, Mark Elliott, Hari Hariharan, Felicia Yan, Kristin Wade, Sara Nguyen, Diana Worsley, Chevonne Parris-Skeete, Elizabeth McCormick, Rui Xiao, Zuela Zolkipli Cunningham, Lauren Fishbein, Katherine L. Nathanson, David R. Lynch, Virginia A. Stallings, Marc Yudkoff, Marni J. Falk, Ravinder Reddy, Shana E. McCormack
Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in
Isabel Huang-Doran, Patsy Tomlinson, Felicity Payne, Alexandra Gast, Alison Sleigh, William Bottomley, Julie Harris, Allan Daly, Nuno Rocha, Simon Rudge, Jonathan Clark, Albert Kwok, Stefano Romeo, Emma McCann, Barbara Müksch, Mehul Dattani, Stefano Zucchini, Michael Wakelam, Lazaros C. Foukas, David B. Savage, Rinki Murphy, Stephen O’Rahilly, Inês Barroso, Robert K. Semple
Maternal obesity is proposed to alter the programming of metabolic systems in the offspring, increasing the risk for developing metabolic diseases; however, the cellular mechanisms remain poorly understood. Here, we used a nonhuman primate model to examine the impact of a maternal Western-style diet (WSD) alone, or in combination with obesity (Ob/WSD), on fetal skeletal muscle metabolism studied in the early third trimester. We find that fetal muscle responds to Ob/WSD by upregulating fatty acid metabolism, mitochondrial complex activity, and metabolic switches (CPT-1, PDK4) that promote lipid utilization over glucose oxidation. Ob/WSD fetuses also had reduced mitochondrial content, diminished oxidative capacity, and lower mitochondrial efficiency in muscle. The decrease in oxidative capacity and glucose metabolism was persistent in primary myotubes from Ob/WSD fetuses despite no additional lipid-induced stress. Switching obese mothers to a healthy diet prior to pregnancy did not improve fetal muscle mitochondrial function. Lastly, while maternal WSD alone led only to intermediary changes in fetal muscle metabolism, it was sufficient to increase oxidative damage and cellular stress. Our findings suggest that maternal obesity or WSD, alone or in combination, leads to programmed decreases in oxidative metabolism in offspring muscle. These alterations may have important implications for future health.
Carrie E. McCurdy, Simon Schenk, Byron Hetrick, Julie Houck, Brian G. Drew, Spencer Kaye, Melanie Lashbrook, Bryan C. Bergman, Diana L. Takahashi, Tyler A. Dean, Travis Nemkov, Ilya Gertsman, Kirk C. Hansen, Andrew Philp, Andrea L. Hevener, Adam J. Chicco, Kjersti M. Aagaard, Kevin L. Grove, Jacob E. Friedman
Diabetes is associated with altered cellular metabolism, but how altered metabolism contributes to the development of diabetic complications is unknown. We used the BKS
Kelli M. Sas, Pradeep Kayampilly, Jaeman Byun, Viji Nair, Lucy M. Hinder, Junguk Hur, Hongyu Zhang, Chengmao Lin, Nathan R. Qi, George Michailidis, Per-Henrik Groop, Robert G. Nelson, Manjula Darshi, Kumar Sharma, Jeffrey R. Schelling, John R. Sedor, Rodica Pop-Busui, Joel M. Weinberg, Scott A. Soleimanpour, Steven F. Abcouwer, Thomas W. Gardner, Charles F. Burant, Eva L. Feldman, Matthias Kretzler, Frank C. Brosius III, Subramaniam Pennathur
The prevalence of fatty liver reaches alarming proportions. Fatty liver increases the risk for insulin resistance, cardiovascular disease, and nonalcoholic steatohepatitis (NASH). Although extensively studied in a preclinical setting, the lack of noninvasive methodologies hampers our understanding of which pathways promote hepatic fat accumulation in humans. Dietary fat retention is one of the pathways that may lead to fatty liver. The low (1.1%) natural abundance (NA) of carbon-13 (13C) allows use of 13C-enriched lipids for in vivo MR studies. Successful implementation of such methodology, however, is challenging due to low sensitivity of 13C-magnetic resonance spectroscopy (13C-MRS). Here, we investigated the use of 1-dimensional gradient enhanced heteronuclear single quantum coherence (ge-HSQC) spectroscopy for the in vivo detection of hepatic 1H-[13C]-lipid signals after a single high-fat meal with 13C-labeled fatty acids in 5 lean and 6 obese subjects. Postprandial retention of orally administered 13C-labeled fatty acids was significant (
Lucas Lindeboom, Robin A. de Graaf, Christine I. Nabuurs, Petronella A. van Ewijk, Matthijs K.C. Hesselink, Joachim E. Wildberger, Patrick Schrauwen, Vera B. Schrauwen-Hinderling
Dermal white adipose tissue (dWAT) was recently recognized for its potential to modify whole body metabolism. Here, we show that dWAT can be quantified using a high-resolution, fat-specific magnetic resonance imaging (MRI) technique. Noninvasive MRI has been used to describe adipocyte depots for many years; the MRI technique we describe uses an advanced fat-specific method to measure the thickness of dWAT, together with the total volume of WAT and the relative activation/fat depletion of brown adipose tissues (BAT). Since skin-embedded adipocytes may provide natural insulation, they provide an important counterpoint to the activation of thermogenic brown and beige adipose tissues, whereby these distinct depots are functionally interrelated and require simultaneous assay. This method was validated using characterized mouse cohorts of a lipodystrophic, dWAT-deficient strain (syndecan-1 KO) and 2 obese models (diet-induced obese mice and genetically obese animals,
Ildiko Kasza, Diego Hernando, Alejandro Roldán-Alzate, Caroline M. Alexander, Scott B. Reeder
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