title: Discordant signaling and autophagy response to fasting in hearts of obese mice: Implications for ischemia tolerance.
abstract: Autophagy is regulated by nutrient and energy status and plays an adaptive role during nutrient deprivation and ischemic stress. Metabolic syndrome (MetS) is a hypernutritive state characterized by obesity, dyslipidemia, elevated fasting blood glucose levels, and insulin resistance. It has also been associated with impaired autophagic flux and larger-sized infarcts. We hypothesized that diet-induced obesity (DIO) affects nutrient sensing, explaining the observed cardiac impaired autophagy. We subjected male friend virus B NIH (FVBN) mice to a high-fat diet, which resulted in increased weight gain, fat deposition, hyperglycemia, insulin resistance, and larger infarcts after myocardial ischemia-reperfusion. Autophagic flux was impaired after 4 wk on a high-fat diet. To interrogate nutrient-sensing pathways, DIO mice were subjected to overnight fasting, and hearts were processed for biochemical and proteomic analysis. Obese mice failed to upregulate LC3-II or to clear p62/SQSTM1 after fasting, although mRNA for LC3B and p62/SQSTM1 were appropriately upregulated in both groups, demonstrating an intact transcriptional response to fasting. Energy- and nutrient-sensing signal transduction pathways [AMPK and mammalian target of rapamycin (mTOR)] also responded appropriately to fasting, although mTOR was more profoundly suppressed in obese mice. Proteomic quantitative analysis of the hearts under fed and fasted conditions revealed broad changes in protein networks involved in oxidative phosphorylation, autophagy, oxidative stress, protein homeostasis, and contractile machinery. In many instances, the fasting response was quite discordant between lean and DIO mice. Network analysis implicated the peroxisome proliferator-activated receptor and mTOR regulatory nodes. Hearts of obese mice exhibited impaired autophagy, altered proteome, and discordant response to nutrient deprivation.
authors.affiliation: Cedars-Sinai Heart Institute and Department of Medicine, Los Angeles, California; Barbra Streisand Women's Heart Center of Cedars-Sinai Medical Center, Los Angeles, California; and Allen.Andres@cshs.org.
authors.forename: Allen M
authors.initials: AM
authors.lastname: Andres
authors.affiliation: Cedars-Sinai Heart Institute and Department of Medicine, Los Angeles, California; Barbra Streisand Women's Heart Center of Cedars-Sinai Medical Center, Los Angeles, California; and.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Kooren
authors.affiliation: Cedars-Sinai Heart Institute and Department of Medicine, Los Angeles, California; Barbra Streisand Women's Heart Center of Cedars-Sinai Medical Center, Los Angeles, California; and.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Parker
authors.affiliation: Cedars-Sinai Heart Institute and Department of Medicine, Los Angeles, California; Barbra Streisand Women's Heart Center of Cedars-Sinai Medical Center, Los Angeles, California; and.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Tucker
authors.affiliation: Donald P. Shiley BioScience Center, San Diego State University, San Diego, California.
authors.forename: Nandini
authors.initials: N
authors.lastname: Ravindran
authors.affiliation: Donald P. Shiley BioScience Center, San Diego State University, San Diego, California.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Ito
authors.affiliation: Cedars-Sinai Heart Institute and Department of Medicine, Los Angeles, California; Barbra Streisand Women's Heart Center of Cedars-Sinai Medical Center, Los Angeles, California; and.
authors.forename: Chengqun
authors.initials: C
authors.lastname: Huang
authors.affiliation: Cedars-Sinai Heart Institute and Department of Medicine, Los Angeles, California; Barbra Streisand Women's Heart Center of Cedars-Sinai Medical Center, Los Angeles, California; and.
authors.forename: Vidya
authors.initials: V
authors.lastname: Venkatraman
authors.affiliation: Cedars-Sinai Heart Institute and Department of Medicine, Los Angeles, California; Barbra Streisand Women's Heart Center of Cedars-Sinai Medical Center, Los Angeles, California; and.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Van Eyk
authors.affiliation: Cedars-Sinai Heart Institute and Department of Medicine, Los Angeles, California; Barbra Streisand Women's Heart Center of Cedars-Sinai Medical Center, Los Angeles, California; and.
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Gottlieb
authors.affiliation: Cedars-Sinai Heart Institute and Department of Medicine, Los Angeles, California; Barbra Streisand Women's Heart Center of Cedars-Sinai Medical Center, Los Angeles, California; and.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Mentzer
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D060066:Protein Interaction Maps; D059748:Proteolysis; D040901:Proteomics / Q000379:methods; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors
chemical_list: C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: mammalian target of rapamycin; metabolic syndrome; peroxisome proliferator-activated receptor-α/γ; proteomics